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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.
`
`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.
`
`
`TABLE OF CONTENTS
`
`
`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.
`
`2.
`
`2.
`
`
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`2
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`DECLARATION OF ADAM J. MATZGER, PH.D.
`
`
`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
`
`
`
`
`
`2.
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`3.
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`4.
`5.
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`6.
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`3
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`
`
`I.
`
`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.
`
`claims 1–3, 17, 19, and 21–23 of U.S. Patent No. 7,326,708 (“the ’708 patent”),
`
`including to address certain opinions provided by Dr. Mukund Chorghade. See
`
`EX1002 (“Chorghade Dec.”).
`
`2.
`
`The ’708 patent is titled “Phosphoric Acid Salt of a Dipeptidyl
`
`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.
`
`Wenslow, Jr. as inventors.
`
`3.
`
`The ’708 patent was filed on June 23, 2004 and claims priority on its
`
`face to a provisional application filed on June 24, 2003. I have reviewed the
`
`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
`
`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
`
`19. The conclusions I reach would not change if the priority date was June 24,
`
`2003, except insofar as I must account for certain additional references as prior art.
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`
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`4
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`4.
`
`DECLARATION OF ADAM J. MATZGER, PH.D.
`
`
`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.
`
`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
`
`Science and Engineering in the College of Engineering, both at the University of
`
`Michigan. I have held the title of Professor since 2009. A true and correct copy of
`
`my curriculum vitae is EX2104.
`
`6.
`
`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.
`
`7.
`
`I obtained my Ph.D. in Chemistry from the University of California at
`
`Berkeley in 1997. My doctoral thesis encompassed synthetic, theoretical and
`
`
`
`
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`5
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`
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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
`
`microscopy. I obtained my B.A. in Chemistry from Oberlin College in 1992.
`
`8.
`
`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
`
`of crystallization with a strong emphasis on multicomponent crystallization. I was
`
`at Caltech until I joined the University of Michigan in 2000 as Assistant Professor
`
`of Chemistry and of Macromolecular Science and Engineering.
`
`9.
`
`I teach courses at the University of Michigan at the undergraduate
`
`level in the area of organic chemistry. At the graduate level, I teach classes about
`
`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.
`
`10.
`
`I have published over 200 papers in peer reviewed journals. The vast
`
`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.
`
`11. My current research interests focus on organic materials in the solid
`
`state ranging from crystalline polymorphs to porous materials. My work on crystal
`
`
`
`
`
`6
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`
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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.
`
`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.
`
`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.
`
`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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`
`
`
`
`7
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`
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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.
`
`16.
`
`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.
`
`I have been informed that the priority date of an invention depends on
`
`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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`
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`
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`8
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`B. Anticipation
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`DECLARATION OF ADAM J. MATZGER, PH.D.
`
`
`
`18.
`
`I have been informed that a patent claim is “anticipated,” and thus
`
`invalid, if a single prior art reference discloses every claim limitation as arranged
`
`in the claim. One exception to the requirement that the prior art reference must
`
`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.
`
`19.
`
`I have also been informed that a prior art reference may inherently
`
`anticipate a claimed invention without expressly disclosing a feature of the claimed
`
`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.
`
`I have also been informed that a prior art reference can inherently
`
`anticipate a claimed invention by disclosing a process that inevitably results in the
`
`claimed invention. I understand there is no inherent anticipation if practicing the
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`
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`
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`9
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`
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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
`
`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.
`
`C. Obviousness
`
`21.
`
`I understand that a patent claim would have been “obvious,” and thus
`
`invalid, 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 at the
`
`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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`10
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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.
`
`party challenging the patent must demonstrate that a skilled artisan would have
`
`been motivated to combine the teachings of the prior art to achieve the claimed
`
`invention. As such, the challenger must prove not only that the prior art taught or
`
`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
`
`way claimed by the patent at issue.
`
`23.
`
`I further understand that, in order to demonstrate that a chemical
`
`compound would have been obvious, the challenger must prove (1) that the skilled
`
`artisan would have selected the asserted prior art compounds as lead compounds,
`
`or starting points, for further development, and (2) that the skilled artisan would
`
`have been motivated to modify the lead compound to make the claimed
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`compound.1
`
`24.
`
`I also understand that references that “teach away” from the
`
`invention—in other words, references that would lead the POSA in a different
`
`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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`
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`11
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`
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`that the direction taken by the patentee was unsuitable—must be considered. In
`
`determining whether the invention would have been obvious, one must consider
`
`the prior art as a whole.
`
`25.
`
`I understand that, in addition to having a motivation to achieve the
`
`claimed invention, the POSA must have had a reasonable expectation of success. I
`
`understand that to have a reasonable expectation of success, one must be motivated
`
`to do more than merely vary all parameters or try each of numerous possible
`
`choices until one possibly arrived at a successful result, where the prior art gave
`
`either no indication of which parameters were critical or no direction as to which
`
`of many possible choices is likely to be successful.
`
`26.
`
`I understand that, in certain circumstances, a combination of elements
`
`may have been “obvious to try.” Accordingly, when there is a design need or
`
`market pressure to solve a problem and there are a finite number of identified,
`
`predictable solutions, the POSA has good reason to pursue the known options
`
`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
`
`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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`12
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`
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`D. Claim Construction
`
`27.
`
`I understand that the words of a claim are generally given their
`
`ordinary and customary meaning, which is the meaning that the term would have
`
`to the person of ordinary skill in question at the time of the invention. I understand
`
`the person of ordinary skill in the art is deemed to read the claim term not only in
`
`the context of the particular claim in which the disputed term appears, but also in
`
`the context of the entire patent. I also understand the transitional phrase
`
`“comprising” as used in the ’708 patent to be open ended—that it can include other
`
`components, elements, or steps not explicitly mentioned in the claim language.
`
`28. After reviewing the ’708 patent and its prosecution history, I do not
`
`think that any of the claims require construction. That is to say, I apply the
`
`meaning the meaning that the claim term would have to a POSA in question at the
`
`time of the invention of the ’708 patent.
`
`IV.
`
` BACKGROUND
`Pharmaceutical Salt Formation Is An Unpredictable Process.
`A.
`
`29.
`
`In the pharmaceutical sciences, discovering a compound or class of
`
`compounds with desired biological activity is often only the first step in
`
`developing a commercializable drug product. In order to formulate a
`
`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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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`but are not limited to, stability, hygroscopicity, aqueous solubility, penetration
`
`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
`
`manufacturing processes. Salt formation provides a way to potentially modify
`
`some of the aforementioned physiochemical qualities. Salt formation in the
`
`pharmaceutical context, which involves a proton transfer accompanied by the
`
`appearance of a solid form, itself is unpredictable as to any particular salt. See
`
`infra at ¶31. And although dissolution and solubility can often be improved if a
`
`salt is formed, other critical quality attributes such as stability or hygroscopicity
`
`may be jeopardized, making salt selection a multi-dimensional approach. See
`
`EX1006 (Bastin) at 430 (“Also, it is occasionally found that the overall properties
`
`of the free acid/base are much better than any of the salts. This occurs more
`
`frequently where the candidate has a low pKa value and the resulting salts are less
`
`stable than required or when the salts are particularly hygroscopic or when they
`
`exhibit complex polymorphism/pseudopolymorphism (hydration or solvation).”),
`
`435.
`
`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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`
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`
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`
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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.
`
`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
`
`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,
`
`among others. Thus, whether any particular salt would form could not have been
`
`predicted in advance. See EX2193 (Serajuddin 2007)2 at 604 (“For most practical
`
`purposes, identification and selection of salt forms of NCEs still remain a trial and
`
`error process.”); EX2042 (Serajuddin 2002)3 at 137 (“No predictive procedure to
`
`determine whether a particular acidic or basic drug would form a salt with a
`
`
`2 A.T.M. Serajuddin, “Salt formation to improve drug solubility,” Advanced Drug
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`Delivery Reviews, 59: 603–16 (2007).
`
`3 A.T.M. Serajuddin & Pudipeddi, “Salt-Selection Strategies,” in HANDBOOK OF
`
`PHARMACEUTICAL SALTS (P.H. Stahl & C.G. Wermuth, eds., 2002).
`
`
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`
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`DECLARATION OF ADAM J. MATZGER, PH.D.
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`
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`particular counter-ion has been reported in the literature.”); id. at 138 (“[A] more
`
`predictive method for assessing the feasibility of salt formation would be necessary
`
`to minimize trials and errors in a salt-selection program.”); EX2194 (Berge 1977)4
`
`at 1 (“Unfortunately, there is no reliable way of predicting the influence of a
`
`particular salt species on the behavior of the parent compound. Furthermore, even
`
`after many salts of the same basic agent have been prepared, no efficient screening
`
`technique exist to facilitate selection of the salt most likely to exhibit the desired
`
`pharmacokinetic, solubility, and formulation profiles.”); EX2195 (Davies 2001)5 at
`
`322 (“There is, as yet, no reliable way of predicting exactly what effect changing
`
`the salt form of an active drug will have on its biological activity, and the
`
`supposition that the same salt form of two related parent compounds will behave in
`
`exactly the same way may not be correct.”); EX2196 (Verbeeck 2006)6 at 2
`
`
`4 S.M. Berge, L.D. Bighley, & D.C. Monkhouse, “Pharmaceutical Salts,” Journal
`
`of Pharmaceutical Sciences, 66:1–19 (1977).
`
`5 G. Davies, “Changing the Salt, Changing the Drug,” Pharmaceutical Journal,
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`266(7138):322–323 (2001).
`
`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
`
`(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
`
`can have a dramatic influence on the overall properties of a drug, the selection of
`
`the salt form that exhibits the desired combination of properties remains a difficult
`
`semi-empirical choice . . .Thus, a clear compromise of properties for the salt form
`
`is required, but the difficulty remains of assessing which salt forms are best to
`
`screen for a particular drug candidate.”).
`
`32. Based on his deposition testimony, Dr. Chorghade appears to agree
`
`that salt formation is unpredictable. The formation of a particular salt requires that
`
`a chemical reaction take place, EX2051 (Chorghade Tr.) at 90:18–22, and Dr.
`
`Chorghade agreed that an acid-base chemical reaction will not always form a salt.
`
`See id. at 105:4–9 (“Q: [I]s it true that some combinations will not work to form a
`
`salt?” “A: It is possible. . . . it all depends on the amine.”). He further agreed that
`
`one needs to actually run the reaction to determine whether a salt would form. See
`
`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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`
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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
`
`work, it was a trial and error process, and there was no . . . predictive algorithms
`
`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
`
`experiments.”).
`
`33. Beyond the threshold issue of whether a salt will form between a basic
`
`compound and acid, there is the issue that acids and bases can often form salts with
`
`a varying stoichiometry, i.e., the ratio of acid to base in the salt form. This is
`
`because the base may be protonated (that is, it may accept a proton from an acid) at
`
`more than one site, and the acid may have more than one proton capable of
`
`engaging in an acid-base reaction (that is, it may be polyprotic).
`
`34. For example, ammonia (NH3) is a free base and phosphoric acid
`
`(H3PO4) is a polyprotic acid. Phosphoric acid is more specifically triprotic,
`
`meaning that it has three protons that can be donated to a base to form salts. In
`
`reactions with phosphoric acid, the resulting salt can be a dihydrogenphosphate salt
`
`(phosphoric acid donates one proton and becomes H2PO4
`
`-), a
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`monohydrogenphosphate salt (phosphoric acid donates two protons and becomes
`
`HPO4
`
`-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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`
`
`
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`18
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`different salts can form: (NH4)H2PO4 (ammonium dihydrogenphosphate–1
`
`molecule of ammonium to 1 molecule of phosphoric acid, a 1:1 salt), (NH4)2HPO4
`
`(diammonium phosphate–2 molecules of ammonium to 1 molecule of phosphoric
`
`acid, a 2:1 salt) and (NH4)3PO4 (triammonium phosphate–3 molecules of
`
`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;
`
`EX2200 (Triammonium Phosphate Trihydrate).10 Different salt forms of the same
`
`acid and base that have different stoichiometries can have different physiochemical
`
`properties.
`
`
`8 Ammonium phosphate monobasic, Sigma Aldrich Catalog, available at
`
`https://www.sigmaaldrich.com/catalog/substance/ammoniumphosphatemonobasic1
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`1503772276111?lang=en&region=US.
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`9 Ammonium phosphate dibasic, Sigma Aldrich Catalog, available at
`
`https://www.sigmaaldrich.com/catalog/substance/ammoniumphosphatedibasic1320
`
`6778328011?lang=en&region=US.
`
`10 Triammonium phosphate trihydrate, Combi-Blocks, available at
`
`https://www.combi-blocks.com/cgi-bin/find.cgi.
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`
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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
`
`35.
`
`I understand that Merck initially developed the free base form of 4-
`
`oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-
`
`(2,4,5-trifluorophenyl)butan-2-amine, the R-configuration of which is known as
`
`sitagliptin.11
`
`36. Merck scientists discovered, however, that the free base form of
`
`sitagliptin suffered from stability problems that the POSA would not have
`
`foreseen. Namely, the free base degraded in solution and in the solid state because
`
`of deamination and hydrolysis of the amide bond. EX2140 (Schultz Decl.) at 13-
`
`19. Furthermore, the free base suffered from needle-like morphology that made it
`
`
`11 Whi