Case 3:14-cv-05499-PGS-LHG Document 42-5 Filed 07/07/15 Page 1 of 122 PageID: 1010
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`
`
`
`
`UNITED THERAPEUTICS
`CORPORATION,
`
`Plaintiff,
`
`
`
`
`v.
`
`
`
`SANDOZ, INC.,
`
`Defendant.
`
`
`
`
`
`
`
`
`
`Civil Action No. 3:14-cv-5499
`(PGS)(LHG)
`
`
`
`
`DECLARATION OF ROBERT M. WILLIAMS, PH.D.
`
`1
`
`
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`
`
`
`
`UNITED THERAPEUTICS
`CORPORATION,
`
`Plaintiff,
`
`
`
`
`v.
`
`
`
`SANDOZ, INC.,
`
`Defendant.
`
`
`
`
`
`
`
`
`
`Civil Action No. 3:14-cv-5499
`(PGS)(LHG)
`
`
`
`
`DECLARATION OF ROBERT M. WILLIAMS, PH.D.
`
`1
`
`
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`Case 3:14-cv-05499-PGS-LHG Document 42-5 Filed 07/07/15 Page 2 of 122 PageID: 1011
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`I, Robert M. Williams, Ph.D. declare as follows:
`
`I.
`
`BACKGROUND
`
`1.
`
`I am currently a tenured University Distinguished Professor of
`
`Chemistry at Colorado State University (CSU). I also serve as the Director for the
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`Colorado Center for Drug Discovery. I am also co-Director (Experimental
`
`Therapeutics) for the Infectious Diseases Supercluster Initiative and co-Director
`
`for the Cancer Supercluster Initiative at CSU. I have been retained by United
`
`Therapeutics Corp. (“UTC”) as an expert in connection with the above-captioned
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`matter.
`
`2.
`
`I obtained my Bachelor of Arts degree in Chemistry from Syracuse
`
`University in 1975, and did laboratory research in the field of synthetic organic
`
`chemistry under the guidance of the Nobel Laureate Professor Ei-ichi Negishi. I
`
`obtained my Master’s degree and Ph.D. in Organic Chemistry in 1979 from the
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`Massachusetts Institute of Technology (MIT). Upon graduating from MIT, I spent
`
`one year (1979-80) as a post-doctoral fellow at Harvard University in the
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`laboratories of the Nobel Laureate, the late Professor Robert B. Woodward and
`
`Professor Yoshito Kishi. I have been a professor of chemistry since 1980.
`
`3.
`
`I have extensive knowledge and experience in the area of synthetic
`
`organic chemistry and medicinal chemistry with an emphasis on biologically active
`
`compounds. My organic chemistry research interests include the total synthesis of
`
`
`
`2
`
`
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`novel natural and synthetic products, heterocyclic chemistry, asymmetric synthesis,
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`synthetic methodology, and reaction mechanisms. In addition to over 300
`
`publications in the field, I have taught classes and conducted research in the area of
`
`synthetic organic chemistry and more specifically on prostaglandins, prostacyclins,
`
`thromboxanes, and related compounds. I also served as Principal Investigator (PI)
`
`on a research grant from the National Institutes of Health, to study the synthesis of
`
`thromboxane A2, a member of the natural eicosanoids and researched the structure
`
`and function of this family of fatty acid derivatives including the prostaglandins.
`
`4.
`
`I also have expertise in drug formulation for injectable, topical and
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`oral medications. I have directed research programs for numerous therapeutic
`
`indications and I have consulted on many aspects of pharmaceutical drug
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`discovery, development and manufacturing. This includes basic discovery and
`
`optimization, early process research, large-scale manufacturing and drug
`
`formulation.
`
`5.
`
`I also currently serve on the Editorial board for Chemistry & Biology,
`
`and served as Editor for the Organic Chemistry Series published by Pergamon
`
`Press and Elsevier (1997-2012), and Mini Reviews in Organic Chemistry (Bentham
`
`Science). I have served as an editor for several other journals in the past, including
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`Tetrahedron: Asymmetry, Tetrahedron Publications, Amino Acids, and the Journal
`
`of the American Chemical Society.
`
`
`
`3
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`6.
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`I am a member of the American Chemical Society, the Japan
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`Antibiotics Research Association, and the International Society of Heterocyclic
`
`Chemistry. I have served as the Vice President of the International Society of
`
`Heterocyclic Chemistry, Chairing the 2003 International Congress of Heterocyclic
`
`Chemistry as organizer or co-organizer of numerous scientific meetings and
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`symposia and.
`
`7.
`
`I have been awarded numerous prizes and awards including the NIH
`
`Research Career Development Award (1984-89), the Eli Lilly Young Investigator
`
`Award (1986), the Merck, Sharp & Dohme Academic Development Award (1991),
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`the Japanese Society for the Promotion of Science Fellowship (1999), the Arthur
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`C. Cope Scholar Award sponsored by The American Chemical Society (2002), the
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`Multiple Myeloma Research Foundation Senior Award (2010), the ACS Ernest
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`Guenther Award in the Chemistry of Natural Products sponsored by Givoudan and
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`The American Chemical Society (2011), the Japanese Society for the Promotion of
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`Science Long-term Fellowship (2012-2013) and the local Rocky Mountain section
`
`of the American Chemical Society Organic Synthesis Award (2012).
`
`8. My educational background, work experience, publications, and
`
`honors are set forth in my curriculum vitae, attached to this report as Exhibit A.
`
`9.
`
`Below is a list of the cases where I have testified as an expert at trial
`
`or by deposition in the past four years: Lundbeck v. Infosint., C.A. No. 1:06-cv-
`
`
`
`4
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`
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`02869-LAK-RLE (S.D.N.Y.); Sanofi-Aventis v. Apotex and Hospira; C.A. No.
`
`1:07-cv-00721-GMS (D. Del.) (consolidated); Johnson & Johnson, Cordis Corp.,
`
`and Wyeth ("J&J") v. Abbott Laboratories, Abbott Cardiovascular Systems, Inc.,
`
`Boston Scientific Corp., Boston Scientific SciMed, Inc., Medtronic, Inc., and
`
`Medtronic AVE, Inc., C.A. Nos. 3:08-cv-00230-JAP-TJB (D.N.J.) and 3:08-cv-
`
`01021-JAP-TJB (D.N.J.); Allergan, Inc. v. Athena Cosmetics, Inc., C.A. Nos. 8:07-
`
`01316-JVS-RNB (C.D. Cal.) and 8:09-cv-00328-JVS-RNB (C.D. Cal.); United
`
`Therapeutics Corp. v. Sandoz, Inc., C.A. Nos.: 12-cv-01617-PGS-LHG (D.N.J.)
`
`and 3:13-cv-00316-PGS-LHG (D.N.J.); Gilead Sciences, Inc. and Emory
`
`University v. Cipla, Ltd., C.A. No.: 1:12-cv-06350-RJS (S.D.N.Y.); Andrulis
`
`Pharmaceuticals v. Celgene Corp., C.A. No. 1:13-cv-01644-RGA (D. Del.); and
`
`Genzyme Corp. v. Dr. Reddy’s Laboratories, Ltd., C.A. No. 13-1506-GMS (D.
`
`Del.).
`
`10.
`
` For this declaration, I have reviewed the ’393 patent, its
`
`corresponding and related prosecution histories, certain documents referenced
`
`therein, and additional references that were part of the state of the art at the time of
`
`the invention, as listed in Exhibit B. In addition, I have reviewed the Joint Claim
`
`Construction and Pre-Hearing Statement. My opinions are also based on my
`
`knowledge, education, training, and experience, in addition to the materials I have
`
`relied upon.
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`
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`5
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`11.
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`I am being compensated for the time I have spent on this litigation at
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`my customary rate of $650 per hour. My compensation does not depend on the
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`outcome of this litigation.
`
`12.
`
`I understand that I may be asked to provide background information
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`in this proceeding that will assist the Court to understand the science and
`
`technology relevant to the asserted patents. At hearings and/or trial, I may rely on
`
`materials and documents publicly available or produced in this litigation by UTC,
`
`Sandoz, and/or third parties. I may also rely on visual aids and demonstrative
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`exhibits that I may prepare or have prepared. I reserve the right to supplement or
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`amend the foregoing as appropriate if I become aware of any additional relevant
`
`information, or in response to testimony, deposition, reports, or analyses of other
`
`witnesses, including expert witnesses.
`
`13.
`
`I understand that there is one patent at issue in this litigation: U.S.
`
`patent No. 8,497,393 (“the ʼ393 patent”). It is my understanding that the priority
`
`date of the ’393 patent is at least as early as December 17, 2007.
`
`14.
`
`I understand that the claims are viewed from the perspective of a
`
`person of ordinary skill in the art (“POSA”) as of the earliest possible priority date
`
`for the patent-in-suit. A POSA with respect to the patent-in-suit would have had,
`
`at the time of the claimed invention, a doctorate degree in chemistry,
`
`pharmaceutics, pharmaceutical sciences, medicine, or a related discipline.
`
`
`
`6
`
`
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`Alternatively, the POSA may have had a lesser degree in one of those fields, with
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`correspondingly more experience. To the extent necessary, a POSA may have
`
`collaborated with others of skill in the art, such that the individual and/or team
`
`collectively would have had experience in synthesizing and analyzing complex
`
`organic compounds.
`
`15. Although my experience exceeds that of a POSA, I understand that
`
`the claims and specification of the patent-in-suit are to be read in view of the
`
`understanding of a POSA as of the priority date of the patent.
`
`16.
`
`I understand that UTC is asserting claims against Sandoz that claim
`
`products comprising treprostinil and other related products made by certain
`
`processes. I further understand that UTC is asserting claims 1, 2, 4, 8, 9, and 16 of
`
`the ’393 patent against Sandoz.
`
`II.
`
`BASE RELATED CLAIM TERMS
`
`17. Claim terms “a base B” and “HB+” are found in the asserted claims of
`
`the ’393 patent and both relate to the chemical concept of a base. In understanding
`
`the meaning of these terms, a POSA would consider the conventional usage of
`
`these terms in the intrinsic and extrinsic evidence. I have been informed that UTC
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`proposes that each of these terms should be given their plain and ordinary
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`meaning. Based on my knowledge and experience, I agree that the usage of these
`
`terms in the ’393 patent is consistent with their plain and ordinary meaning.
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`
`
`7
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`Case 3:14-cv-05499-PGS-LHG Document 42-5 Filed 07/07/15 Page 8 of 122 PageID: 1017
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`18. There are two main mechanistic families of acid-base reactions in
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`chemistry and two simple theories have been developed and widely accepted in the
`
`chemical arts to describe and understand such reactions and the participating
`
`chemical species. See, e.g., Delafield Decl. Ex. 7 at UTC_REM_II_000001597-
`
`610. These are:
`
`(1)
`
`Bronsted-Lowry acid-base theory. This theory holds that when an acid
`
`and a base react with each other, a proton from the acid is transferred to the
`
`base. In this proton exchange, the acid forms its corresponding conjugate
`
`base and the base forms its corresponding conjugate acid. Many different
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`structural families of Bronsted-Lowry bases exist and are commonly used in
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`the pharmaceutical arts to make salts of acidic drug molecules, such as
`
`Treprostinil. All of the base species “B” identified in the ‘393 patent, are
`
`Bronsted-Lowry bases that accept a proton from Treprostinil which
`
`functions as a Bronsted-Lowry acid and proton donor. It is important to
`
`understand the different structural families of Bronsted-Lowry bases, and a
`
`POSA would apply these simple chemical concepts in each specific context
`
`to understand in what structural form the produced salt would exist.
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`
`
`8
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`
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`(2)
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`Lewis acid-base theory. A Lewis acid is a chemical substance that
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`reacts with a Lewis base to form a Lewis adduct. Proton transfer is typically
`
`not involved in Lewis acid/Lewis base reactions. For example, ammonia
`
`(NH3) and hydroxide ion (OH-) are Lewis bases due to their capacity to
`
`donate a pair of electrons to a Lewis acid (an electron pair-acceptor). An
`
`example is given below where the Lewis base ammonia reacts with trimethyl
`
`borane to form the Lewis acid-base adduct where no proton transfer has
`
`occurred.
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`9
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`19. To exemplify and understand how the drug substance Treprostinil,
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`which is an acid, can be converted into a salt, below is the related simple organic
`
`acid acetic acid dissociating in water (as a solvent). In this process, water acts as
`
`the (weak) base that accepts the proton from the acid. The arrows of this equation,
`
`go in both the forward and reverse direction to indicate that the reaction is rapidly
`
`reversible and would be understood by a POSA to represent an equilibrium. Upon
`
`accepting the proton from acetic acid, a water molecule will become protonated
`
`forming the positively charged hydronium ion in the aqueous solution and having
`
`lost a proton (H+), acetic acid is transformed into the conjugate base acetate anion.
`
`In this particular situation, the equilibrium lies strongly to the left because water is
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`a very weak base.
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`
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`
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`In order to make a stable salt of acetic acid, a POSA would know that a stronger
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`base would be needed and two examples are provided below.
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`20.
`
`In the first example, acetic acid is reacted with the common base
`
`NaOH (sodium hydroxide) to form the salt, sodium acetate plus one molecule of
`
`water. Please note that the proton was transferred from the acid, acetic acid to the
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`
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`10
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`Case 3:14-cv-05499-PGS-LHG Document 42-5 Filed 07/07/15 Page 11 of 122 PageID: 1020
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`hydroxide ion (OH-) to form a molecule of water. The positively charged sodium
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`cation pairs with the negatively charged acetate anion to form the salt, sodium
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`acetate. Please note that the atomic cation Na+ does not have a hydrogen atom (H)
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`associated with it.
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`21.
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`In the second example, acetic acid is reacted with the base
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`diethanolamine to form the corresponding amine salt. Please note that in this case,
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`the positively charged amine counterion accepts the proton from acetic acid.
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`22. Treprostinil, which is a carboxylic acid, and has the COOH functional
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`group that acetic acid has, can also form the corresponding salt forms discussed
`
`above for acetic acid as shown below.
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`11
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`(A) Reaction of Treprostinil acid (also called Treprostinil free acid) with
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`sodium hydroxide forms the salt form, Treprostinil sodium.
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`(B) Treprostinil acid is reacted with the base diethanolamine to form the
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`corresponding amine salt.
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`
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`23. The term “a base B” is found in independent claims 1 and 9 of the
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`’393 patent. “A base B” is used consistently in each claim which reflects the
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`conventional usage of this term in the art and therefore does not need to be
`
`construed. I also understand that to the extent the Court requires a construction,
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`12
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`Case 3:14-cv-05499-PGS-LHG Document 42-5 Filed 07/07/15 Page 13 of 122 PageID: 1022
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`UTC’s proposed construction for “a base B” is “a substance that produces
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`hydroxide ions in aqueous solution, a proton acceptor.”
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`24. To the degree the term needs to be construed, UTC’s proposed
`
`definition is consistent with how that term would be understood by a POSA.
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`25.
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`In the chemical context, “a base” can exhibit its property of basicity
`
`through a number of mechanisms. One specific definition out of a well-known
`
`chemistry textbook defines “base” as “a substance that produces hydroxide ions in
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`aqueous solution, a proton acceptor.” Delafield Decl. Ex. 2 at
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`UTC_REM_II_000001647. I agree with this definition and have used this
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`conceptual understanding to teach undergraduate and graduate students
`
`fundamental principles of acid-base chemistry for over thirty-five years.
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`26. A POSA would understand this as a complete definition for a base
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`because it includes different mechanisms for which the base may exhibit its
`
`basicity as it encompasses bases that act as hydroxide ion producers or proton
`
`acceptors. The letter “B” itself was (at the time of the invention) and still today is
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`ubiquitously used to generically represent a base and was readily understood by
`
`POSAs at the time of the invention to include substances that exhibit basic
`
`properties.
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`27.
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`It is common in the chemical literature, to see the generic descriptor
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`“B” used to describe both net neutral as well as negatively charged species. For
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`
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`13
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`example, the generic descriptor “B” is commonly used to embrace the two generic
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`descriptors shown below. Delafield Decl. Ex. 3 at UTC_REM_II_000001758;
`
`Delafield Decl. Ex. 4 at UTC_REM_II_ 000005497-98.
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`Base B in aqueous solution
`
`B + H2O
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` BH+ + OH-
`
`Base B as hydroxide ion producer
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`Mg(OH)2
`
` Mg2+ + 2OH-
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`Base B as proton acceptor
`
`NH3 + H2O
`
` NH4
`
`+ + OH-
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`In the first reaction, a generic base B is put in solution to form BH+ and OH-. This
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`general reaction form demonstrates that a base may act as a proton (H+) acceptor
`
`and/or a hydroxide ion (OH-) producer. In the second reaction, the base magnesium
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`(magnesium hydroxide (Mg(OH)2) in solution)1, will spontaneously dissociate in
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`aqueous solution and produces hydroxide ions (OH-). In the third reaction, the base
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`ammonia (NH3) accepts a proton (H+) to form the ammonium ion (NH4
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`+). Both the
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`magnesium-sourced base magnesium hydroxide and ammonia are bases and form
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`basic solutions in water.
`
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`1 A POSA would understand that magnesium in water, or aqueous solution, would form
`magnesium hydroxide.
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`14
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`28. A POSA seeing the descriptor “B” will be able to determine the
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`appropriate charges, if any, on the species functioning as a base depending on the
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`specific chemical context of a specific chemical reaction:
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`29. A POSA reading the ’393 patent needing to understand the claim
`
`language specifying a base “B” would rely on the specification of the ’393 patent
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`and his or her knowledge and experience in pharmaceutical formulations of acidic
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`drugs, such as Treprostinil which contains a carboxylic acid functional group
`
`capable of forming various types of salts. The ’393 patent uses the broad term
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`“magnesium” (see for instance, Claim 13 which depends from Claim 9) as a
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`possible base. A POSA would understand that regardless of the actual specific
`
`magnesium-based chemical species chosen as the base as “magnesium”, the
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`magnesium salt form would have one of two possible forms as shown below. The
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`commonly deployed forms of “magnesium” as a base would be the following
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`species:
`
`(1) Mgo = elemental magnesium
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`15
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`(2) Mg(OH)2 = magnesium hydroxide
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`(3) MgH2 = magnesium hydride
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`(4) MgO = magnesium oxide
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`(5) MgCO3 = magnesium carbonate
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`
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`30.
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`If the magnesium-based form of the base “B” were elemental
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`magnesium (Mgo), a POSA would know that Mgo reacts rapidly with water to form
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`Mg(OH)2 (magnesium hydroxide). Thus, if the solvent medium for this step was
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`water or a mixed organic-aqueous solvent system, Mg(OH)2 would be generated
`
`that would react with Treprostinil free acid to form the magnesium salt forms
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`16
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`depicted above.
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`31.
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`If the magnesium-based form of the base “B” were Mg(OH)2
`
`(magnesium hydroxide), a POSA would know that one molar equivalent of
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`Mg(OH)2 (magnesium hydroxide) could react with one molar equivalent of
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`Treprostinil free acid forming two molecules of water and form the magnesium salt
`
`
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`forms depicted above.
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`
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`32.
`
`If the magnesium-based form of the base “B” were magnesium
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`hydride (MgH2), a POSA would know that MgH2, reacts with water to form
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`Mg(OH)2 (magnesium hydroxide) plus two molar equivalents of hydrogen gas.
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`Thus, if the solvent medium for this step was water or a mixed organic-aqueous
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`17
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`solvent system, Mg(OH)2 would be generated that would react with Treprostinil
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`free acid to form the magnesium salt forms discussed above.
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`33. Alternatively, if magnesium hydride (MgH2) were used in a non-
`
`protic solvent (such as ether), one molar equivalent of magnesium hydride would
`
`react with one molar equivalent of Treprostinil free acid to form the intermediate
`
`magnesium hydride salt. This species, while capable of existence, would be
`
`unstable to reaction with moisture or a second molar equivalent of Treprostinil free
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`acid to form the same magnesium salt species described above.
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`
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`34.
`
`If the magnesium-based form of the base “B” were magnesium oxide
`
`(MgO), a POSA would know that MgO, reacts with water to form Mg(OH)2
`
`(magnesium hydroxide). Thus, if the solvent medium for this step was water or a
`
`mixed organic-aqueous solvent system, Mg(OH)2 would be generated that would
`
`react with Treprostinil free acid to form the magnesium salt forms discussed above.
`
`35.
`
`If the magnesium-based form of the base “B” were magnesium
`
`carbonate (MgCO3), a POSA would know that MgCO3, would react with
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`Treprostinil free acid to form the magnesium salt forms discussed above.
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`18
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`36. What is evident from an analysis of the commonly employed forms of
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`“magnesium” in the context of serving as a base, a POSA would know that the
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`final magnesium salt form would be the same type of species regardless of the
`
`magnesium base source and a POSA would know how to manipulate the
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`stoichiometry, solvent and reaction conditions to achieve the desired magnesium
`
`salt form.
`
`37. As called out in the ’393 patent specification, sodium is specifically
`
`identified as an inorganic base that can be used to form pharmaceutically
`
`acceptable base addition salts. See, ¶ 71; Delafield Decl. Ex. 1 at
`
`UTC_REM_II_000003358, Col. 5:8. Similar to the inventors use of the term
`
`“magnesium”, a POSA would understand that regardless of the actual specific
`
`sodium-based chemical species chosen as the base as “sodium”, the sodium salt
`
`form would have only one possible structure as shown below. The commonly
`
`deployed forms of “sodium” as a base would be the following species:
`
`(1) Nao = elemental sodium
`
`(2) NaOH = sodium hydroxide
`
`(3) NaH = sodium hydride
`
`(4) NaHCO3 = sodium bicarbonate
`
`(5) Na2CO3 = sodium carbonate
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`19
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`38. The ’393 patent itself also uses “B” to denote a base. The ’393 patent
`
`also states that “base B in step (c) may be ammonia, N-methylglucamine, procaine,
`
`tromethamine, magnesium, L-lysine, L-arginine, or triethanolamine” and further
`
`specifies that “those who are skilled in the art will appreciate that [sic] how to
`
`select necessary reagents and solvents in practicing the invention.” Delafield Decl.,
`
`Ex. 1 at UTC_REM_II_000003360, Col. 9:3-5, 15-23. Similarly, claims 5, 13, and
`
`17 of the ’393 patent specifies that base B “is selected from a group consisting of
`
`ammonia, N-methylglucamine, procaine, tromethamine, magnesium, L-lysine, L-
`
`arginine, triethanolamine and diethanolamine.” Id. at UTC_REM_II_000003365.
`
`Thus, a POSA would understand that “a base B” as used in the ’393 patent is used
`
`according to its plain and ordinary meaning or “a substance that produces
`
`hydroxide ions in aqueous solution, a proton acceptor.”
`
`39.
`
`Indeed, many well-known chemistry textbooks specifically define
`
`“base” as a proton acceptor or a hydroxide ion producer, as described in the ’393
`
`patent. Delafield Decl. Ex. 5 at UTC_REM_II_000001586; Delafield Decl. Ex. 6
`
`
`
`20
`
`
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`Case 3:14-cv-05499-PGS-LHG Document 42-5 Filed 07/07/15 Page 21 of 122 PageID: 1030
`
`at UTC_REM_II_000001589-91; Delafield Decl. Ex. 7 at
`
`UTC_REM_II_000001597-98; Delafield Decl. Ex. 8 at
`
`UTC_REM_II_000001622-23; Delafield Decl. Ex. 9 at
`
`UTC_REM_II_000001641; Delafield Decl. Ex. 10 at UTC_REM_II_000001644;
`
`Delafield Decl. Ex. 4 at UTC_REM_II_000005497-98.
`
`40.
`
`I disagree with Sandoz’s proposed construction of “a base B” as “a
`
`chemical species capable of receiving a proton (hydrogen ion, i.e., H+) from the
`
`product of step (b) to form the positively charged conjugate acid HB+.” A POSA
`
`would not understand that “a base B” would be limited to “a chemical species
`
`capable of receiving a proton (hydrogen ion, i.e., H+) from the product of step (b)
`
`to form the positively charged conjugate acid HB+.” Bases can exhibit their
`
`property of basicity through a number of mechanisms, including by being proton
`
`acceptors or hydroxide ion producers. Those bases that produce hydroxide ion, are
`
`proton acceptors by virtue of the hydroxide ion (OH-) accepting a proton from the
`
`acid forming a water molecule and the positively charged counterion will not
`
`always strictly adopt the formula “BH+” as Sandoz is incorrectly proposing. By
`
`limiting the definition to only “a chemical species capable of receiving a proton
`
`(hydrogen ion, i.e., H+) from the product of step (b) to form the positively charged
`
`conjugate acid HB+”, Sandoz’s construction would eliminate many of the
`
`commonly employed bases in pharmaceutical salt formation, including those
`
`
`
`21
`
`
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`Case 3:14-cv-05499-PGS-LHG Document 42-5 Filed 07/07/15 Page 22 of 122 PageID: 1031
`
`specifically called out in the ‘393 patent. A POSA would not understand the claim
`
`term “a base B” to be so limited. Sandoz is attempting to narrow the plain and
`
`ordinary meaning and ubiquitously recognized definition of a base “B” to exclude
`
`most of the commonly used bases in pharmaceutical chemistry and manufacturing.
`
`These commonly employed bases are specifically called out in the ‘393 patent and
`
`it was clearly the inventors intention to include such bases.
`
`41.
`
`In fact, Sandoz’s construction for “a base B” is contrary to the
`
`examples in the ’393 patent. Both the specification and several dependent claims
`
`specifically list magnesium as a base B. See, ¶ 38. Magnesium-sourced bases form
`
`the corresponding metal salts (magnesium salts) and are distinct from amine salts
`
`wherein the nitrogen atom of the amine base receives a proton directly from the
`
`acid, such as in the example of diethanolamine. Thus, a POSA would not interpret
`
`“a base B” as “a chemical species capable of receiving a proton (hydrogen ion, i.e.,
`
`H+) from the product of step (b) to form the positively charged conjugate acid
`
`HB+” because Sandoz’s definition limits bases to only one structural type of base
`
`counterion (or the conjugate acid) and the patent itself clearly identifies bases that
`
`produce common pharmaceutical salt forms with their characteristic counterions.
`
`42. For similar reasons I previously described regarding the term “a base
`
`B”, it is my opinion that a POSA would understand the plain and ordinary meaning
`
`of the claim term “HB+” as it is cast in the context of the structural formulae Is and
`
`
`
`22
`
`
`
`Case 3:14-cv-05499-PGS-LHG Document 42-5 Filed 07/07/15 Page 23 of 122 PageID: 1032
`
`IVs that describes the salt forms of Treprostinil. Alternatively, if the Court
`
`determines that the descriptor “HB+” requires construction, a POSA would
`
`understand the descriptor as “the cation formed in aqueous solution by base B
`
`subsequent to reacting base B with the product of step (b).”
`
`43. First, “B” is often used to refer to a base in general. See, ¶¶ 26-28, 38.
`
`Likewise, “BH+” or “HB+” can be used to represent the cation (or positively
`
`charged ion) formed in aqueous solution when it is used in the context of a generic
`
`base B, regardless of the mechanism by which it functions as a base. This is true in
`
`the ’393 patent itself. Both the specification and several dependent claims
`
`specifically list magnesium as a base B. See, ¶ 38. Yet, magnesium-sourced bases
`
`form the corresponding metal salt (magnesium salt) that are distinct from an amine
`
`salt that accepts a proton as part of the cationic species paired with the Treprostinil
`
`anion.
`
`44. My opinion is further supported by the well-known pharmaceutical
`
`reference Aulton’s Pharmaceutics. In Aulton’s, the formula for calculating the pH
`
`of a base uses “B” to represent a base and “BH+” to represent the cation formed
`
`from base B. See, Delafield Decl. Ex. 3 at UTC_REM_II_000001758. On the
`
`same page, base cations are listed such as magnesium, potassium, sodium, calcium,
`
`and lithium alongside others such as diethanolamine. Id. While all of these form
`
`positively charged cations, the majority of the cations listed (such as magnesium,
`
`
`
`23
`
`
`
`Case 3:14-cv-05499-PGS-LHG Document 42-5 Filed 07/07/15 Page 24 of 122 PageID: 1033
`
`potassium, sodium, calcium and lithium) do not accept the proton that was
`
`transferred from the acid as that proton typically forms a neutral molecule of water.
`
`A POSA would understand that the commonly used shorthand “BH+” or “HB+”
`
`does not necessarily indicate that the base must accept the proton from the acid as
`
`part of the cationic species paired with the Treprostinil anion (or carboxylate).
`
`45. Like Sandoz’s construction for “a base B,” their construction for
`
`“HB+” is also contrary to the examples in the ’393 patent. Both the specification
`
`and several dependent claims specifically list magnesium as a base B. See, ¶ 38.
`
`Magnesium-sourced bases form metal salts (the corresponding magnesium salt)
`
`whose positively-charged counterions are distinct from amine salts that accept the
`
`proton on the atom bearing the formal positive charge, such as the nitrogen atom of
`
`diethanolamine as shown above. Likewise, magnesium is unable “to form the
`
`positively charged conjugate acid HB+” which under Sandoz’s construction
`
`indicates a covalent bond between the atom of “B” carrying the net positive charge
`
`and “H.” Thus, a POSA would readily understand the structural context of “HB+”
`
`depending on the specific base used in the salt formation and as clearly specified in
`
`the ‘393 patent.
`
`
`
`
`
`
`
`24
`
`
`
`Case 3:14-cv-05499-PGS-LHG Document 42-5 Filed 07/07/15 Page 25 of 122 PageID: 1034
`
`III.
`
`PRODUCT RELATED CLAIM TERMS
`
`46. The claim terms “product”; “a product comprising a compound of
`
`formula I2:
`
`
`
`
`
`
`
`or a pharmaceutically acceptable salt thereof”; “(c) contacting the product of step
`
`(h) with a base B to form a salt of formula Is3
`
`
`
`
`
`
`
`”;
`
`“The product of claim 1, wherein the purity of compound of formula I in said
`
`product is at least 99.5%”; “The product of claim 1”; “A product comprising a
`
`compound having formula IV4
`
`
`2 The structure of Formula I is shown here which I will refer to as “Formula I” for the
`remainder of my declaration.
`
`3 The structure of Formula Is is shown here which I will refer to as “Formula Is” for the
`remainder of my declaration.
`
`4 The structure of Formula IV is shown here which IV will refer to as “Formula IV” for the
`remainder of my declaration.
`
`
`
`25
`
`
`
`Case 3:14-cv-05499-PGS-LHG Document 42-5 Filed 07/07/15 Page 26 of 122 PageID: 1035
`
`
`
`
`
`
`
`or a pharmaceutically acceptable salt thereof”; (c) contacting the product of step
`
`5
`(h) with a base B to form a salt of formula IVs
`
`
`
`
`
`
`
`”; and
`
`“The product of claim 9” are found in the asserted claims of the ’393 patent. In
`
`understanding the meaning of these terms, a POSA would consider the
`
`conventional usage of these terms in the intrinsic and extrinsic evidence. I have
`
`been informed that UTC proposes that each of these terms should be given their
`
`plain and ordinary meaning. Based on my knowledge and experience, I agree that
`
`the usage of these terms in the ’393 patent is consistent with their plain and
`
`ordinary meaning.
`
`
`5 The structure of Formula IVs is shown here which IVs will refer to as “Formula IVs” for the
`remainder of my declaration.
`
`
`
`26
`
`
`
`Case 3:14-cv-05499-PGS-LHG Document 42-5 Filed 07/07/15 Page 27 of 122 PageID: 1036
`
`47. The term “product” is found in each of these claim terms and is used
`
`consistently in each term which reflects the conventional usage of this term in the
`
`art and therefore does not need to be construed. I also understand that to the extent
`
`the Court requires a construction, UTC’s proposed construction for “product” is “a
`
`substance resulting from a chemical reaction.”
`
`48.
`
`In the chemical context, “product” generally refers to the real world
`
`outcome or r
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