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`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`
`v.
`
`MERCK SHARP & DOHME CORP.,
`Patent Owner.
`__________________
`
`Case IPR2020-00040
`U.S. Patent 7,326,708
`__________________
`
`DECLARATION OF ADAM J. MATZGER, PH.D.
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`Merck Exhibit 2103, Page 1
`Mylan Pharmaceuticals Inc. v. Merck Sharp & Dohme Corp.
`IPR2020-00040
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`TABLE OF CONTENTS
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`
`I.
`INTRODUCTION ........................................................................................... 4
`QUALIFICATIONS AND EXPERIENCE ..................................................... 5
`II.
`III. LEGAL STANDARDS ................................................................................... 8
`A.
`Priority Date .......................................................................................... 8
`B.
`Anticipation ........................................................................................... 9
`C.
`Obviousness ......................................................................................... 10
`D.
`Claim Construction.............................................................................. 13
`IV. BACKGROUND ........................................................................................... 13
`A.
`Pharmaceutical Salt Formation Is An Unpredictable Process. ........... 13
`B. Merck’s Discovery of the 1:1 DHP Salt of Sitagliptin ....................... 20
`THE ’708 PATENT ....................................................................................... 23
`V.
`VI. PRIORITY DATE OF THE ’708 PATENT ................................................. 26
`A.
`Claim 1 ................................................................................................ 27
`B.
`Claim 2 ................................................................................................ 31
`C.
`Claim 17 .............................................................................................. 31
`D.
`Claim 19 .............................................................................................. 34
`E.
`Claims 21–23 ....................................................................................... 36
`VII. PERSON OF ORDINARY SKILL IN THE ART (“POSA”) ....................... 36
`VIII. THE CHALLENGED CLAIMS ARE NOT ANTICIPATED
`(GROUNDS 1 AND 2). ................................................................................. 38
`A. WO ’498 Does Not Explicitly Disclose The 1:1 DHP Salt of
`Sitagliptin. ........................................................................................... 41
`The POSA Could Not Have at Once Envisaged A Sitagliptin
`Phosphate Salt From The Compounds And Counterions
`Disclosed in WO ’498. ........................................................................ 43
`1.
`Dr. Chorghade Improperly Narrows the Disclosures of
`WO ’498. ................................................................................... 44
`The POSA Would Not Have Immediately Envisaged a
`Phosphoric Acid Salt of Sitagliptin. ......................................... 50
`C. WO ’498 Does Not Explicitly or Inherently Disclose a 1:1
`Stoichiometry of Dihydrogenphosphate to Sitagliptin........................ 59
`1.
`The Structure of Sitagliptin and the Polyprotic Nature of
`Phosphoric Acid Suggests That the Formation of Non-1:1
`Are Possible. ............................................................................. 60
`Non-1:1 Phosphoric Acid–Sitagliptin Salts Exist, So the
`Claimed 1:1 Sitagliptin Dihydrogenphosphate Salt Is Not
`Inherently Disclosed. ................................................................ 76
`
`B.
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`2.
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`2.
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`D. WO ’498 Does Not Disclose The S-Configuration of the 1:1
`DHP Salt. ........................................................................................... 131
`E. Mylan Does Not Prove that WO ’498 Discloses A
`“Therapeutically Effective Amount” Of The 1:1 DHP Salt Of
`Sitagliptin. ......................................................................................... 132
`F. WO ’498 Does Not Teach a Salt Formation Process of
`Contacting One Equivalent of Sitagliptin With One Equivalent
`of Phosphoric Acid. ........................................................................... 134
`IX. THE CHALLENGED CLAIMS ARE NOT OBVIOUS (GROUNDS
`3 AND 4). .................................................................................................... 138
`A. WO ’498 in View of Bastin Does Not Render The 1:1 DHP Salt
`Of Sitagliptin Obvious. ..................................................................... 139
`1.
`The POSA Would Not Have Been Motivated To Select A
`Lead Compound From WO ’498. ........................................... 141
`The POSA Would Not Have Been Motivated To Select
`Sitagliptin Or The Hydrochloride Salt Of Sitagliptin. ............ 146
`The POSA Would Not Have Been Motivated To Modify
`Sitagliptin or Sitagliptin Hydrochloride and Select the
`Phosphate Salt. ........................................................................ 147
`The Prior Art Taught Away From The Phosphate Salt. ......... 154
`The POSA Would Not Have a Reasonable Expectation of
`Success in Making 1:1 DHP Sitagliptin Salt. ......................... 157
`The 1:1 DHP Salt Of Sitagliptin Displays An Unexpected
`Combination Of Superior Properties. ..................................... 159
`B. WO ’498 In View Of Bastin Does Not Render The (S)-
`Configuration Of The 1:1 DHP Salt of Sitagliptin Obvious. ............ 173
`C. WO ’498 In View Of Bastin Does Not Render Obvious A Salt
`Formation Process Of Contacting One Equivalent Of Sitagliptin
`With One Equivalent Of Phosphoric Acid. ....................................... 174
`D. WO ’498 Alone Does Not Render The (S)-Configuration Of, A
`“Therapeutically Effective Amount” Of, Or A Process For
`Making The 1:1 DHP Salt Of Sitagliptin Obvious. .......................... 176
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`2.
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`3.
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`4.
`5.
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`6.
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`I.
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`I, Adam J. Matzger, Ph.D., declare as follows:
`
`INTRODUCTION
`I have been asked to opine on the anticipation and obviousness of
`1.
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`claims 1–3, 17, 19, and 21–23 of U.S. Patent No. 7,326,708 (“the ’708 patent”),
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`including to address certain opinions provided by Dr. Mukund Chorghade. See
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`EX1002 (“Chorghade Dec.”).
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`2.
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`The ’708 patent is titled “Phosphoric Acid Salt of a Dipeptidyl
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`Peptidase-IV Inhibitor” and names Stephen Howard Cypes, Alex Minhua Chen,
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`Russell R. Ferlita, Karl Hansen, Ivan Lee, Vicky K. Vydra, and Robert M.
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`Wenslow, Jr. as inventors.
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`3.
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`The ’708 patent was filed on June 23, 2004 and claims priority on its
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`face to a provisional application filed on June 24, 2003. I have reviewed the
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`declarations of Drs. Robert Wenslow, Karl Hansen, and Vicky Vydra and
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`determined that the inventors of the ’708 patent reduced claims 1–2, 17, 19, and
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`21–23 well before June 23, 2004. See infra Section VI. For this declaration, I
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`apply the following relevant priority dates: (1) December 13, 2001 for claims 1–2
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`and 21–23, (2) March 12, 2002 for claim 17, and (3) November 22, 2002 for claim
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`19. The conclusions I reach would not change if the priority date was June 24,
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`2003, except insofar as I must account for certain additional references as prior art.
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`4.
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`In reaching the opinions I express herein, I have considered the ’708
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`patent and its prosecution history, the materials cited in this declaration, the
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`materials cited in Mylan’s Petition for Inter Partes Review, the Declaration by Dr.
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`Mukund Chorghade and all materials cited therein, the transcript and exhibits from
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`the deposition of Dr. Mukund Chorghade taken August 6, 2020, as well as my
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`training, general knowledge, basic principles, and experience in the relevant
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`scientific disciplines.
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`II. QUALIFICATIONS AND EXPERIENCE
`I am the Charles G. Overberger Collegiate Professor of Chemistry in
`5.
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`the College of Literature, Science and the Arts and a Professor of Macromolecular
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`Science and Engineering in the College of Engineering, both at the University of
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`Michigan. I have held the title of Professor since 2009. A true and correct copy of
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`my curriculum vitae is EX2104.
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`6.
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`I am also President and CEO of ChemXLerate LLC a company that
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`provides analytical services primarily in the area of pharmaceutical solid forms.
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`My work with ChemXLerate encompasses polymorph, hydrate, and salt form
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`production as well as characterization by techniques including X-ray diffraction
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`and vibrational spectroscopy.
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`7.
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`I obtained my Ph.D. in Chemistry from the University of California at
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`Berkeley in 1997. My doctoral thesis encompassed synthetic, theoretical and
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`structural studies on dehydrobenzoanulenes and phenylenes, and included
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`extensive analytical work using different techniques such as X-ray diffraction,
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`vibrational spectroscopy, nuclear magnetic resonance spectroscopy, and electron
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`microscopy. I obtained my B.A. in Chemistry from Oberlin College in 1992.
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`8.
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`After obtaining my Ph.D. in 1997, I conducted postdoctoral research
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`at the California Institute of Technology (Caltech), involving fundamental studies
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`of crystallization with a strong emphasis on multicomponent crystallization. I was
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`at Caltech until I joined the University of Michigan in 2000 as Assistant Professor
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`of Chemistry and of Macromolecular Science and Engineering.
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`9.
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`I teach courses at the University of Michigan at the undergraduate
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`level in the area of organic chemistry. At the graduate level, I teach classes about
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`spectroscopic characterization of organic molecules, polymer chemistry, and also a
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`course on solid state chemistry with a large component on structure and X-ray
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`diffraction analysis.
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`10.
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`I have published over 200 papers in peer reviewed journals. The vast
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`majority of my publications relate to polymorphism, crystal structure or
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`solvates/cocrystals. My work has garnered over 18,000 citations from other
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`researchers around the world.
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`11. My current research interests focus on organic materials in the solid
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`state ranging from crystalline polymorphs to porous materials. My work on crystal
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`polymorphism relates to the ability of molecules to crystallize in more than one
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`arrangement in the solid state, and includes issues relating to polymorphism,
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`hydrates, solvates, amorphous states and cocrystals.
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`12. As part of my current research, and dating back to the start of graduate
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`school (1992), I have been involved in the synthesis of organic molecules using
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`organic synthesis methodologies and have introduced novel synthetic approaches
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`to assemble complex products. This work has frequently involved using
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`techniques that are used in attempting to form pharmaceutical salts, including
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`purification and crystallization.
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`13.
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`I have been awarded numerous patents by the U.S. Patent and
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`Trademark Office, including several directed to crystalline materials.
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`14.
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`I am a past member of the Editorial Advisory Board of the Journal of
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`Pharmaceutical Sciences, and served as an Associate Editor for the American
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`Chemical Society Journal Crystal Growth and Design. I serve as a reviewer for
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`journals and grant agencies evaluating characterization of materials in the area of
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`solid-state chemistry.
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`15.
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`I have received various awards and honors, including being named as
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`an Alfred P. Sloan Foundation Research Fellow and American Association for the
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`Advancement of Science Fellow. I have also received the Beckman Foundation
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`Young Investigator, Ralph E. Powe Junior Faculty Enhancement Award, and the
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`3M Untenured Faculty Award to name a few.
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`16.
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`I am being compensated at my customary rate of $800 per hour for
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`my work in connection with this litigation. ChemXLerate is being compensated at
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`a rate of $400/hr for technician time and $400/hr for instrument time. My
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`compensation is in no way dependent on the outcome of my analysis or opinions
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`rendered in this litigation.
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`III. LEGAL STANDARDS
`Priority Date
`A.
`17.
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`I have been informed that the priority date of an invention depends on
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`the date that the invention was reduced to practice. I have been informed that there
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`are two types of reduction to practice: actual and constructive. To demonstrate an
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`actual reduction to practice, I have been informed that the inventor must have
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`constructed an embodiment or performed a process that met all the limitations of
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`the claim and determined that the invention would work for its intended purpose.
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`This does not require that the inventor be personally involved in all aspects of the
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`invention process. Those working implicitly or explicitly at the inventor’s request
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`can also be involved. I understand constructive reduction to practice occurs when
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`a patent application is filed.
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`B. Anticipation
`I have been informed that a patent claim is “anticipated,” and thus
`18.
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`invalid, if a single prior art reference discloses every claim limitation as arranged
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`in the claim. One exception to the requirement that the prior art reference must
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`disclose every claim limitation as arranged is when the POSA reading the
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`reference, would “at once envisage” the claimed range or combination. Whether
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`the POSA can “at once envisage” the claimed range or combination of separate
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`components listed in different parts of the single reference depends on whether the
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`number of combinations is too large or undefined, and whether the reference
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`contemplates or suggests combinability of components from different parts of the
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`reference. I understand that the POSA is not permitted to fill in any missing
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`limitations that she or he can immediately envision.
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`19.
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`I have also been informed that a prior art reference may inherently
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`anticipate a claimed invention without expressly disclosing a feature of the claimed
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`invention if that missing characteristic is necessarily present in a single anticipating
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`reference. It cannot be established by mere possibilities or even probabilities; it
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`must be there each and every time, with no exception.
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`20.
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`I have also been informed that a prior art reference can inherently
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`anticipate a claimed invention by disclosing a process that inevitably results in the
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`claimed invention. I understand there is no inherent anticipation if practicing the
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`prior art process would only possibly or probably result in the claimed invention.
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`Rather, the prior art process must necessarily result in the claimed invention.
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`Therefore, I understand that a prior art reference does not inherently anticipate a
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`patent claim if the prior art process can be practiced in a way that yields a product
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`that does not meet the claim limitations.
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`C. Obviousness
`I understand that a patent claim would have been “obvious,” and thus
`21.
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`invalid, if the differences between the subject matter sought to be patented and the
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`prior art are such that the subject matter as a whole would have been obvious at the
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`time the invention was made to the POSA to which said subject matter pertains. I
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`understand that analysis of whether a claim would have been obvious depends on
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`(a) the scope and content of the prior art, (b) the differences between the claimed
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`invention and the prior art, (c) the level of ordinary skill in the art, and (d) any
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`objective indicia of non-obviousness. I understand that the use of hindsight must
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`be avoided because the obviousness of an invention is evaluated from the
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`perspective of the POSA at the time the invention was made. Thus, in conducting
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`an obviousness inquiry, one must be aware of the distortion caused by hindsight
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`bias and must be cautious to avoid reading into the prior art the teachings of the
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`claimed invention at issue.
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`I understand that, to show that a patent would have been obvious, the
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`22.
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`party challenging the patent must demonstrate that a skilled artisan would have
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`been motivated to combine the teachings of the prior art to achieve the claimed
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`invention. As such, the challenger must prove not only that the prior art taught or
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`suggested the invention, but also that the POSA would have had a reason to
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`combine the teachings of the prior art references to achieve the claimed invention.
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`In other words, there needs to be a reason to combine the known elements in the
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`way claimed by the patent at issue.
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`23.
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`I further understand that, in order to demonstrate that a chemical
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`compound would have been obvious, the challenger must prove (1) that the skilled
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`artisan would have selected the asserted prior art compounds as lead compounds,
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`or starting points, for further development, and (2) that the skilled artisan would
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`have been motivated to modify the lead compound to make the claimed
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`compound.1
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`24.
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`I also understand that references that “teach away” from the
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`invention—in other words, references that would lead the POSA in a different
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`direction from that taken by the patentee and that would lead the POSA to believe
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`1 My conclusions on obviousness in this declaration would not change if I omitted
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`these factors from my analysis.
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`that the direction taken by the patentee was unsuitable—must be considered. In
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`determining whether the invention would have been obvious, one must consider
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`the prior art as a whole.
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`25.
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`I understand that, in addition to having a motivation to achieve the
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`claimed invention, the POSA must have had a reasonable expectation of success. I
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`understand that to have a reasonable expectation of success, one must be motivated
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`to do more than merely vary all parameters or try each of numerous possible
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`choices until one possibly arrived at a successful result, where the prior art gave
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`either no indication of which parameters were critical or no direction as to which
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`of many possible choices is likely to be successful.
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`26.
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`I understand that, in certain circumstances, a combination of elements
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`may have been “obvious to try.” Accordingly, when there is a design need or
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`market pressure to solve a problem and there are a finite number of identified,
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`predictable solutions, the POSA has good reason to pursue the known options
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`within her or his technical grasp. If this leads to the anticipated success, it is likely
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`the product not of innovation but of ordinary skill and common sense. Conversely,
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`where the prior art at best gives only general guidance as to the particular form of
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`the claimed invention or how to achieve it, the combination would not have been
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`obvious to try. I further understand that where the options do not behave
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`predictably, this principle of obvious to try does not apply.
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`D. Claim Construction
`I understand that the words of a claim are generally given their
`27.
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`ordinary and customary meaning, which is the meaning that the term would have
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`to the person of ordinary skill in question at the time of the invention. I understand
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`the person of ordinary skill in the art is deemed to read the claim term not only in
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`the context of the particular claim in which the disputed term appears, but also in
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`the context of the entire patent. I also understand the transitional phrase
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`“comprising” as used in the ’708 patent to be open ended—that it can include other
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`components, elements, or steps not explicitly mentioned in the claim language.
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`28. After reviewing the ’708 patent and its prosecution history, I do not
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`think that any of the claims require construction. That is to say, I apply the
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`meaning the meaning that the claim term would have to a POSA in question at the
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`time of the invention of the ’708 patent.
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`IV.
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` BACKGROUND
`Pharmaceutical Salt Formation Is An Unpredictable Process.
`A.
`29.
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`In the pharmaceutical sciences, discovering a compound or class of
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`compounds with desired biological activity is often only the first step in
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`developing a commercializable drug product. In order to formulate a
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`pharmaceutically active compound into a commercial drug, various
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`physiochemical properties of the compound must be considered. These include,
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`but are not limited to, stability, hygroscopicity, aqueous solubility, penetration
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`through biological membranes, morphology, particle size and shape, stickiness,
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`agglomeration of particles, bulk density, flowability, compatibility with other
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`components of the formulation, compressibility, and other properties related to the
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`manufacturing processes. Salt formation provides a way to potentially modify
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`some of the aforementioned physiochemical qualities. Salt formation in the
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`pharmaceutical context, which involves a proton transfer accompanied by the
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`appearance of a solid form, itself is unpredictable as to any particular salt. See
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`infra at ¶31. And although dissolution and solubility can often be improved if a
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`salt is formed, other critical quality attributes such as stability or hygroscopicity
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`may be jeopardized, making salt selection a multi-dimensional approach. See
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`EX1006 (Bastin) at 430 (“Also, it is occasionally found that the overall properties
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`of the free acid/base are much better than any of the salts. This occurs more
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`frequently where the candidate has a low pKa value and the resulting salts are less
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`stable than required or when the salts are particularly hygroscopic or when they
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`exhibit complex polymorphism/pseudopolymorphism (hydration or solvation).”),
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`435.
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`30. Salts are electrically neutral compounds that consist of atoms or
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`molecules held together by some degree of ionic transfer between an acid and a
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`base. The positive ion is known as the cation, and the negative ion is known as the
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`anion. Pharmaceutical salts are typically formed by reacting the “free” form of the
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`compound with either an acid or base, depending on the properties of this “free”
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`form. If the “free” form of the compound is basic, it is reacted with an acid; and if
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`it is acidic, it is reacted with a base.
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`31. As of the priority date, forming a salt required an empirical R&D
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`process that is unpredictable and fraught with trial and error. This is because the
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`formation and stability of a salt depends on multiple factors, including but not
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`limited to the pKa of the compound, the pKa of the counterion used, the intrinsic
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`solubility of the drug, temperature, the concentration of the salt counterion, the
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`concentration of the free from of the drug compound, and the solvents being used,
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`among others. Thus, whether any particular salt would form could not have been
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`predicted in advance. See EX2193 (Serajuddin 2007)2 at 604 (“For most practical
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`purposes, identification and selection of salt forms of NCEs still remain a trial and
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`error process.”); EX2042 (Serajuddin 2002)3 at 137 (“No predictive procedure to
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`determine whether a particular acidic or basic drug would form a salt with a
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`2 A.T.M. Serajuddin, “Salt formation to improve drug solubility,” Advanced Drug
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`Delivery Reviews, 59: 603–16 (2007).
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`3 A.T.M. Serajuddin & Pudipeddi, “Salt-Selection Strategies,” in HANDBOOK OF
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`PHARMACEUTICAL SALTS (P.H. Stahl & C.G. Wermuth, eds., 2002).
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`particular counter-ion has been reported in the literature.”); id. at 138 (“[A] more
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`predictive method for assessing the feasibility of salt formation would be necessary
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`to minimize trials and errors in a salt-selection program.”); EX2194 (Berge 1977)4
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`at 1 (“Unfortunately, there is no reliable way of predicting the influence of a
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`particular salt species on the behavior of the parent compound. Furthermore, even
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`after many salts of the same basic agent have been prepared, no efficient screening
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`technique exist to facilitate selection of the salt most likely to exhibit the desired
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`pharmacokinetic, solubility, and formulation profiles.”); EX2195 (Davies 2001)5 at
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`322 (“There is, as yet, no reliable way of predicting exactly what effect changing
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`the salt form of an active drug will have on its biological activity, and the
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`supposition that the same salt form of two related parent compounds will behave in
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`exactly the same way may not be correct.”); EX2196 (Verbeeck 2006)6 at 2
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`4 S.M. Berge, L.D. Bighley, & D.C. Monkhouse, “Pharmaceutical Salts,” Journal
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`of Pharmaceutical Sciences, 66:1–19 (1977).
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`5 G. Davies, “Changing the Salt, Changing the Drug,” Pharmaceutical Journal,
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`266(7138):322–323 (2001).
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`6 R.K. Verbeeck, I. Kanfer, & R.B. Walker, “Generic substitution: The use of
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`medicinal products containing different salts and implications for safety and
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`efficacy,” European Journal of Pharmaceutical Sciences, 28:1–6 (2006).
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`16
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`(“Unfortunately, there is no reliable way of predicting the influence of a particular
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`salt species on the behavior of the parent compound in dosage forms.”); EX2197
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`(Gould 1986)7 at 201 (“The importance of choosing the ‘correct’ salt form of a
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`drug is well outlined in a published review (Berge 1977) but, although salt form
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`can have a dramatic influence on the overall properties of a drug, the selection of
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`the salt form that exhibits the desired combination of properties remains a difficult
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`semi-empirical choice . . .Thus, a clear compromise of properties for the salt form
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`is required, but the difficulty remains of assessing which salt forms are best to
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`screen for a particular drug candidate.”).
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`32. Based on his deposition testimony, Dr. Chorghade appears to agree
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`that salt formation is unpredictable. The formation of a particular salt requires that
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`a chemical reaction take place, EX2051 (Chorghade Tr.) at 90:18–22, and Dr.
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`Chorghade agreed that an acid-base chemical reaction will not always form a salt.
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`See id. at 105:4–9 (“Q: [I]s it true that some combinations will not work to form a
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`salt?” “A: It is possible. . . . it all depends on the amine.”). He further agreed that
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`one needs to actually run the reaction to determine whether a salt would form. See
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`id. at 10:11–13 (agreeing that “[Y]ou need to run that salt screen to know whether
`
`
`7 P.L. Gould, “Salt selection for basic drugs,” International Journal of
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`Pharmaceutics, 33:201–17 (1986).
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`17
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`the particular combination will form a salt.”). In discussing salt formation, Dr.
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`Chorghade explained “at the time of the patent or at the time of the discovery
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`work, it was a trial and error process, and there was no . . . predictive algorithms
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`built into the system.” See id. at 116:22–117:3; see also id. at 116:17–18 (“At the
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`time of the priority date, it was mainly trial and error, where people would do the
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`experiments.”).
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`33. Beyond the threshold issue of whether a salt will form between a basic
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`compound and acid, there is the issue that acids and bases can often form salts with
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`a varying stoichiometry, i.e., the ratio of acid to base in the salt form. This is
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`because the base may be protonated (that is, it may accept a proton from an acid) at
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`more than one site, and the acid may have more than one proton capable of
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`engaging in an acid-base reaction (that is, it may be polyprotic).
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`34. For example, ammonia (NH3) is a free base and phosphoric acid
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`(H3PO4) is a polyprotic acid. Phosphoric acid is more specifically triprotic,
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`meaning that it has three protons that can be donated to a base to form salts. In
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`reactions with phosphoric acid, the resulting salt can be a dihydrogenphosphate salt
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`(phosphoric acid donates one proton and becomes H2PO4
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`-), a
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`monohydrogenphosphate salt (phosphoric acid donates two protons and becomes
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`HPO4
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`-2), or a phosphate salt (phosphoric acid donates three protons and becomes
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`PO4
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`-3). When the ammonia free base is reacted with phosphoric acid, three
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`18
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`different salts can form: (NH4)H2PO4 (ammonium dihydrogenphosphate–1
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`molecule of ammonium to 1 molecule of phosphoric acid, a 1:1 salt), (NH4)2HPO4
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`(diammonium phosphate–2 molecules of ammonium to 1 molecule of phosphoric
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`acid, a 2:1 salt) and (NH4)3PO4 (triammonium phosphate–3 molecules of
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`ammonium to 1 molecule of phosphoric acid, a 3:1 salt). See EX2198
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`(Ammonium Phosphate Monobasic)8; EX2199 (Ammonium Phosphate Dibasic)9;
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`EX2200 (Triammonium Phosphate Trihydrate).10 Different salt forms of the same
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`acid and base that have different stoichiometries can have different physiochemical
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`properties.
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`8 Ammonium phosphate monobasic, Sigma Aldrich Catalog, available at
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`https://www.sigmaaldrich.com/catalog/substance/ammoniumphosphatemonobasic1
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`1503772276111?lang=en®ion=US.
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`9 Ammonium phosphate dibasic, Sigma Aldrich Catalog, available at
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`https://www.sigmaaldrich.com/catalog/substance/ammoniumphosphatedibasic1320
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`6778328011?lang=en®ion=US.
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`10 Triammonium phosphate trihydrate, Combi-Blocks, available at
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`https://www.combi-blocks.com/cgi-bin/find.cgi.
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`19
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`B. Merck’s Discovery of the 1:1 DHP Salt of Sitagliptin
`I understand that Merck initially developed the free base form of 4-
`35.
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`oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-
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`(2,4,5-trifluorophenyl)butan-2-amine, the R-configuration of which is known as
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`sitagliptin.11
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`36. Merck scientists discovered, however, that the free base form of
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`sitagliptin suffered from stability problems that the POSA would not have
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`foreseen. Namely, the free base degraded in solution and in the solid state because
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`of deamination and hydrolysis of the amide bond. EX2140 (Schultz Decl.) at 13-
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`19. Furthermore, the free base suffered from nee