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®
`
`DECLARATION OF JEFFREY D. WINKLER, PH.D.
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW
`OF U.S. Patent No. 9,593,066
`
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`

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`Table of Contents
`
`
`
`INTRODUCTION ............................................................................... 1
`I.
`QUALIFICATIONS ............................................................................ 2
`II.
`III. MATERIALS CONSIDERED ............................................................ 3
`IV. PERSONS OF ORDINARY SKILL IN THE ART ............................ 4
`V. UNDERSTANDING OF LEGAL CONCEPTS .................................. 5
`A. Anticipation ............................................................................... 5
`B.
`Obviousness ............................................................................... 6
`C.
`Product-By-Process Claims ....................................................... 6
`VI. OVERVIEW OF THE ’066 PATENT ................................................. 7
`VII. CLAIM INTERPRETATION ............................................................ 13
`VIII. THE ’066 PATENT IS INVALID ..................................................... 13
`A.
`Summary .................................................................................. 13
`B.
`The Synthesis of Treprostinil Was Well-Known .................... 14
`C.
`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 ................................................. 17
`The Claimed Treprostinil and Treprostinil
`Diethanolamine Salt Disclosed in the ’066 Patent is Not
`Distinct from the Prior Art ....................................................... 20
`IX. PHARES RENDERS OBVIOUS CLAIMS 1-7 OF THE ’066
`PATENT ............................................................................................ 21
`A. Overview of Phares ................................................................. 21
`B.
`Independent Claim 1 ................................................................ 25
`1. Phares discloses claim element 1[a] ...................................25
`
`D.
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`Table of Contents
`
`X.
`
`2. Phares discloses claim element 1[b] ...................................28
`3. Phares discloses claim element 1[c] ...................................31
`4. Phares discloses claim element 1[d] ...................................31
`5. Phares renders obvious claim element 1[e] ........................32
`6. Phares discloses claim element 1[f] ...................................33
`7. Phares discloses claim element 1[g] ...................................35
`Dependent Claim 2 .................................................................. 37
`C.
`D. Dependent Claims 3 and 4 ....................................................... 37
`E.
`Dependent Claim 5 .................................................................. 38
`F.
`Dependent Claim 6 .................................................................. 39
`G. Dependent Claim 7 .................................................................. 40
`PHARES ANTICIPATES CLAIMS 8-10 OF THE ’066
`PATENT ............................................................................................ 41
`A.
`Independent Claim 8 ................................................................ 41
`1. Phares discloses claim elements 8[a] and 8[b] ...................41
`2. Phares discloses claim element 8[c] ...................................42
`3. Phares discloses claim elements 8[d] and 8[e] ...................43
`4. Phares discloses claim element 8[f] ...................................45
`5. Phares discloses claim element 8[g] ...................................45
`Dependent Claim 9 .................................................................. 46
`B.
`Dependent Claim 10 ................................................................ 46
`C.
`XI. MORIARTY IN COMBINATION WITH PHARES
`RENDERS OBVIOUS CLAIMS 1-10 OF THE ’066 PATENT ...... 47
`A. Overview of Moriarty .............................................................. 47
`B. Motivation to Combine Moriarty with Phares ......................... 49
`C.
`Independent Claim 1 ................................................................ 50
`iii
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`Table of Contents
`
`1. Moriarty in combination with Phares teaches claim element
`1[a] ............................................................................................50
`2. Moriarty in combination with Phares teaches claim element
`1[b] ............................................................................................54
`3. Moriarty in combination with Phares teaches claim element
`1[c] ............................................................................................55
`4. Phares teaches claim element 1[d] .....................................56
`5. Phares teaches claim element 1[e] ......................................57
`6. Moriarty in combination with Phares teaches claim element
`1[f] 58
`7. Moriarty in combination with Phares teach claim element
`1[g] ............................................................................................60
`D. Dependent Claim 2 .................................................................. 62
`E.
`Dependent Claims 3, 4 and 5 ................................................... 63
`F.
`Dependent Claim 6 .................................................................. 64
`G. Dependent Claim 7 .................................................................. 65
`H.
`Independent Claim 8 ................................................................ 67
`1. Moriarty in combination with Phares teach claim elements
`8[a]-8[c] ....................................................................................67
`2. Phares teach claim elements 8[d]-[f] ..................................70
`3. Moriarty in combination with Phares teaches claim element
`8[g] ............................................................................................70
`Dependent Claim 9 .................................................................. 71
`I.
`Dependent Claim 10 ................................................................ 71
`J.
`XII. NO SECONDARY CONSIDERATIONS OF NON-
`OBVIOUSNESS ................................................................................ 72
`XIII. CONCLUSION .................................................................................. 72
`
`
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,593,066 B2
`I, Jeffrey D. Winkler, hereby declare and state as follows:
`
`I.
`
`INTRODUCTION
`
`1.
`
`I am over the age of eighteen and otherwise competent to make this
`
`declaration.
`
`2.
`
`I have been retained by counsel for the Petitioner to offer technical
`
`opinions with respect to U.S. Patent No. 9,593,066 (“the ’066 patent”) and prior art
`
`references cited in inter partes review proceedings for the ’066 patent.
`
`3.
`
`I am being compensated for my time in connection with this IPR at my
`
`standard consulting rate, which is $850 per hour. My compensation is not dependent
`
`on the outcome of, or the content of my testimony in, the present IPR.
`
`4.
`
`I have reviewed the ’066 patent and, in assessing it, I have considered
`
`the teachings of the scientific literature before December 17, 2007, in light of general
`
`knowledge in the art before that date.
`
`5.
`
`This declaration presents my opinion that Claims 1-10 of the ’066
`
`patent would have been anticipated and/or obvious to a person of ordinary skill in
`
`the art before December 17, 2007. The technology of the ’066 patent involves
`
`nothing more than basic organic chemistry techniques – in my view, “organic
`
`chemistry 101” – all of which were well-known in the art prior to December 17,
`
`2007.
`
`
`
`1
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,593,066 B2
`II. QUALIFICATIONS
`
`6. My background, qualifications, and experience relevant to the issues
`
`raised in this proceeding are summarized below. A full description of my
`
`background and qualifications is set forth in my curriculum vitae, attached hereto.
`
`7.
`
`I am a professor of chemistry with more than 35 years of experience in
`
`academia, as well as experience in drug design. For over three decades, my
`
`laboratory has focused and continues to focus on the development of new
`
`methodology in organic synthesis and the application of this methodology to the
`
`synthesis of naturally occurring compounds and molecules of design (unnatural
`
`products) with important biological activity.
`
`8.
`
`In 1977, I received my Bachelor of Arts, cum laude, in Chemistry from
`
`Harvard College. In 1978, I received my Master of Arts in Chemistry from
`
`Columbia University. In 1981, I received my Ph.D. in Chemistry from Columbia
`
`University. From 1981 to 1983, I was an American Cancer Society post-doctoral
`
`fellow in the laboratory of Professor Ronald Breslow in the Chemistry Department
`
`at Columbia University.
`
`9.
`
`From July 1990 until June 1996, I was an Associate Professor in the
`
`Department of Chemistry at the University of Pennsylvania (the “University”).
`
`From July 1996 until present, I have been a Professor in the University’s Department
`
`of Chemistry. In January 2001, I became the University’s Merriam Professor of
`2
`
`
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,593,066 B2
`Chemistry, a position I still hold today. In July 2018, I became the Undergraduate
`
`Chair in the University’s Department of Chemistry.
`
`10. During my time at the University, I have taught both undergraduate
`
`organic chemistry as well as several graduate-level courses in the Department of
`Chemistry including Organic Reaction Mechanisms, Bioorganic Chemistry, and
`Special Topics in Organic Chemistry. Since 2002, I have given over 80 invited
`
`lectures at universities, conferences and various companies,
`
`typically
`
`pharmaceutical companies, around the world in the areas of the design and synthesis
`
`of organic molecules.
`
`11.
`
`I have authored or co-authored about 130 peer-reviewed articles
`
`published in scholarly journals, including more than 25 articles since 2011.
`
`12. Accordingly, I am an expert in the field of organic chemistry, and I have
`
`been an expert in this field since prior to December 17, 2007. Further information
`
`regarding my qualifications and credentials are fully set forth in my curriculum vitae,
`
`attached as Ex. A.
`
`III. MATERIALS CONSIDERED
`
`13.
`
`In forming my opinions, I have reviewed the materials cited in the
`
`Petition, the materials cited in this report, as well as those listed in the publications
`
`listed on my curriculum vitae (Ex. 1003). In addition to these materials, I may
`
`consider additional documents and information in forming any supplemental
`3
`
`
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,593,066 B2
`opinions. To the extent I am provided additional documents or information,
`
`including any expert declarations in this proceeding, I may offer further opinions.
`
`IV. PERSONS OF ORDINARY SKILL IN THE ART
`
`14.
`
`I understand that “one of ordinary skill in the art” is not a specific, real
`
`individual, but rather a hypothetical individual who is presumed to have known the
`
`relevant art at the time of the invention. In defining “one of ordinary skill in the art,”
`
`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 that
`
`is the subject of the case, but also others working in the pertinent art at the time of
`
`the invention; the types of problems encountered in the art; the teachings of the prior
`
`art; patents and publications or other persons or companies; and the sophistication
`
`of the technology.
`
`15.
`
`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.
`
`16. Given the high education level of the scientists actually working in this
`
`field, a person of ordinary skill in the art (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. Alternatively, a POSA would include an
`
`
`
`4
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,593,066 B2
`individual with a bachelor’s degree and at least five years of practical experience in
`
`medicinal or organic chemistry.
`
`17. As reflected in my qualifications set forth above and in my curriculum
`
`vitae (Ex. 1003), I qualified as a POSA at the time of the alleged invention (before
`
`December 17, 2007).
`
`V. UNDERSTANDING OF LEGAL CONCEPTS
`
`A. Anticipation
`
`18.
`
`I understand from counsel that the law recognizes a concept called
`
`“anticipation.” As I understand it, a single prior art reference must disclose each and
`
`every element of a claim, either expressly or inherently, to anticipate the claim and
`
`render it invalid.
`
`19.
`
`I understand that, to establish inherent anticipation, properties that are
`
`inherently anticipated must be necessarily present in a single prior art reference. I
`
`understand that a prior art reference inherently discloses an element or limitation if
`
`science or technical information necessarily requires that the element or limitation
`
`is included in what was disclosed in the prior art reference. I also understand that
`
`these inherent properties cannot merely be probably or possibly present. It is my
`
`understanding that one of ordinary skill in the art may not have recognized the
`
`inherent characteristics or functioning of the prior art at the time.
`
`
`
`5
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,593,066 B2
`B. Obviousness
`
`20.
`
`I understand from counsel that the law recognizes a concept called
`
`“obviousness.” I understand that a patent claim is invalid for obviousness if the
`
`differences between the subject matter sought to be patented and the prior art are
`
`such that the subject matter as a whole would have been obvious to a person of
`
`ordinary skill in the art at the time of the invention. I understand that for a single
`
`reference or a combination of references to render the claimed invention obvious, a
`
`person of ordinary skill in the art must have been able to arrive at the claims by
`
`modifying or combining the applied references.
`
`21.
`
`It is my further understanding that there must be a motivation to
`
`combine or modify the applied references.
`
`22.
`
`It is my further understanding that, in order to render an invention
`
`obvious, a person of ordinary skill in the art must have a reasonable expectation of
`
`success that making the combination will make the invention work.
`
`C.
`
`23.
`
`Product-By-Process Claims
`
`I understand that the challenged claims are “product by process” claims.
`
`I understand that this means that the claims cover a recited product made by a process
`
`that includes the recited process steps.
`
`24.
`
`I further understand that as a result of the claims being classified as
`
`“product by process” claims, the claims should be analyzed both through the claimed
`6
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`Petition for Inter Partes Review of
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`product, and also through the processes that are recited in the claims. If the processes
`
`in the claims are in the prior art, then the claims are invalid. As noted below, I
`
`further understand the process in a product-by-process claim merits weight in
`
`comparing it to the prior art only if it imparts some unique and novel property or
`
`structure in the resulting product.
`
`VI. OVERVIEW OF THE ’066 PATENT
`
`25.
`
`I understand that 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.
`
`26. The ’066 patent discloses an “improved process” to prepare
`
`prostacyclin derivatives such as treprostinil. (Ex. 1001, Abstract.) Claim 1 is drawn
`
`to a 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 and
`
`hydrolyzing to form treprostinil or a pharmaceutically acceptable salt thereof. (Id.,
`
`claims 1 and 8.)
`
`27. Each of the independent claims include limitations that the claimed
`
`pharmaceutical composition/product is made by a process comprising: (a) providing
`
`a starting batch of treprostinil having one or more impurities resulting from prior
`7
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`Petition for Inter Partes Review of
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`alkylation and hydrolysis steps; (b) forming a treprostinil salt by adding a base; and
`
`(c) preparing a pharmaceutical composition/product comprising treprostinil or a
`
`pharmaceutically acceptable salt thereof from the isolated treprostinil salt.
`
`28. The claim limitations of the ’066 patent are as follows:
`
`1[b]
`1[c]
`
`1[d]
`
`1[e]
`1[f]
`
`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.
`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.
`
`3
`
`4
`
`5
`
`
`
`8
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,593,066 B2
`6
`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:
`
`8[b]
`
`7
`
`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
`diethanolamine to treprostinil.
`
`9
`10
`
`
`
`29. The ’066 patent discloses a process for the preparation of a compound
`
`of Formula I (which includes treprostinil) shown below,
`
`
`
`9
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`Petition for Inter Partes Review of
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`
`
`(Ex. 1001 at col. 2:7-21), where: w = 1, 2, or 3; Y1 is trans-CH=CH-, cis-CH=CH-,
`C C
`
`; m is 1, 2, or 3; M1 is α-OH: β-R5 or α-R5: β-OH or α-
`
`-CH2(CH2)m-, or
`
`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 are other than alkyl, with the proviso that R7, is phenoxy or
`
`substituted phenoxy, only when R3 and R4 are hydrogen or methyl, being the same
`
`or different, (3) phenyl, benzyl, phenylethyl, or phenylpropyl optionally substituted
`
`on the aromatic ring by one, two or three chloro, fluoro, trifluoromethyl, (C1-
`
`C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than two substituents are
`
`
`
`10
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`Petition for Inter Partes Review of
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`other than alkyl, (4) cis-CH=CH—CH2—CH3, (5) —(CH2)2—CH(OH) —CH3, or
`
`(6) —(CH2)3—CH=C(CH3)2; wherein —C(L1)R71 taken together is: (1) (C4-
`
`C7)cycloalkyl optionally substituted by 1 to 3 (C1-C5)alkyl; (2) 2-(2-furyl)ethyl; (3)
`
`2-(3-thienyl)ethoxy; or (4) 3-thienyloxymethyl. (Id. at cols. 2:46-3:15.) Treprostinil
`
`is the specific Formula I compound where w = 1; Y1 is—CH2(CH2)m- and m is 1;
`
`M1 is α-OH: β-R5 or α-R5: β-OH, wherein R5 is hydrogen; L1 is α-R3: β-R4, α-R4: β-
`
`R3, or a mixture of α-R3: β-R4 and α-R4: β-R3, wherein R3 and R4 are hydrogen; and
`
`R7 is —CpH2p—CH3, wherein p is an integer from 1 to 5 inclusive (p=3).
`
`30. The ’066 patent discloses alkylating the treprostinil precursor
`
`(benzindene triol, a.k.a. treprostinil triol) with an alkylating agent and then
`
`hydrolyzing with a base. (Id. at col. 2:7-3:17.) The ’066 patent further discloses
`
`contacting the product from the alkylation and hydrolysis steps with a base to form
`
`a salt (e.g. using the base diethanolamine to form treprostinil diethanolamine salt)
`
`of Formula IS shown below (where B is diethanolamine and where the other
`
`variables are the same as for the treprostinil-specific version of Formula I
`
`explained in the previous paragraph):
`
`
`
`
`1 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.)
`
`11
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`
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,593,066 B2
`
`
`(Id. at col. 3:19-30.) The treprostinil salt can then be reacted with an acid to form
`
`the compound of treprostinil-specific Formula I. (Id. at col. 3:31-33.)
`
`31. Formula I is a general formula, while Formula IV is specifically
`
`treprostinil. Formula IV, which is treprostinil, is disclosed to be at least 90.0%,
`
`95.0%, or 99.0% pure. (Id. at col. 9:22-23.) Formula IVs is the formula for a
`
`generic salt formed from treprostinil. When “B” in Formula IVs is diethanolamine,
`
`as taught at columns 9, 12, and 14 of the ’066 patent, Formula IVs is treprostinil
`
`diethanolamine salt.
`
`32. The ’066 patent further discloses alkylating a treprostinil triol
`
`intermediate (Formula V, shown below) to form treprostinil or a pharmaceutically
`
`acceptable salt thereof:
`
`
`
`12
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,593,066 B2
`(Id. at col. 3:52-66.)
`
`33. The ’066 patent discloses
`
`that
`
`the resulting
`
`treprostinil, or
`
`pharmaceutically acceptable salt thereof, can be stored at ambient temperatures. (Id.
`
`at col. 17:32-36.)
`
`34. These purification procedures were well-known in the art – indeed, they
`
`are no more than basic organic chemistry techniques and standard chemical
`
`purification – and they were fully disclosed in numerous prior art references,
`
`including basic organic chemistry textbooks.
`
`VII. CLAIM INTERPRETATION
`
`35.
`
`I have reviewed the claims of the ’066 patent. I believe a person of
`
`ordinary skill in the art would understand each of the claim terms to take on its plain
`
`and ordinary meaning.
`
`VIII. THE ’066 PATENT IS INVALID
`
`A.
`
`Summary
`
`36. There are at least three strong reasons for invalidation of the ’066
`
`patent: (1) as explained in the following sections, the synthesis of the claimed
`
`compounds, including treprostinil and treprostinil diethanolamine salt, was well-
`
`known in the art; (2) as detailed in Sections IX and X, the claims of the ’066 patent
`
`are product-by-process claims and the claimed process does not produce a product
`
`that is materially distinct from the product produced by the prior art, thus, the claims
`13
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,593,066 B2
`of the ’066 patent are invalid as anticipated and obvious; and (3) the parent patent,
`
`U.S. patent No. 8,497,393 (the “’393 patent”) was declared invalid and/or
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`unenforceable in IPR2016-00006 under 35 U.S.C. §§ 102(b) and 103(a) and since
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`the claim limitations of the ’066 patent are substantively similar to the invalidated
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`’393 patent, the ’066 patent should be similarly declared invalid. (Exs. 1004 and
`
`1005.)
`
`37.
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`I have reviewed the ’393 patent and ’393 IPR Decision. In addition, I
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`served as an expert in the ’393 IPR for Petitioner SteadyMed and am thus familiar
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`with the arguments and prior art contained therein. Claims 1-10 of the ’066 patent
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`should be held invalid for similar reasons as the ’393 patent because the claims of
`
`the ’066 patent are substantively similar to those of the ’393 patent in that they
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`disclose the same treprostinil and the identical treprostinil salt.
`
`B.
`
`The Synthesis of Treprostinil Was Well-Known
`
`38. Before December 17, 2007, synthesis for numerous prostacylcin
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`derivatives, such as treprostinil, and intermediate compounds useful in their
`
`synthesis were well-known.
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`39. These prostacyclin derivatives and intermediates include the following
`
`general structure:
`
`
`
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,593,066 B2
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`
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`(See e.g., the ’117 patent, Ex. 1007, claim 1.)
`
`40. The ’117 patent includes the synthesis of treprostinil (which is the case
`
`in which: Z is O, n is 1, X is COOH, Y1 is CH2CH2-, M1 is an H and an OH group
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`in the S configuration (i.e., the same stereoisomer configuration found in the
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`structure of treprostinil), L1 is α-H; β-H, and R7 is –(CH2)3-CH3 amongst its many
`
`examples. (Id.)
`
`41. Claim 3 of the ’117 patent (Ex. 1007) discloses the structure of
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`treprostinil below:
`
`
`which is produced by a process for making 9-deoxy-PGF1-type compounds, the
`
`process comprising cyclizing the following starting compound:
`
`
`
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,593,066 B2
`42. The process steps recited in claims 1 and 8 of the ’066 patent disclose
`
`the synthesis of prostacyclin derivative acids that include treprostinil acid, which is
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`also disclosed in Moriarty (Ex. 1009) and the ’117 patent (Ex. 1007).
`
`43.
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`In addition, both Phares (Ex. 1008) and Moriarty (Ex. 1009) further
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`disclose syntheses of treprostinil. Phares discloses the synthesis of (-)-treprostinil,
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`the enantiomer of (+)-treprostinil. (Id. at 39-40.) Phares explains that
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`“[e]nantiomers of these compounds…can be synthesized using reagents and
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`synthons of enantiomeric chirality of the above reagents,” thereby inherently
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`teaching the synthesis of both enantiomeric forms of treprostinil, both (-)-treprostinil
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`and (+)-treprostinil. (Id. at 39.)
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`44. Moriarty discloses the following synthetic scheme for making
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`treprostinil acid (Ex. 1009 at 4, 6):
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`45. The ’066 patent discloses the same scheme for making treprostinil acid
`
`(Ex. 1001 at Examples 1 and 2):
`
`
`
`
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,593,066 B2
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`
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`46. Accordingly, the only alleged “improvement” to Moriarty in the ’066
`
`patent was the preparation of a treprostinil diethanolamine salt (from a starting batch
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`of treprostinil or treprostinil diethanolamine salt having one or more impurities
`
`resulting from alkylation and/or hydrolysis) without isolation of the treprostinil acid.
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`This represents nothing more than a routine, elementary organic chemistry technique
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`for the purification of a carboxylic acid, such as treprostinil acid. In addition, Phares
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`discloses methods of synthesis to produce treprostinil diethanolamine salt using the
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`same starting material (prepared by the same chemical steps) as disclosed in
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`Moriarty.
`
`C.
`
`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
`
`47. The process steps of claims 1 and 8 disclose nothing more than
`
`elementary organic chemistry techniques for purification of a carboxylic acid, such
`
`as treprostinil acid, which were well described in the prior art years before December
`
`17, 2007. The formation of a carboxylate salt, by the addition of a base to a neutral
`
`
`
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,593,066 B2
`carboxylic acid, and the subsequent addition of a strong acid to regenerate carboxylic
`
`acid, as disclosed in claims 1 and 8, are standard chemistry purification procedures
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`– i.e., organic chemistry 101. Indeed, similar general purification techniques were
`
`described in numerous textbooks and literature, such as basic introductory organic
`
`chemistry textbooks, well before the December 17, 2007 priority date for the ’066
`
`patent.
`
`48. For example, Wiberg, an organic chemistry lab textbook provided to
`
`organic chemistry students, explicitly states:
`
`A typical example is the purification of a water-insoluble
`solid carboxylic acid by dissolving it in sodium hydroxide
`solution, filtering, precipitating the compound by the
`addition of acid. A similar procedure may be used with
`amines: dissolve the compound in acid and precipitate it
`with a base. These procedures usually work quite well in
`that they utilize a chemical reaction to aid in separation
`from nonacidic or nonbasic impurities.
`
`(Ex. 1010 at 6.)
`
`49. Similarly, Schoffstall (Ex. 1011), describes an experiment in which
`
`carboxylic acid is separated from neutral and basic organic compounds by
`
`conversion to a salt. Addition of an acid, such as HCl, then regenerates the
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`carboxylic acid from the salt, which can then be filtered or extracted into an organic
`
`solvent. (Ex. 1011 at 3-40.)
`
`
`
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,593,066 B2
`50. More specifically, contacting a carboxylic acid of a prostacyclin
`
`derivative, such as treprostinil, with a base to form a salt, followed by the addition
`
`of a strong acid to regenerate the carboxylic acid, was a well-known chemical
`
`purification technique in the prior art. For example:
`
`• Kawakami
`
`(Ex. 1012),
`
`entitled
`
`“Crystalline Amine Salt of
`
`Methanoprostacyclin Derivative, Manufacturing Method thereof, and
`
`Purifying Method thereof” (bolding added), is directed to the preparation
`
`and use of dicyclohexylamine (i.e., an amine base with similar reactivity
`
`to diethanolamine) to form a crystalline dicyclohexylamine salt of a
`
`methanoprostacyclin
`
`derivative,
`
`in
`
`order
`
`to
`
`purify
`
`the
`
`methanoprostacyclin.
`
` Kawakami
`
`further
`
`discloses
`
`that
`
`the
`
`dicyclohexylamine sa