Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 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. 9,604,901
`
`Issue Date: March 28, 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. 9,604,901
`
`
`
`
`
`
`Liquidia's Exhibit 1039
`IPR2020-00770
`Page 1
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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.  Obviousness ............................................................................... 5 
`B. 
`Product-By-Process Claims ....................................................... 6 
`VI.  OVERVIEW OF THE ’901 PATENT ................................................. 6 
`VII.  CLAIM INTERPRETATION ............................................................ 14 
`VIII.  THE ’901 PATENT IS INVALID ..................................................... 14 
`A. 
`Summary .................................................................................. 14 
`B. 
`The Synthesis of Treprostinil Was Well-Known ..................... 15 
`C. 
`Formation of a Carboxylate Salt from a Carboxylic Acid
`and the Addition of an Acid to a Carboxylic Salt to
`Regenerate the Carboxylic Acid is Standard Chemical
`Purification Known in the Art .................................................. 18 
`The Claimed Treprostinil and Treprostinil
`Diethanolamine Salt Disclosed in the ’901 Patent is Not
`Distinct from the Prior Art ....................................................... 20 
`IX.  PHARES RENDERS OBVIOUS THE CLAIMS OF THE ’901
`PATENT ............................................................................................. 21 
`A.  Overview of Phares .................................................................. 21 
`B. 
`Independent Claim 1 ................................................................ 25 
`1.  Phares discloses claim element 1[a] ................................... 25 
`2.  Phares discloses claim element 1[b] ................................... 29 
`3.  Phares discloses claim element 1[c] ................................... 32 
`4.  Phares renders obvious claim element 1[d] ........................ 33 
`
`D. 
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`Table of Contents
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`5.  Phares discloses claim element 1[e] ................................... 35 
`6.  Claim element 1[f] is optional and obvious to a POSA ..... 35 
`7.  Phares renders obvious claim element 1[g] ........................ 36 
`Dependent Claim 2 .................................................................. 37 
`C. 
`D.  Dependent Claims 3 and 4 ....................................................... 37 
`E. 
`Dependent Claim 5 .................................................................. 39 
`F. 
`Dependent Claim 6 .................................................................. 40 
`G.  Dependent Claim 7 .................................................................. 42 
`H.  Dependent Claim 8 .................................................................. 43 
`1.  Phares discloses claim elements 8[a] and 8[b] ................... 43 
`2.  Phares discloses claim element 8[c] ................................... 44 
`3.  Phares renders obvious claim element 8[d] ........................ 46 
`4.  Phares discloses claim element 8[e] ................................... 47 
`5.  Claim element 8[f] is optional and obvious to a POSA ..... 47 
`Dependent Claim 9 .................................................................. 49 
`I. 
`X.  MORIARTY IN COMBINATION WITH PHARES
`RENDERS OBVIOUS THE CLAIMS OF THE ’901 PATENT ...... 49 
`A.  Overview of Moriarty .............................................................. 49 
`B.  Motivation to Combine Moriarty with Phares ......................... 51 
`C. 
`Independent Claim 1 ................................................................ 53 
`1.  Moriarty in combination with Phares teaches claim element
`1[a] ............................................................................................ 53 
`2.  Moriarty in combination with Phares teaches claim element
`1[b] ............................................................................................ 57 
`3.  Moriarty in combination with Phares teaches claim element
`1[c] ............................................................................................ 59 
`4.  Phares renders obvious claim element 1[d] ........................ 61 
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`Table of Contents
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`5.  Phares discloses claim element 1[e] ................................... 63 
`6.  Claim element 1[f] is optional and obvious to a POSA ..... 63 
`7.  Moriarty in combination with Phares teaches claim element
`1[g] ............................................................................................ 64 
`D.  Dependent Claim 2 .................................................................. 66 
`E. 
`Dependent Claims 3 and 4 ....................................................... 66 
`F. 
`Dependent Claim 5 .................................................................. 69 
`G.  Dependent Claim 6 .................................................................. 69 
`H.  Dependent Claim 7 .................................................................. 72 
`I. 
`Dependent Claim 8 .................................................................. 73 
`1.  Moriarty in combination with Phares teaches claim
`elements 8[a]-[b] ....................................................................... 73 
`2.  Moriarty in combination with Phares teaches claim element
`8[c] ............................................................................................ 74 
`3.  Moriarty in combination with Phares teaches claim element
`8[d] ............................................................................................ 76 
`4.  Phares discloses claim element 8[e] ................................... 78 
`5.  Claim element 8[f] is optional and obvious to a POSA ..... 78 
`Dependent Claim 9 .................................................................. 79 
`J. 
`XI.  NO SECONDARY CONSIDERATIONS OF NON-
`OBVIOUSNESS ................................................................................ 80 
`XII.  CONCLUSION .................................................................................. 80 
`
`
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 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. 9,604,901 (“the ’901 patent”) and prior art
`
`references cited in inter partes review proceedings for the ’901 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 ’901 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 1-9 of the ’901 patent
`
`would have been obvious to a person of ordinary skill in the art before December
`
`17, 2007. The technology of the ’901 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. 9,604,901 B2
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`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. 9,604,901 B2
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`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. 9,604,901 B2
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`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. 9,604,901 B2
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`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. Obviousness
`
`18.
`
`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.
`
`19.
`
`It is my further understanding that, in order to render an invention
`
`obvious, there must be a motivation to combine or modify the applied references.
`
`20.
`
`It is my further understanding that a person of ordinary skill in the art
`
`must have a reasonable expectation of success that making the combination will
`
`make the invention work.
`
`5
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
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`
`B.
`
`Product-By-Process Claims
`
`21.
`
`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.
`
`22.
`
`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
`
`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 ’901 PATENT
`
`23.
`
`I understand that the ’901 patent is entitled “Process to Prepare
`
`Treprostinil, the Active Ingredient in Remodulin®.” The claims of the ’901 patent
`
`are product-by-process claims. These claims include one independent (claim 1) and
`
`eight dependent claims.
`
`24. The ’901 patent discloses an “improved process” to prepare
`
`prostacyclin derivatives such as treprostinil. (Ex. 1001, Abstract.) Claim 1 is drawn
`
`to a pharmaceutical batch comprising treprostinil or a salt thereof. (Id., cols. 17-18,
`
`claim 1.)
`
`6
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
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`
`25. The
`
`independent claim
`
`includes
`
`limitations
`
`that
`
`the claimed
`
`composition is made by a process comprising: (a) alkylating a benzindene triol; (b)
`
`hydrolyzing the resulting product to form a solution comprising treprostinil; (c)
`
`contacting that treprostinil solution with a base to form a salt of treprostinil; (d)
`
`isolating the salt of treprostinil and; (e) optionally reacting the salt of treprostinil
`
`with an acid to form treprostinil. The claimed composition contains at least 2.9 g of
`
`treprostinil or its salt.
`
`26. The claim limitations of the ’901 patent are as follows:
`
`1[b]
`1[c]
`
`1[d]
`
`1[e]
`1[f]
`
`Claim Limitation
`
`1[a] A pharmaceutical batch consisting of treprostinil or a salt thereof and
`impurities resulting from:
`(a) alkylating a benzindene triol,
`(b) hydrolyzing the product of step (a) to form a solution comprising
`treprostinil,
`(c) contacting1 the solution comprising treprostinil from step (b) with a
`base to form a salt of treprostinil,
`(d) isolating the salt of treprostinil, and
`(e) optionally reacting the salt of treprostinil with an acid to form
`treprostinil, and
`1[g] wherein the pharmaceutical batch contains at least 2.9 g of treprostinil
`or its salt.
`The pharmaceutical batch of claim 1, which has been dried under
`vacuum.
`
`2
`
`
`1 Certificate of correction: “(c) containing the” should be –“(c) contacting the--.”
`(Ex. 1006 at 2.)
`
`7
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
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`
`3
`
`4
`
`5
`
`6
`
`7
`
`A pharmaceutical product comprising a therapeutically effective
`amount of treprostinil from a pharmaceutical batch as claimed in claim
`1.
`A pharmaceutical product comprising a therapeutically effective
`amount of a salt treprostinil from a pharmaceutical batch as claimed in
`claim 1.
`The product of claim 4, wherein the salt is the diethanolamine salt of
`treprostinil.
`A method of preparing a pharmaceutical product from a
`pharmaceutical batch as claimed in claim 1, comprising storing a
`pharmaceutical batch of a salt of treprostinil as claimed in claim 1 at
`ambient temperature, and preparing a pharmaceutical product from the
`pharmaceutical batch after storage.
`A method as claimed in claim 6, wherein the salt of treprostinil is a
`diethanolamine salt.
`8[a] A method of preparing a pharmaceutical batch as claimed in claim 1,
`comprising:
`(a) alkylating a benzindene triol,
`(b) hydrolyzing the product of step (a) to form a solution comprising
`treprostinil,
`(c) contacting the solution comprising treprostinil from step (b) with a
`base to form a salt of treprostinil,
`(d) isolating the salt of treprostinil, and
`(e) optionally reacting the salt of treprostinil with an acid to form
`treprostinil.
`A method as claimed in claim 8, wherein the salt of treprostinil is a
`diethanolamine salt.
`
`8[b]
`8[c]
`
`8[d]
`
`8[e]
`8[f]
`
`9
`
`27. The ’901 patent discloses a process for the preparation of a compound
`
`of Formula I (which includes treprostinil) shown below,
`
`8
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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—
`
`, —CH2(CH2)m—, or
`
`; m is 1, 2, or 3; M1 is α-OH: β-R5 or α-R5: β-OH
`
`or α-OR2: β-R5 or α-R5: β-OR2, wherein R5 is hydrogen or methyl, R2 is an alcohol
`
`protecting group; L1 is α-R3: β-R4, α-R4: β-R3, or a mixture of α-R3: β-R4 and α-R4:
`
`β-R3, wherein R3 and R4 are hydrogen, methyl, or fluoro, being the same or different,
`
`with the proviso that one of R3 and R4 is fluoro only when the other is hydrogen or
`
`fluoro; and R7 is (1) —CpH2p—CH3, wherein p is an integer from 1 to 5, inclusive,
`
`(2) phenoxy optionally substituted by one,
`
`two or
`
`three chloro, fluoro,
`
`trifluoromethyl, (C1-C3)alkyl, or (C1-C3)alkoxy, with the proviso that not more than
`
`two substituents 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
`
`other than alkyl, (4) cis-CH=CH—CH2—CH3, (5) —(CH2)2—CH(OH) —CH3, or
`
`9
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`(6) —(CH2)3—CH=C(CH3)2; wherein —C(L1)-R7 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. 2:46-3:20.) 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).
`
`28. The ’901 patent discloses alkylating benzindene triol (a.k.a. treprostinil
`
`triol) with an alkylating agent and then hydrolyzing with a base to form a solution
`
`comprising treprostinil. (Id. at cols. 10:12-12:18.)
`
`29. The ’901 patent further discloses contacting the solution from the
`
`alkylation and hydrolysis steps with a base to form a salt (e.g. using the base
`
`diethanolamine to form treprostinil diethanolamine salt) of Formula IS shown below
`
`(where B is diethanolamine and where the other variables are the same as for the
`
`treprostinil-specific version of Formula I explained above):
`
`10
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`Petition for Inter Partes Review of
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`
`
`(Id. at 3:30-40).
`
`30. Formula I is a general formula, while Formula IV is specifically
`
`treprostinil. Formula IVs is the formula for a generic salt formed from treprostinil.
`
`When “B” in Formula IVs is diethanolamine, as taught at columns 9, 12, and 14 of
`
`the ’901 patent, Formula IVs is treprostinil diethanolamine salt. The resulting salt is:
`
`
`
`(Id. at cols. 9:33-45, 12:45-59, 14:35-47.)
`
`31. The treprostinil salt can then be isolated and reacted with an acid to
`
`form treprostinil:
`
`11
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`Petition for Inter Partes Review of
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`(Id. at col. 14:30-15:24, Example 5.) As disclosed in one embodiment, the resulting
`
`carboxylic acid, Formula IV, is at least 90.0%, 95.0%, 99.0%, or 99.5% pure. (Id.
`
`at col. 9:49-50.)
`
`
`
`12
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
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`32. The ’901 patent further discloses alkylating a treprostinil triol
`
`intermediate (Formula V, shown below) to form treprostinil or a pharmaceutically
`
`acceptable salt thereof:
`
`
`
`(Id. at col. 3:46-4:49.)
`33. The ’901 patent discloses that the resulting pharmaceutical batch
`
`contains at least 2.9 g of treprostinil or its salt which has been dried under a vacuum.
`
`(Id. at 15:8-11.) The ’901 patent does not teach storing the resulting treprostinil salt
`
`at ambient temperature; it only specifically discloses this for a “crude” salt. (Id. at
`
`col. 17:4-8.)
`
`34. These precipitation 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.
`
`13
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
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`VII. CLAIM INTERPRETATION
`
`35.
`
`I have reviewed the claims of the ’901 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 ’901 PATENT IS INVALID
`
`A.
`
`Summary
`
`36. There are at least three strong bases for invalidation of the ’901 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 ’901 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 of the ’901 patent
`
`are invalid as obvious; and (3) the parent patent, U.S. patent No. 8,497,393 (the
`
`“’393 patent”) was declared invalid and/or unenforceable in IPR2016-00006 under
`
`35 U.S.C. §§ 102(b) and 103(a) and since the claim limitations of the ’901 patent are
`
`substantively similar to the invalidated ’393 patent, the ’901 patent should be
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`similarly declared invalid. (Exs. 1004 and 1005.)
`
`37.
`
`I have reviewed the ’393 patent and ’393 IPR Decision. In addition, I
`
`served as an expert in the ’393 IPR for Petitioner SteadyMed and am thus familiar
`
`with the arguments and prior art contained therein. Claims 1-9 of the ’901 patent
`
`14
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
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`should be held invalid for similar reasons as the ’393 patent because the claims of
`
`the ’901 patent are substantively similar to those of the ’393 patent in that they
`
`disclose the same treprostinil and the identical treprostinil diethanolamine salt.
`
`B.
`
`The Synthesis of Treprostinil Was Well-Known
`
`38. Before December 17, 2007, synthesis for numerous prostacylcin
`
`derivatives, such as treprostinil, and intermediate compounds useful in their
`
`synthesis were well known.
`
`39. These prostacyclin derivatives and intermediates include the following
`
`general structure:
`
`
`
`(See e.g., the ’117 patent, Ex. 1007, claim 1.)
`
`40. Claim 1 of the ’117 patent includes the synthesis of treprostinil. It 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 in the S configuration (i.e., the same stereoisomer configuration found in the
`
`structure of treprostinil), L1 is α-H; β-H, and R7 is –(CH2)3-CH3. (Id.)
`
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
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`
`41. Claim 3 of the ’117 patent (Ex. 1007) discloses the structure of
`
`treprostinil below:
`
`
`which is produced by a process for making 9-deoxy-PGF1-type compounds, the
`
`process comprising cyclizing the following starting compound:
`
`
`42. The process steps recited in claims 1 and 8 of the ’901 patent disclose
`
`the synthesis of prostacyclin derivative acids that include treprostinil acid, which is
`
`also disclosed in Moriarty (Ex. 1009) and the ’117 patent (Ex. 1007).
`
`43.
`
`In addition, as explained in detail below, both Phares (Ex. 1008) and
`
`Moriarty (Ex. 1009) further disclose syntheses of treprostinil.
`
`44. Moriarty discloses the following synthetic scheme for making
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`treprostinil acid (Ex. 1009 at 3, 6):
`
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
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`
`
`
`
`
`45. The ’901 patent discloses the same scheme for making treprostinil acid
`
`(Ex. 1001 at col. 10:10-12:17, Examples 1 and 2):
`
`46. Accordingly, the only alleged “improvement” to Moriarty in the ’901
`
`patent was the preparation of a treprostinil diethanolamine salt (from a starting batch
`
`of treprostinil having one or more impurities likely resulting from alkylation and/or
`
`hydrolysis) without isolation of the treprostinil acid. These represent nothing more
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`than a routine, elementary organic chemistry technique for purification of a
`
`carboxylic acid, such as treprostinil acid. In addition, Phares discloses methods of
`
`synthesis to produce treprostinil diethanolamine salt using the same starting
`
`material, treprostinil carboxylic acid, as disclosed in Moriarty.
`
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`
`
`C.
`
`Formation of a Carboxylate Salt from a Carboxylic Acid and the
`Addition of an Acid to a Carboxylic Salt to Regenerate the
`Carboxylic Acid is Standard Chemical Purification Known in the
`Art
`
`47. The process steps of claim 1 that involve salt formation and carboxylic
`
`acid regeneration (claim elements 1[c]-1[e]) disclose nothing more than elementary
`
`organic chemistry techniques for purification of a carboxylic acid, such as
`
`treprostinil acid, 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 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 – 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 ’901
`
`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, and 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
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
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`
`from nonacidic or nonbasic impurities.
`
`(Ex. 1010 at 6.) 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
`
`carboxylic acid from the salt, which can then be filtered or extracted into an organic
`
`solvent. (Ex. 1011 at 3-4.)
`
`49. 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”, 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 salt of a methanoprostacyclin derivative can be easily reverted
`
`to the free methanoprostacyclin derivative by conventional methods, such as treating
`
`the salt with a strong acid such as HCl or H2SO4. (Ex. 1012 at 6.) Per Kawakami,
`
`the salt that is obtained has “fairly high purity, and the purity can be further improved
`
`by recrystallization as needed with the use of an appropriate solvent.” (Id.) And
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`Petition for Inter Partes Review of
`U.S. Patent No. 9,604,901 B2
`
`Ege (Ex. 1013), an organic chemistry textbook, discloses that sodium benzoate (i.e.,
`
`a carboxylate salt) can be converted back to benzoic acid (i.e., a carboxylic acid) by
`
`treatment with the acid HCl, which is prototypical of the reaction of the treprostinil
`
`diethanolamine salt with an acid to regenerate treprostinil carboxylic acid. (Ex. 1013
`
`at 8.)
`
`D. The Claimed Treprostinil and Treprostinil Diethanolamine Salt
`Disclosed in the ’901 Patent is Not Distinct from the Prior Art
`
`50.
`
`I understand that the ’901 patent claims are product-by-process claims.
`
`It has been explained to me that the process limitations are not accorded any weight
`
`for determining the validity of the claims of the ’901 patent. I understand that the
`
`process in a product-by-process claim merits weight in reviewing the prior art only
`
`if it imparts some unique and novel property or structure in the resulting product.
`
`Such is not the case here.
`
`51. As discussed above and in detail below, treprostinil and