UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________
`
`STEADYMED LTD.
`
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION
`
`Patent Owner.
`
`Case IPR Unassigned
`
`Patent No. 8,497,393
`
`____________
`
`DECLARATION OF JEFFREY D. WINKLER IN SUPPORT OF PETITION
`FOR INTER PARTES REVIEW OF
`CLAIMS 1 – 22 OF U.S. PATENT NO. 8,497,393
`
`Mail Stop "Patent Board"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`SteadyMed - Exhibit 1009- Page 1
`
`

`

`I.
`II.
`III.
`IV.
`
`V.
`VI.
`
`VII.
`
`VIII.
`
`A.
`B.
`C.
`
`A.
`B.
`C.
`
`A.
`
`B.
`
`A.
`
`B.
`
`TABLE OF CONTENTS
`
`QUALIFICATIONS.............................................................................1
`MATERIALS CONSIDERED.............................................................2
`PERSONS OF ORDINARY SKILL IN THE ART ("POSA") ...........3
`LEGAL CONCEPTS THAT WERE EXPLAINED TO ME ..............4
`Anticipation..........................................................................................4
`Obviousness..........................................................................................5
`Product-By-Process Claims..................................................................6
`OVERVIEW OF THE '393 PATENT..................................................6
`THE '393 PATENT IS INVALID........................................................8
`Summary ..............................................................................................8
`The Synthesis Of Treprostinil Was Well-Known ................................9
`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..........................12
`ANTICIPATION ARGUMENTS......................................................15
`Phares Inherently Anticipates The Claims Of The '393 Patent..........15
`1.
`The Phares Reference ..............................................................15
`2.
`Phares Inherently Discloses the Same Synthesis of
`Treprostinil Under Independent Claims 1 & 9 ........................16
`The '393 Patent Process Does Not Result In A "Physically
`Different" Or Unique Product Than The Prior Art ............................21
`OBVIOUSNESS ARGUMENTS ......................................................23
`The Motivation To Combine Moriarty With Phares Or
`Kawakami...........................................................................................24
`1.
`The Purification Step and the Purity of Treprostinil Salt ........24
`2.
`Purification of the Product of the Alkylation Reaction ...........25
`3.
`Regeneration of Carboxylic Acid ............................................26
`The Reasonable Expectation Of Success That The Combination
`Of Moriarty With Phares Or Kawakami Will Work As Intended .....27
`
`i
`
`SteadyMed - Exhibit 1009- Page 2
`
`

`

`C.
`
`D.
`
`The Motivation To Combine Moriarty With Phares Or
`Kawakami In View Of Ege ................................................................27
`The Reasonable Expectation Of Success That The Combination
`Of Moriarty With Phares Or Kawakami In View Of Ege Will
`Work As Intended ..............................................................................30
`
`ii
`
`SteadyMed - Exhibit 1009- Page 3
`
`

`

`1.
`
`I have been retained by counsel for the Petitioner, SteadyMed Ltd., to
`
`offer technical opinions with respect to U.S. Patent No. 8,497,393 ("the '393
`
`Patent") and prior art references cited in inter partes review proceedings for the
`
`'393 Patent.
`
`2.
`
`I have reviewed the '393 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.
`
`3.
`
`This declaration presents my opinion that Claims 1-22 of the '393
`
`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 '393 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.
`
`I.
`
`QUALIFICATIONS
`
`4.
`
`am the Merriam Professor of Chemistry at
`
`the University of
`
`Pennsylvania, a position I have held since 2001. Prior to that time, I was a
`
`Professor of Chemistry from 1996 to 2001, and an Associate Professor of
`
`Chemistry from 1990 to 1996 at the University of Pennsylvania. I was an Assistant
`
`Professor of Chemistry at the University of Chicago from 1983 to 1990.
`
`1
`
`SteadyMed - Exhibit 1009- Page 4
`
`

`

`5.
`
`I have over 30 years of experience in the fields of organic and
`
`medicinal chemistry. My area of expertise includes design and synthesis of various
`
`biologically active natural and unnatural products, as well as mechanisms and
`
`stereochemistry in organic synthesis.
`
`6.
`
`I earned my A.B. in Chemistry from Harvard College in 1977 and my
`
`Ph.D. in Chemistry from Columbia University in 1981.
`
`7.
`
`have an excellent reputation in the field of organic chemistry as
`
`evidenced by several awards, including the American Chemical Society Cope
`
`Scholar Award and an Alfred P. Sloan Fellowship.
`
`8.
`
`I have co-authored numerous publications reporting results of my
`
`research in the field of organic chemistry in peer-reviewed journals. I have also
`
`presented numerous lectures on organic chemistry at national and international
`
`scientific meetings around the world.
`
`9.
`
`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. 1010.
`
`II. MATERIALS CONSIDERED
`
`10.
`
`In forming my opinions, I have had available the materials cited in the
`
`Petition, the materials cited in this report, as well as those listed in the publications
`
`2
`
`SteadyMed - Exhibit 1009- Page 5
`
`

`

`listed on my curriculum vitae (Ex. 1010).
`
`In addition to these materials, I may
`
`consider additional documents and information in forming any supplemental
`
`opinions. To the extent I am provided additional documents or information,
`
`including any expert declarations in this proceeding, I may offer further opinions.
`
`III. PERSONS OF ORDINARY SKILL IN THE ART ("POSA")
`
`11.
`
`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.
`
`12.
`
`I have assessed the level of ordinary skill in the art based upon my
`
`review of the prior art, the patent, and my thirty years of working in the field of
`
`organic chemistry.
`
`13.
`
`In this case, the inventors—Dr. Hitesh Batra, Sudersan Tuladhar, Raju
`
`Penmasta, and Dr. David Walsh—are all senior scientists or managers at United
`
`Therapeutics, according to their LinkedIn profiles. Similarly, the prior art is written
`
`3
`
`SteadyMed - Exhibit 1009- Page 6
`
`

`

`by very educated authors, including Dr. Ken Phares, a scientist in charge of United
`
`Therapeutics' pharmaceutical development program, who has many years of
`
`experience and a Ph.D. in Pharmaceutical Chemistry, as per his LinkedIn profile.
`
`14. 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 person of ordinary
`
`skill would include an individual with a bachelor’s degree and at least five years of
`
`practical experience in medicinal or organic chemistry.
`
`15. As reflected in my qualifications set forth above and in my curriculum
`
`vitae (Ex. 1010), I qualified as a person of ordinary skill in the art at the time
`
`before December 17, 2007.
`
`IV. LEGAL CONCEPTS THAT WERE EXPLAINED TO ME
`
`A.
`
`16.
`
`Anticipation
`
`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.
`
`17.
`
`I understand that, to establish inherent anticipation, properties that are
`
`inherently anticipated must be necessarily present in a single prior art reference. I
`
`4
`
`SteadyMed - Exhibit 1009- Page 7
`
`

`

`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.
`
`B.
`
`18.
`
`Obviousness
`
`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 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
`
`SteadyMed - Exhibit 1009- Page 8
`
`

`

`C.
`
`21.
`
`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.
`
`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.
`
`V.
`
`OVERVIEW OF THE '393 PATENT
`
`23.
`
`I understand that
`
`the '393 Patent, entitled "Process to Prepare
`
`Treprostinil, Ingredient in Remodulin™, issued on July 30, 2013, and claims
`
`priority to a provisional application filed on December 17, 2007.
`
`I understand,
`
`therefore, that the priority date of the '393 Patent is December 17, 2007.
`
`24.
`
`The '393 Patent discloses an "improved process" to prepare
`
`prostacyclin derivatives such as treprostinil. (Ex. 1001, Abstract).
`
`25.
`
`Each of the independent claims includes limitations that the claimed
`
`compound is made by a process comprising three specified steps and one optional
`
`6
`
`SteadyMed - Exhibit 1009- Page 9
`
`

`

`step: (a) alkylating a prostacyclin derivative (e.g., a benzindene triol precursor to
`
`treprostinil acid) to form an alkylated prostacyclin derivative (e.g., a benzindene
`
`nitrile precursor to treprostinil acid); (b) hydrolyzing the alkylated prostacyclin
`
`derivative with a base to form a prostacyclin acid (e.g., treprostinil acid); (c)
`
`contacting the prostacyclin acid (e.g., treprostinil acid) with a base to form a
`
`prostacyclin carboxylate salt (e.g., a treprostinil salt); and (d) optionally reacting
`
`the prostacyclin carboxylate salt (e.g., a treprostinil salt) formed in step (c) with an
`
`acid to form a compound or a pharmaceutically acceptable salt of:
`
`(Ex. 1001).
`
`26.
`
`The alkylating and hydrolyzing steps in the synthesis of treprostinil
`
`and the other claimed compounds, as set forth in steps (a) – (b) of Claims 1 and 9,
`
`were fully disclosed in prior art to the '393 Patent, including U.S. Patent No.
`
`6,765,117 (the '117 Patent) (Ex. 1003), and in Moriarty et al., J. Org. Chem. 1890-
`
`1902 (2004) (Ex. 1004, referred to as "Moriarty"), as well as other publications.
`
`7
`
`SteadyMed - Exhibit 1009- Page 10
`
`

`

`27.
`
`I understand that
`
`the '393 Patent
`
`inventors admit
`
`that steps (a)
`
`("alkylating") and (b) ("hydrolyzing") were in the prior art. (See Ex. 1002-1, p.
`
`109); '393 Patent, Ex. 1001, col. 1, lines 22-28 (incorporating Moriarty (Ex. 1004),
`
`the '117 Patent (Ex. 1003), and U.S. Patent No. 6,441,245 (Ex. 1013) by reference,
`
`and col.7, lines 17-20 (describing '245 Patent's process as the same as in '393
`
`Patent)).
`
`28.
`
`The '393 Patent addresses an alleged "improvement" to Moriarty
`
`through the addition of steps (c) and optionally 1(d), which claim a standard
`
`organic chemistry purification by a precipitation technique: converting a free
`
`carboxylic acid into a salt using a weak base and then precipitating it to remove
`
`potential impurities, and then, optionally converting the salt back to the free acid.
`
`(Ex. 1001, col. 19, lines 28-29).
`
`29.
`
`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.
`
`VI. THE '393 PATENT IS INVALID
`
`A.
`
`30.
`
`Summary
`
`The prior art discloses all claims of the '393 Patent, as (1) the
`
`synthesis of the claimed compound, treprostinil, was well-known in the art well
`
`8
`
`SteadyMed - Exhibit 1009- Page 11
`
`

`

`before December 17, 2007, the priority date for the '393 Patent, and (2) the '393
`
`Patent's only alleged "improvement" over the prior art involves nothing more than
`
`basic organic chemistry 101 – standard chemical purification through salt
`
`formation and precipitation that I have taught and utilized throughout my over
`
`thirty years in the field of organic chemistry. Further, as discussed below, the
`
`claimed process of the '393 Patent does not produce a product that is materially
`
`distinct from the product produced by the prior art.
`
`31.
`
`I outline my specific opinions related to anticipation and obviousness,
`
`below.
`
`B.
`
`The Synthesis Of Treprostinil Was Well-Known
`
`32. Before December 17, 2007, syntheses for numerous prostacyclin
`
`derivatives, such as treprostinil, and intermediate compounds useful
`
`in their
`
`syntheses were well-known.
`
`33.
`
`These prostacyclin derivatives
`
`and intermediates
`
`include
`
`the
`
`following general structures:
`
`(see e.g., the '117 Patent, Ex. 1003, Claim 1).
`
`9
`
`SteadyMed - Exhibit 1009- Page 12
`
`

`

`34.
`
`For example, the '117 Patent (Ex. 1003) 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 a H and a OH group in the S configuration (i.e., the same stereoisomeric
`
`configuration found in the structure of treprostinil (below)), L1 is -H; -H, and R7
`
`is –(CH2)3-CH3) amongst its many examples.
`
`In addition, both Moriarty (Ex.
`
`1004) and prior art reference Phares (Ex. 1005) further disclose syntheses of
`
`treprostinil. For example, Claim 3 of the '117 Patent (Ex. 1003) 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:
`
`35. As noted above, steps (a) – (b) of Claims 1 and 9 of the '393 Patent
`
`disclose the synthesis of prostacyclin derivative acids that include treprostinil acid,
`
`10
`
`SteadyMed - Exhibit 1009- Page 13
`
`

`

`which is also disclosed in Moriarty (Ex. 1004) and the '117 Patent (Ex. 1003). For
`
`example, Moriarty (Ex. 1004) at p. 6 and p. 3 discloses the following synthetic
`
`scheme for making treprostinil acid:
`
`36. And the '393 Patent (Ex. 1001) at columns 9-10 discloses the same
`
`synthetic scheme for making treprostinil acid:
`
`37. Accordingly, the only alleged "improvement" to Moriarty in the '393
`
`Patent was the addition of step (c) and optionally step (d) of Claims 1 and 9.
`
`38. Despite
`
`the
`
`alleged claimed "improvement,"
`
`the
`
`treprostinil
`
`compound made by the '393 Patent processes has comparable purity to the
`
`compound disclosed by Phares (Ex. 1005) based on an analysis of the melting
`
`point of the Form B salt, as explained in further detail below.
`
`11
`
`SteadyMed - Exhibit 1009- Page 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
`
`39.
`
`Steps (c) and (d) of Claims 1 and 9 disclose nothing more than basic
`
`organic chemistry techniques for purification of a prostacyclin compound, such as
`
`treprostinil, which was well-described in the prior art years before December 17,
`
`2007.
`
`40. A person of ordinary skill
`
`in the art would recognize that
`
`the
`
`formation of a carboxylate salt, by the addition of a weak base to a neutral
`
`carboxylic acid, and the subsequent addition of a strong acid to regenerate
`
`carboxylic acid, as disclosed in steps (c) and (d), is standard chemistry purification
`
`– i.e., organic chemistry 101.
`
`41.
`
`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 '393 Patent. Indeed, I have
`
`taught these general purification techniques to my organic chemistry students for
`
`over thirty years.
`
`42.
`
`For example,
`
`the following organic chemistry textbooks disclose
`
`similar purification techniques as those disclosed in the '393 Patent:
`
` Wiberg (Ex. 1012), entitled "Laboratory Technique in Organic
`
`Chemistry", an organic chemistry lab textbook provided to organic
`
`12
`
`SteadyMed - Exhibit 1009- Page 15
`
`

`

`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. 1012, p. 6).
`
` Schoffstall
`
`(Ex. 1014), entitled "Microscale & Miniscale Organic
`
`Chemistry Laboratory Experiments (Second Edition)" (pp. 3-4), similarly
`
`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, which can
`
`then be filtered or extracted into an organic solvent:
`
`13
`
`SteadyMed - Exhibit 1009- Page 16
`
`

`

`43. 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.
`
`1007),
`
`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., a base) to form a
`
`crystalline dicyclohexylamine salt of a methanoprostacyclin derivative, in
`
`order to facilitate the purification of 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 (Ex. 1007, p.
`
`6), such as treating the salt with a strong acid such as HCl or H2SO4. 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.).
`
` Phares (Ex. 1005), entitled "Compounds and Methods for Delivery of
`
`Prostacyclin Analogs," discloses that
`
`the preparation of treprostinil
`
`diethanolamine includes the step of adding diethanolamine (i.e., a base)
`
`14
`
`SteadyMed - Exhibit 1009- Page 17
`
`

`

`to a solution of treprostinil acid in a 1:1 molar ratio mixture of ethanol:
`
`water. (Ex. 1005, p. 24, bottom para.).
`
` Ege (Ex. 1008), 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.1 (Ex. 1008, p. 8).
`
`VII. ANTICIPATION ARGUMENTS
`
`A.
`
`Phares Inherently Anticipates The Claims Of The '393 Patent
`
`1.
`
`The Phares Reference
`
`44.
`
`The Phares reference (Ex. 1005), is International Publication No. WO
`
`2005/007081 to Phares, et al, entitled "Compounds and Methods for Delivery of
`
`Prostacyclin Analogs," and published January 27, 2005. It is prior art to the '393
`
`Patent.
`
`45. As previously discussed, I understand that the '393 Patent claims are
`
`product-by-process claims. 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. No novel property
`
`or structure exists in the claimed treprostinil product as compared to the prior art.
`
`1 The following prior art includes other examples discussing purifying
`prostacyclin derivatives using a base to form a salt. See, e.g., U.S. Patent No,
`3,703,544, entitled "Process for Preparing the Tris(Hydroxy-Methyl –
`Aminomethane Salt of PGE2" (Ex. 1015, col. 4, lines 58-73); U.S. Patent No.,
`3,888,916 entitled "Amantadine salt of 16,16-dimethyl-PGE.sub.2". (Ex. 1016, col.
`2, lines 47-57).
`
`15
`
`SteadyMed - Exhibit 1009- Page 18
`
`

`

`46.
`
`Further, I have reviewed the arguments presented in Ground 1 of the
`
`Petition and agree that at least for the reasons stated in the Petition, Claims 1-5, 11-
`
`14, and 16-20 are anticipated by Phares.
`
`47.
`
`In particular, I was asked to opine whether: (1) Phares inherently
`
`discloses the same synthesis of treprostinil as disclosed in the '393 Patent; (2)
`
`Phares inherently discloses the same degree of purity of treprostinil as disclosed in
`
`the '393 Patent; and (3) whether the '393 patent processes result in a "physically
`
`different" or unique product over the prior art.
`
`2.
`
`Phares Inherently Discloses the Same Synthesis of
`Treprostinil Under Independent Claims 1 & 9
`
`48.
`
`Phares inherently discloses the same synthesis of treprostinil as set
`
`forth in the independent claims, Claims 1 and 9, of the '393 Patent in the case
`
`where w is 1, Y1 is CH2CH2-, M1 is a H and a OH group in the S configuration; L1
`
`is -H; -H, and R7 is –(CH2)3-CH3. (Ex. 1005, pp. 41-42). Accordingly, Phares
`
`inherently anticipates both independent Claims 1 & 9.
`
`49.
`
`I understand that Claim 1 is drawn to a product comprising a
`
`compound of
`
`a genus
`
`that
`
`includes
`
`the
`
`treprostinil
`
`compound, or
`
`a
`
`pharmaceutically acceptable salt thereof. Claim 9 is identical to Claim 1 except
`
`that it is drawn to a product comprising the specific treprostinil compound, a
`
`species of the genus of Claim 1, made by the same process. Accordingly, my
`
`analysis evaluates Claims 1 and 9 together.
`
`16
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`SteadyMed - Exhibit 1009- Page 19
`
`

`

`50.
`
`I base my opinion on the following: (1) Phares discloses the same
`
`treprostinil diethanolamine salt (Ex. 1005, p. 24; pp.85-93; p. 99, Claim 49) as the
`
`'393 Patent, (2) Phares details the same procedures as were used to make
`
`treprostinil in the '117 Patent and Moriarty, but also details how to use them to
`
`make (-)-treprostinil, the enantiomer of (+)- treprostinil (Ex. 1005, p. 42), and (3)
`
`Phares discloses the treprostinil diethanolamine salt in the same "polymorph"
`
`(crystal form) – Form B – as the '393 Patent (Ex. 1001, col. 12, lines 34-51; Ex.
`
`1005, pp. 90-91) as well as a higher melting point of the Form B salt than that
`
`reported in the ‘393 Patent. (Ex. 1005, p. 91).
`
`51.
`
`First, the treprostinil diethanolamine salt is made by exactly the same
`
`process step as claimed in the '393 Patent's Claim 1(c) and 9(c): by contacting the
`
`product of step (b) with diethanolamine base to form the salt whose structure is
`
`displayed in Phares Claim 49. (Ex. 1005, p. 99, Claim 49).
`
`52.
`
`For example, Phares discloses in its Claim 49 the identical,
`
`pharmaceutically acceptable treprostinil diethanolamine salt that Claim 1 claims:
`
`17
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`SteadyMed - Exhibit 1009- Page 20
`
`

`

`Phares (Ex. 1005), Claim 49
`
`'393 Patent (Ex. 1001), Claims 1 &
`9 (column 8)
`
`53. Other than a change in formatting, the two structures from Phares and
`
`the '393 Patent are identical.
`
`54. As Phares necessarily discloses the same process steps to make
`
`treprostinil diethanolamine salt claimed in the '393 Patent and even discloses the
`
`same structure, Phares inherently anticipates Claims 1 and 9 of the '393 Patent.
`
`55.
`
`Second, Phares also details the same Claim 1 and 9 steps (a) or (b) as
`
`were used to make treprostinil in the '117 Patent and Moriarty reference, but
`
`applies them to make (-)-treprostinil, the enantiomer of (+)- treprostinil (Ex. 1005,
`
`p. 42). The '393 Patent and prosecution history admits using these steps (a) and (b)
`
`in the prior art.
`
`('393 Patent, (Ex. 1001), col. 1, lines 22-28 (incorporating
`
`Moriarty (Ex. 1004), the '117 Patent (Ex. 1003), and U.S. Patent No. 6,441,245
`
`(Ex. 1013) by reference, and col.7, lines 17-20 (describing '245 Patent's process as
`
`the same as in the '393 Patent); see also Ex. 1002-1, p. 109).
`
`18
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`SteadyMed - Exhibit 1009- Page 21
`
`

`

`56.
`
`Phares explains that the reaction scheme where "the enantiomer of the
`
`commercial drug (+)-Treprostinil was synthesized using the stereoselective
`
`intramolecular Pauson Khand reaction as a key step and Mitsunobu inversion of
`
`the side-chain hydroxyl group," (Ex. 1005, p. 42) was also used to make the (-)-
`
`treprostinil enantiomer, and then details the exact same alkylation and hydrolyzing
`
`steps (both included in Phares as "step (l)." (Ex. 1005, p. 42).
`
`57.
`
`This is the identical procedure claimed in steps (a) and (b). (Compare
`
`Ex. 1005, p. 42, "1) i. C1CH2CN, K2CO3. ii, KOH, CH3OH, reflux. 83 % (2
`
`steps)," with '393 Patent Claim 1 and 9 steps (a) and (b) and '393 Patent col. 9, line
`
`25 – col. 11, line 37 ('393 Patent, Examples 1 and 2).) This provides further
`
`confirmation that under the doctrine of inherent anticipation, Phares anticipates
`
`Claims 1 & 9.
`
`58.
`
`Third, Phares discloses the treprostinil diethanolamine salt in the same
`
`"polymorph" (crystal form) – Form B – as the '393 Patent. (Ex. 1001, col. 12, lines
`
`34-51; Ex. 1005, pp. 90-91). Polymorphs are different crystalline forms of the
`
`same substance in which molecules may have different arrangements and/or
`
`different molecular conformations.
`
`59.
`
`In both the '393 Patent and Phares
`
`(Ex. 1005),
`
`treprostinil
`
`diethanolamine salt Form B is made. Phares demonstrated that Form B is the more
`
`stable form as compared to Form A. (Ex. 1005, pp. 88-93). Phares further
`
`19
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`SteadyMed - Exhibit 1009- Page 22
`
`

`

`discloses a melting point of 107º C (Ex. 1005, p. 91 & Fig. 21) for the Form B salt.
`
`The '393 Patent, however, discloses lower melting point ranges for the Form B salt
`
`in the ranges of 104.3-106.3º C (Batch No. 1) and 104.7-106.6º C (Batch No. 3)
`
`(Ex. 1001, col. 12, line 65 – col. 13, line 11, Example 3), as well as 105.0-106.5º C
`
`(Batch No. 1) and 104.5-105.5 ºC (Batch No. 2) (Ex. 1001, col. 13, line 59,
`
`Example 4); see also (Ex. 1001, col. 12, lines 53-55 (noting Form B requires a
`
`melting point of the treprostinil diethanolamine salt of more than 104º C).
`
`60.
`
`The higher melting point disclosed in Phares is consistent with the
`
`product of Phares having higher purity than the '393 Patent's product. See (Gilbert,
`
`Ex. 1018, p. 6) (a higher melting point typically indicates that a product has higher
`
`purity).
`
`61. Of note, in the '393 Patent, treprostinil diethanolamine Form B was
`
`made directly from precipitation in a mixed solvent of ethanol and ethanol acetate.
`
`In Phares (Ex. 1005), treprostinil diethanolamine Form B was made by first
`
`generating Form A from any of many possible mixed solvents, and then converting
`
`Form A to Form B in a second mixed solvent. No claim in the '393 Patent
`
`specifies what solvents should be used, and thus, all of these procedures described
`
`in Phares fall within the scope of the '393 Patent claims.
`
`62.
`
`In summary, as Phares discloses the same product and same process
`
`of preparing the product disclosed in Claims 1 and 9, including making the most
`
`20
`
`SteadyMed - Exhibit 1009- Page 23
`
`

`

`stable crystal form (Form B) and preparing a product that melts at a higher
`
`temperature higher than that described in the '393 Patent, Phares necessarily
`
`discloses a salt of at least equal purity to the salt in the '393 Patent.
`
`B.
`
`The '393 Patent Process Does Not Result In A "Physically
`Different" Or Unique Product Than The Prior Art
`
`63. Having reviewed the prior art and the prosecution history, no unique
`
`or novel property is found in the resulting treprostinil product disclosed under the
`
`claims of the '393 Patent compared to the prior art. Accordingly, the '393 Patent
`
`processes do not result in a physically different or unique product than that
`
`disclosed in the prior art, and the '393 Patent processes are inherently anticipated
`
`by the prior art.
`
`64.
`
`I base my opinion on an analysis of the prosecution history for the
`
`'393 Patent, and my experience as a professor of organic chemistry for over thirty
`
`years.
`
`65.
`
`I understand that during prosecution of the '393 Patent, Patent Owner
`
`submitted a declaration by Dr. David Walsh, one of the inventors, and Executive
`
`Vice President of Chemical Research and Development at United Therapeutics
`
`Corporation.
`
`(Ex. 1002-2, pp. 346-350, Walsh Declaration). Patent Owner
`
`contended, based upon Dr. Walsh's measurement, that its purification method
`
`achieved 99.8% purity (Ex. 1002-2, pp. 348, Walsh Declaration), while the prior
`
`art Moriarty reference achieved "only" 99.4% (Ex. 1002-2, p. 347) (despite the fact
`
`21
`
`SteadyMed - Exhibit 1009- Page 24
`
`

`

`that Moriarty reported 99.7%, Ex. 1004, p. 13). Patent Owner claims 99.5% purity
`
`or above in Claims 2 and 10, but its use of the Walsh Declaration to support this
`
`claim is unsupportable, for the three reasons discussed below.
`
`66.
`
`First, the data in the Walsh Declaration was derived from a limited
`
`sample set – indeed, only two specific batches of treprostinil – which were self-
`
`selected for presentation to the Patent Office. There could be significant batch-to-
`
`batch variations in the impurity profile of each batch of treprostinil, which does not
`
`provide sufficient evidence to support the conclusion that the purification method
`
`achieves 99.5% purity or above for the claimed treprostinil.
`
`67.
`
`Second, variations in the processes of making the claimed product
`
`could also impact and vary the degree of purity of the product. For example, the
`
`claims do not require the use of any particular reaction conditions when carrying
`
`out steps (a)-(c) and optional step (d) of Claims 1 and 9. Thus, in performing the
`
`claimed process under the '393 Patent, varying levels of purity of the claimed
`
`product could be obtained as a result of variations in the different reagents,
`
`solvents, and reaction conditions utilized.
`
`68.
`
`Third, a 0.1 percentage difference in purity between Walsh's
`
`measurement of Moriarty's purity (99.4%) and Claim 2 and Claim 10's 99.5%
`
`purity is well within experimental error for measuring impurities, and would not
`
`represent a significant deviation from the processes of the prior art.
`
`22
`
`SteadyMed - Exhibit 1009- Page 25
`
`

`

`69.
`
`Even a difference of 0.4%, as discussed below, between the claimed
`
`processes of the '393 Patent and the prior art, such as Moriarty (Ex. 1004), would
`
`be attributable to experimental error, and thus the claimed degree of purity under
`
`