`
`On Behalf Of:
`
`Novartis AG and LTS Lohmann Therapie-Systeme AG
`
`By:
`
`Raymond R. Mandra
`ExelonPatchIPR@fchs.com
`(212) 218-2100
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`NOVEN PHARMACEUTICALS INC.,
`Petitioner
`
`v.
`
`NOVARTIS AG AND LTS LOHMANN THERAPIE-SYSTEME AG,
`Patent Owners
`
`
`
`Inter Partes Review No. 2014-00550
`
`
`U.S. Patent 6,335,031
`
`
`DECLARATION OF PROFESSOR ALEXANDER M. KLIBANOV
`
`
`
`
`
`
`
`
`
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`
`Contents
`
`TABLE OF CONTENTS
`
`
`I.
`
`II.
`
`QUALIFICATIONS ............................................................................................................1
`
`MATERIALS CONSIDERED ............................................................................................4
`
`III.
`
`SUMMARY OF OPINIONS ...............................................................................................4
`
`IV.
`
`LEGAL STANDARDS .......................................................................................................6
`
`V.
`
`THE RELEVANT DATE OF INVENTION, PERSON OF ORDINARY
`SKILL IN THE ART, AND CLAIM CONSTRUCTION ...................................................8
`
`A.
`
`B.
`
`C.
`
`Date Of Invention ....................................................................................................8
`
`A Person Of Ordinary Skill In The Art ....................................................................8
`
`Claim Construction ................................................................................................10
`
`VI.
`
`THE STATE OF THE ART ..............................................................................................12
`
`A.
`
`B.
`
`Dr. Kydonieus’s Opinions On The State Of The Art.............................................12
`
`The True State Of The Art .....................................................................................16
`
`1.
`
`2.
`
`3.
`
`Drug Formulation Work Is Complex And Antioxidants
`Are Not Added To Drug Formulations Unless Necessary.........................16
`
`The Art As A Whole Taught That Rivastigmine Was Stable ....................22
`
`Oxidative Degradation Is Formulation Specific ........................................27
`
`VII. THE OXIDATIVE DEGRADATION OF RIVASTIGMINE WAS
`UNKNOWN IN THE ART ...............................................................................................28
`
`A.
`
`The Rivastigmine/RA7 Art Did Not Teach Or Suggest That
`Rivastigmine Had An Oxidative Degradation Problem .........................................29
`
`1.
`
`2.
`
`3.
`
`GB Patent Application 2 203 040 A (“Enz”) .............................................29
`
`U.S. Patent No. 4,948,807 (“Rosin”) .........................................................33
`
`Elmalem .....................................................................................................41
`
`B.
`
`The Petitioner’s Structural Theories Are Contradicted By
`Pharmaceutical Realities ........................................................................................71
`
`
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`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`Oxidation Is A Complex And Poorly Understood
`Phenomenon ...............................................................................................72
`
`The Structure Of The Molecule As A Whole Influences
`Stability ......................................................................................................75
`
`Dextromethorphan Is Stable And Does Not Require An
`Antioxidant Under Pharmaceutically Relevant Conditions .......................84
`
`Nicotine Is Not Structurally Similar To Rivastigmine And
`Does Not Require An Antioxidant In A Transdermal
`Device ........................................................................................................86
`
`A POSA Would Not Draw Conclusions About The
`Stability Of All Amines In All Formulations Based On The
`Teaching Of Sasaki ....................................................................................91
`
`The Inventors Themselves Did Not Predict Stability
`Problems With Rivastigmine And Discovered A Problem
`Only After Testing .....................................................................................97
`
`C.
`
`Ebert And The Handbook Would Not Have Led A POSA To
`Include An Antioxidant In Formulations Containing Rivastigmine ....................100
`
`1.
`
`2.
`
`PCT Publication WO 95/24172 (“Ebert”) ...............................................100
`
`Handbook Of Pharmaceutical Excipients (“Handbook”) ........................106
`
`VIII. NO CHALLENGED CLAIM OF THE ’031 PATENT IS OBVIOUS
`OVER ANY COMBINATION OF PRIOR ART CITED BY THE
`PETITIONER IN GROUNDS 3-5...................................................................................108
`
`
`
`ii
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`I, Alexander M. Klibanov, Ph.D., declare as follows:
`
`I.
`
`QUALIFICATIONS
`
`1.
`
`I am a Novartis Endowed Chair Professor of Chemistry and
`
`Bioengineering at the Massachusetts Institute of Technology (“M.I.T.”), where I
`
`have been teaching and conducting research for over 35 years. In 2012-2013, I
`
`held the Roger and Georges Firmenich Endowed Chair Professorship in Chemistry
`
`and Bioengineering, and in 2007-2012, a Novartis Endowed Chair Professorship of
`
`Chemistry and Bioengineering at M.I.T.1 Prior to that, I was a Professor of
`
`Chemistry and a Professor of Bioengineering at M.I.T., positions I held from 1988
`
`and 2000, respectively. From 1979 to 1988, I was an Assistant Professor, then
`
`Associate Professor, and thereafter a Full Professor of Applied Biochemistry in the
`
`Department of Applied Biological Sciences (formerly the Department of Nutrition
`
`and Food Science) at M.I.T.
`
`2.
`
`I obtained my M.S. in Chemistry from Moscow University in Russia
`
`in 1971 and Ph.D. in Chemical Enzymology from the same University in 1974.
`
`Thereafter, I was a Research Chemist at Moscow University’s Department of
`
`Chemistry for three years. From 1977 to 1979, following my immigration to the
`
`
`1 Novartis does not decide who receives this position, and this position in no way
`
`affects the content of this declaration.
`
`
`
`1
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`United States, I was a Post-Doctoral Associate at the Department of Chemistry,
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`University of California in San Diego.
`
`3.
`
`Over the last 45 years as a practicing chemist, I have extensively
`
`researched, published, taught, and lectured in many areas of biological, medicinal,
`
`bioorganic, formulation, and polymer chemistry, including oxidations, oxidative
`
`degradation, and antioxidants.
`
`4.
`
`I have earned numerous prestigious professional awards and honors.
`
`For example, I was elected to the U.S. National Academy of Sciences (considered
`
`among the highest honors that can be given to an American scientist) and also to
`
`the U.S. National Academy of Engineering (considered among the highest honors
`
`that can be given to an American engineer or applied scientist). I am also a
`
`Founding Fellow of the American Institute for Medical and Biological Engineering
`
`and a Corresponding Fellow of the Royal Society of Edinburgh (Scotland’s
`
`National Academy of Science and Letters). In addition, I have received the Arthur
`
`C. Cope Scholar Award, the Marvin J. Johnson Award, the Ipatieff Prize, and the
`
`Leo Friend Award, all from the American Chemical Society, as well as the
`
`International Enzyme Engineering Prize.
`
`5.
`
`I currently serve on the Editorial Boards of 12 scientific journals,
`
`including “Open Journal of Pharmacology,” “Applied Biochemistry and
`
`Biotechnology,” ”Nanocarriers,” “Open Access Academic Books in Chemistry,”
`
`
`
`2
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`“Biotechnology and Bioengineering,” “Journal of Biological Chemistry and
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`Molecular Pharmacology,” and “Recent Patents in Biotechnology.”
`
`6.
`
`I have published over 300 scientific papers in various areas of
`
`chemistry and am also a named inventor of 18 issued United States patents and of
`
`many foreign ones. I have given 370 invited lectures at professional conferences,
`
`universities, and corporations all over the world, many dealing with formulation,
`
`stability, delivery, and biological evaluation of pharmaceutically active
`
`compounds.
`
`7.
`
`In addition to my research and teaching activities at M.I.T., I have
`
`consulted widely for pharmaceutical, medical device, chemical, and biotechnology
`
`companies. They have included both innovator companies and generic
`
`pharmaceutical companies.
`
`8.
`
`I have also founded six pharmaceutical companies and have been on
`
`the scientific advisory boards and/or boards of directors of those companies and of
`
`many others. A number of these consulting, advisory, and directorship activities
`
`have dealt specifically with the formulation, stability (including against oxidative
`
`degradation), delivery, administration (including transdermal), and biological
`
`evaluation of pharmaceutically active compounds.
`
`9. My curriculum vitae, which lists my professional experience and
`
`qualifications in greater detail, is attached hereto as Exhibit 2013.
`
`
`
`3
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`10.
`
`I am being compensated for my time spent working on this matter at
`
`my current customary consulting rate of $950 per hour. My compensation does
`
`not affect, or depend on, the content of this declaration.
`
`II. MATERIALS CONSIDERED
`
`11.
`
`In preparing this declaration, I have reviewed U.S. Patent 6,335,031
`
`(“’031 Patent”) (Ex. 1001), the Patent and Trial Appeal Board’s October 14, 2014,
`
`Institution Decision (Paper 10), and the Petitioner’s April 2, 2014, petition (Paper
`
`1) and all exhibits thereto, including the prior art references cited therein (Exs.
`
`1002-1009 and 1012-1021, 1024), the accompanying declaration of Dr. Agis
`
`Kydonieus (Ex. 1010), and the accompanying declaration of Professor Christian
`
`Schöneich (Ex. 1011). I have also considered the exhibits cited herein, including
`
`the transcript of the December 1-3, 2014, trial in the matter of Novartis Pharm.
`
`Corp. et al. v. Noven, Inc., 13-cv-527-RGA (D. Del.) (Exs. 1025-1027) and the
`
`transcript of the January 13, 2015 deposition of Dr. Agis Kydonieus (Ex. 1029).
`
`III. SUMMARY OF OPINIONS
`
`12.
`
`I understand that in this inter partes review proceeding, the Petitioner
`
`is challenging independent claims 1 and 15 and dependent claims 2-3, 7, 16, and
`
`18 of the ’031 Patent.
`
`13.
`
`I was asked to consider whether the challenged claims would have
`
`been obvious to a person of ordinary skill in the art (“POSA”) as of the date of the
`
`
`
`4
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`invention, which is January 12, 1998. Based on my analysis of the prior art as a
`
`whole, as well as the specific references relied upon by the Petitioner, it is my
`
`opinion that the challenged claims would not have been obvious to a POSA as of
`
`January 12, 1998.
`
`14. First, as of 1998, the art taught that the inclusion of excipients,
`
`including antioxidants, in pharmaceutical formulations should be avoided unless
`
`they are necessary. A POSA thus would not add an antioxidant unless it was
`
`required.
`
`15. Second, as of 1998, whether a compound such as rivastigmine would
`
`have undergone oxidative degradation under pharmaceutically relevant conditions
`
`was a question whose answer would not have been reasonably predicted based
`
`upon the structure of the compound. Rather, testing would have been required to
`
`answer that question. It is undisputed that, as of 1998, there were no test data
`
`concerning the oxidative stability of rivastigmine in the art. And there was no
`
`teaching or suggestion in the art that rivastigmine underwent oxidative degradation
`
`under pharmaceutically relevant conditions. Without knowledge that rivastigmine
`
`undergoes oxidative degradation under pharmaceutically relevant conditions, a
`
`POSA would have had no motivation to combine rivastigmine with an antioxidant.
`
`Moreover, a POSA would understand that just because a compound is theoretically
`
`
`
`5
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`“susceptible” to degradation does not mean that such degradation, in fact, will
`
`occur under pharmaceutically relevant conditions.
`
`16. Third, the transdermal device taught by Example 2 in Enz is the
`
`starting point for each of the Petitioner’s obviousness grounds. Even if there were
`
`a teaching or suggestion that rivastigmine would undergo oxidative degradation in
`
`an injectable composition, such as those disclosed in Rosin and Elmalem, that
`
`teaching or suggestion would not have led a POSA to believe that rivastigmine
`
`would undergo oxidative degradation in a transdermal device, such as that
`
`disclosed in Example 2 of Enz. Drs. Kydonieus and Schöneich acknowledge that a
`
`POSA would understand that oxidation is formulation specific. Thus, oxidative
`
`degradation in one pharmaceutical formulation or dosage form may not be a
`
`problem in a different pharmaceutical formulation or dosage form. Accordingly—
`
`even accepting the Petitioner’s reading of Rosin and Elmalem—a POSA would not
`
`have been motivated to modify or improve the transdermal device in Example 2 of
`
`Enz to include an antioxidant.
`
`IV. LEGAL STANDARDS
`
`17. The understanding of obviousness provided in ¶¶ 11-12 of Dr.
`
`Kydonieus’s April 2, 2014, declaration is generally consistent with mine.
`
`However, my understanding of obviousness, obtained from the Patent Owners’
`
`counsel, is further supplemented by the following concepts.
`
`
`
`6
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`18.
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`It is necessary in an obviousness analysis to consider the scope and
`
`content of the prior art as a whole. By contrast, it is improper to rely upon
`
`hindsight knowledge of the patent claims in question to pick and choose isolated
`
`elements from the prior art and to combine them to yield the claimed invention. It
`
`is likewise improper to pick and choose from any reference only so much of it as
`
`will support a given position, to the exclusion of other parts of the reference that
`
`are necessary to give a full appreciation of what the reference fairly teaches or
`
`suggests to a POSA.
`
`19. The length of time that the prior art was available to the public may be
`
`considered as part of the obviousness analysis. For example, the fact that a prior
`
`art reference may have been available for several years, but no one sought to
`
`combine it with other prior art references may show that an alleged motivation to
`
`combine the references is an improper application of hindsight.
`
`20. An invention that combines elements disclosed in the prior art is non-
`
`obvious if it provides a solution to a problem that was not previously known to a
`
`POSA or suggested by the prior art. Stated another way, solving a problem not
`
`previously known or suggested in the art constitutes a patentable and non-obvious
`
`invention because there would have been no motivation for a POSA to combine the
`
`prior art absent knowledge of the problem to be solved by such combination.
`
`
`
`7
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`21. An invention that may be characterized as the result of “routine”
`
`experimentation nevertheless is non-obvious if the results of such experimentation
`
`were not predictable.
`
`22. A lack of objective indicia of non-obviousness (also known as
`
`secondary considerations of non-obviousness) is not evidence of obviousness.
`
`V. THE RELEVANT DATE OF INVENTION,
`PERSON OF ORDINARY SKILL IN THE ART,
`AND CLAIM CONSTRUCTION
`
`A. Date Of Invention
`
`23. The ’031 Patent claims priority to GB 9800526 filed on January 12,
`
`1998. The ’031 Patent filed on April 14, 1999, issued from an application that is a
`
`continuation-in-part of PCT application PCT/EP99/00078 filed on January 8, 1999.
`
`I understand that the Patent Owners are relying on the earliest filing date of the
`
`priority application, namely January 12, 1998, to establish the priority date, and
`
`hence the invention date, for the challenged claims. Having considered the
`
`challenged claims and the priority documents, I agree that the claims are entitled to
`
`a January 12, 1998, date of invention.
`
`B. A Person Of Ordinary Skill In The Art
`
`24. The level of education and skill of a POSA as of the relevant date
`
`would have been a Ph.D. in chemistry, pharmacy, or a related discipline, plus at
`
`least two years of practical experience; or a master’s degree in chemistry,
`
`pharmacy, or a related field, plus at least four years of practical experience; or a
`
`
`
`8
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`bachelor’s degree in chemistry, pharmacy, or a related field, plus at least six years
`
`of practical experience.
`
`25. Dr. Kydonieus sets forth a different definition of the POSA at ¶ 9 of
`
`his declaration: he opines that “the person of ordinary skill would have knowledge
`
`of organic chemistry, or would collaborate with a person having knowledge of
`
`organic chemistry, and would be able to make predictions about the physical
`
`properties of a compound based upon its chemical structure.” I disagree that a
`
`POSA would be able to make predictions about the physical or chemical properties
`
`of a compound based upon its chemical structure. Chemistry and pharmaceutical
`
`formulation are experimental sciences, and testing is required to determine the
`
`physical and chemical properties of a compound. Indeed, Dr. Kydonieus
`
`acknowledges that testing “accompanies the development of any pharmaceutical
`
`formulation, including testing for efficacy and stability.” (Id.) Because Dr.
`
`Kydonieus’s definition of the POSA is incorrect, his conclusions about what the art
`
`would have taught or suggested to the POSA are also incorrect.
`
`26. Dr. Kydonieus also opines at ¶ 9 that a POSA or team of POSAs
`
`would be “familiar with the testing that accompanies the development of any
`
`pharmaceutical formulation, including testing for efficacy and stability.” To the
`
`extent that he suggests by this that there is a set sequence of tests that a POSA must
`
`undertake during the development of a pharmaceutical formulation, I disagree.
`
`
`
`9
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`Pharmaceutical formulation development is complex and unpredictable, decisions
`
`made during such development are data-driven, and the testing that accompanies
`
`such development is done on a case-by-case basis, in response to specific problems
`
`that arise. (See, e.g., European Agency for the Evaluation of Medicinal Products,
`
`Note for Guidance on Stability Testing: Stability Testing of New Drug Substances
`
`and Product (CPMP/ICH/380/95) at 1 (Ex. 1014) (“EMEA Stability Guidance”)
`
`(providing “a general indication on the requirements for stability testing, but
`
`leav[ing] sufficient flexibility to encompass the variety of different practical
`
`situations required for specific scientific situations and characteristics of the
`
`materials being evaluated”).)
`
`C. Claim Construction
`
`27.
`
`In my opinion, an antioxidant is an agent that reduces oxidative
`
`degradation. I, therefore, disagree with Dr. Kydonieus’s opinion at ¶ 15 that the
`
`claim term “antioxidant” should be construed as “a compound which reduces or
`
`prevents the oxidative decomposition of other compounds.” While “reduces” is
`
`supported by the intrinsic evidence, “prevents” is not. (’031 Patent, col. 1, ll. 37-
`
`39 (“The pharmaceutical compositions of the invention show a reduction in
`
`degradation by-products in stress stability tests.”); see also col. 4, ll. 20-30 and col.
`
`7, ll. 19-54 (showing a reduction in degradation products in Examples containing
`
`an antioxidant).) As Dr. Kydonieus acknowledges, a POSA would understand
`
`
`
`10
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`from the specification of the ’031 Patent that the prevention of oxidative
`
`degradation is not required. (Ex. 1029, Kydonieus Tr.2 95:23-96:15.) The ’031
`
`Patent states that an antioxidant of the claimed invention may achieve an “effective
`
`stabilizing effect” even when degradation still occurs. (’031 Patent, col. 4, ll. 10-
`
`31.)
`
`28. Although neither Dr. Kydonieus’s nor Dr. Schöneich’s declaration
`
`addresses the claim term “comprising,” the petition at p. 9 asserts that
`
`“comprising” should be construed to “embrace compositions containing both
`
`rivastigmine and its enantiomer, including compositions containing racemic RA7.”
`
`I disagree that a POSA would read “comprising” that way. As discussed in ¶ 30
`
`below, a racemate and its constituent enantiomers are distinct compounds. If a
`
`patent claim—such as the challenged claims—recites a composition “comprising”
`
`a specific enantiomer, such as an “(S)” enantiomer, the claim cannot be read to
`
`include an equal or greater amount of the opposite enantiomer, and hence the
`
`racemic compound, as this would read the express (S)-enantiomer element out of
`
`the claim.
`
`
`2 “Kydonieus Tr.” refers to the transcript of the January 13, 2015, deposition of Dr.
`
`Agis Kydonieus.
`
`
`
`11
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`VI. THE STATE OF THE ART
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`A. Dr. Kydonieus’s Opinions On The State Of The Art
`
`29. Dr. Kydonieus in Section VI of his declaration (¶¶ 16-25) opines
`
`regarding “background” and the “state of the art.” I believe that his opinions
`
`inaccurately represent the state of the art regarding pharmaceutical formulations
`
`and, specifically, rivastigmine pharmaceutical formulations.
`
`30. A “racemic compound” (or “racemate”) and its constituent
`
`enantiomers are different compounds with distinct physical, chemical, and
`
`pharmacological properties. For example, a racemic compound and a constituent
`
`individual enantiomer typically have distinct melting points, solubilities, and
`
`reactivities with biological receptors. Consequently, a racemic compound typically
`
`differs from its constituent individual enantiomers in terms of pharmaceutical
`
`activity and toxicity.
`
`31. Rivastigmine is the (S)-enantiomer of a racemic compound known as
`
`RA7. For this reason, Dr. Kydonieus’s references to “racemic rivastigmine” in his
`
`declaration (e.g., at ¶¶ 28 and 59) are scientifically inaccurate. Being an
`
`enantiomer itself, rivastigmine has no constituent enantiomers and thus is not a
`
`racemic compound.
`
`32. Dr. Kydonieus states at ¶ 31of his declaration that he has reviewed
`
`and agrees with Dr. Schöneich’s declaration, which purportedly discusses “the
`
`
`
`12
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`general chemistry principles that would have led one of ordinary skill in the art to
`
`reasonably expect that rivastigmine would be susceptible to oxidative
`
`degradation.” The opinions contained in the Schöneich declaration concerning the
`
`supposed predictability of rivastigmine’s susceptibility to oxidative degradation
`
`based on its chemical structure, however, were not “background” or “state of the
`
`art” as of January 12, 1998. At that time, no art taught or suggested that
`
`rivastigmine underwent oxidative degradation under pharmaceutically relevant
`
`conditions. Moreover, as of 1998, the mechanisms of oxidation were known to be
`
`complex and not well understood, and a POSA would have recognized that the
`
`structure of the molecule as a whole influences its stability. (See Section VII.B.
`
`below.)
`
`33. Dr. Kydonieus does not mention the many different types of chemical
`
`and physical degradation that an active pharmaceutical ingredient (“API”)
`
`potentially may undergo in a pharmaceutical formulation. Chemical mechanisms
`
`include solvolysis (degradation caused by reaction with a solvent, e.g., hydrolysis,
`
`which is caused by a reaction with water); photolysis (degradation caused by
`
`light); hydration (degradation caused by the absorption of water); dehydration
`
`(degradation caused by the elimination of water); racemization (conversion of an
`
`individual enantiomer into a racemate); oxidation (degradation caused by
`
`molecular oxygen or free radical species); isomerization (shift in position of a
`
`
`
`13
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`functional group within a molecule); decarboxylation (degradation caused by the
`
`loss of a carboxyl group released in the form of carbon dioxide); and pyrolysis
`
`(thermal degradation). (Modern Pharmaceutics, 181-185 (Gilbert S. Banker and
`
`Christopher T. Rhodes, eds., 3d ed., 1996) (“Modern Pharmaceutics”) (Ex. 2014).)
`
`Physical mechanisms of degradation include the formation of polymorphs
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`(different crystal forms of the same compound); precipitation; changes to the
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`degree of crystallinity; vaporization (loss due to volatilization); aging; and
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`adsorption. (Id. at 185-188.) Whether and to what extent an API undergoes any of
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`these types of degradation under pharmaceutically relevant conditions in general
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`would not reasonably be predicted in advance.
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`34. Dr. Kydonieus opines at ¶ 22 that “[i]ssues of product stability can be
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`especially important in the development of transdermal devices. This is because,
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`for example, the preparation of transdermal patches often involves intermediate
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`steps where the drug substance is in solution, and because the drug substance may
`
`remain in solution in the finished drug product. This permits the drug to undergo
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`reactions more readily.” I disagree that the development of transdermal devices
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`raises “issues of product stability” that are of special import compared with the
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`development of other types of drug formulations. Moreover, Dr. Kydonieus
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`himself has said, and I agree, that transdermal devices do not typically include
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`aqueous solutions (Ex. 1025, Trial Tr.3 186:15-16) and that most transdermal
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`devices are matrix or drug-in-adhesive patches where organic solvents used during
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`conventional manufacture are dried off within a matter of hours. (Id.at 258:14-19,
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`298:13-19.) And the FDA guidelines as of 1998 stated that “all residual solvents
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`should be removed to the extent possible.” (Food and Drug Administration,
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`Guidance for Industry, Q3C Impurities: Residual Solvents, 2 (Dec. 1997) (Ex.
`
`2016).)
`
`35. Dr. Kydonieus opines at ¶ 23 that “[t]he formulator will seek to
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`understand the mechanisms of degradation of the drug substance, including
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`identifying functional groups and labile centers, and will consider how the drug
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`substance behaves under external factors such as pH, temperature, humidity, and
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`light.” And at ¶ 25, he states that “[t]he formulator will also consider drug-
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`excipient interactions, and will take all of this information into account in
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`designing a stable formulation.” To the extent that Dr. Kydonieus implies that a
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`POSA would have predicted that rivastigmine would undergo oxidative
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`degradation under pharmaceutically relevant conditions, or that the addition of an
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`antioxidant would successfully reduce such oxidative degradation, I disagree for
`
`
`3
` “Trial Tr.” refers to the transcript of the December 1-3, 2014, trial of Novartis
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`Pharm. Corp. et al. v. Noven Pharms., Inc., 13-cv-527-RGA (D. Del.).
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`the reasons set forth in Section VII.B. below. Tellingly, Dr. Kydonieus does not
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`offer the opinion that drug substance degradation or the design of a stable
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`formulation is predictable in the absence of testing or that the results of such
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`testing could be reasonably predicted in advance. To the contrary, he observes at ¶
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`25 that “regulatory guidelines in effect as of January 1998 recommended that
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`applicants perform stability tests on the drug substance and drug product. This
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`included stress testing on the drug substance to determine its intrinsic stability and
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`degradation pathways, as well as formal studies on the drug substance to show that
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`it will remain within specification during the re-test period if stored under the
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`recommended storage conditions.” (Citing Ex. 1014, EMEA Stability Guidance.)
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`Thus, as of 1998, it would have been clear to a POSA that testing was needed to
`
`determine whether and to what extent an API would undergo degradation under
`
`pharmaceutically relevant conditions, the type of degradation, and whether and to
`
`what extent an antioxidant would reduce that degradation, if oxidative in nature.
`
`B.
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`The True State Of The Art
`
`1.
`
`Drug Formulation Work Is Complex And Antioxidants
`Are Not Added To Drug Formulations Unless Necessary
`
`36. Drug formulation involves combining an API with other ingredients
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`(“inactive ingredients” or “excipients”) to arrive at a dosage form that can be
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`effectively administered to a patient.
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`37. For each API, there are many potential dosage forms. They include,
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`for example, powders, liquids, immediate-release tablets and capsules for oral or
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`buccal administration; extended-release tablets for oral administration;
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`suppositories for rectal, vaginal, or urethral administration; eyedrops; eardrops;
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`liquid preparations for intravenous infusions; liquid preparations for injections
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`(subcutaneous or intramuscular); lyophilized preparations for injection following
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`reconstitution; nebulized formulations for administration of drug to the lungs;
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`liquid preparations for intranasal administration; topical gels, ointments and
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`creams; and transdermal devices.
`
`38. For each API and dosage form, there is an enormous number of
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`potential excipients (and combinations thereof) with which the API can be
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`combined. However, not every excipient is compatible with a particular API or
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`with other particular inactive ingredients:
`
`Obvious sources of pharmaceutical instability include the
`
`incompatibility of various ingredients within a
`
`formulation. Numerous examples are described in other
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`sections of this book and the literature is replete with
`
`illustrations.
`
`(Remington’s Pharmaceutical Sciences, (Alfonso R. Gennaro, et al., eds., 18th ed.,
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`1990) at 1507 (“Remington’s”) (Ex. 2017).) In general, determining whether and
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`which excipients are compatible with a particular API cannot be reasonably
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`predicted.
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`39.
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`In view of the potential incompatibility that may be caused by the
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`presence of excipients in pharmaceutical formulations, a general principle of
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`pharmaceutical formulation, of which a POSA would have been aware as of 1998,
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`is not to add an excipient to a formulation unless that excipient is required. That
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`common-sense principle is reflected in, for example, U.S. Patent No. 5,508,038
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`(Ex. 2018, “’038 Patent”) which states, with respect to a transdermal delivery
`
`system, that “[i]t is preferable that extraneous components of the adhesives of this
`
`mixture be minimized or eliminated in order to minimize the potential for irritation
`
`or allergic reaction when the transdermal delivery system contacts the skin.” (Ex.
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`2018, ’038 Patent, col. 4, ll. 24-32.)
`
`40. With respect to antioxidants as excipients, the European Agency for
`
`the Evaluation of Medicinal Products (“EMEA”), the European equivalent of the
`
`FDA, issued guidelines in 1997 that urge against including antioxidants in any
`
`pharmaceutical formulation unless required. (EMEA, Committee for Proprietary
`
`Medicinal Products & Committee for Veterinary Medicinal Products, Note for
`
`Guidance on Inclusion of Antioxidants and Antimicrobial Preservative