`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`MYLAN INSTITUTIONAL INC.
`Petitioner,
`
`v.
`
`FRESENIUS KABI USA, LLC,
`Patent Owner.
`
`U.S. Patent No. 9,006,289 to Jiang et al.
`Issue Date: April 14, 2015
`Title: Levothyroxine Formulations
`Case: IPR2017-00645
`
`U.S. Patent No. 9,238,238 to Jiang et al.
`Issue Date: October 27, 2015
`Title: Levothyroxine Formulations
`Case: IPR2017-00643
`
`U.S. Patent No. 9,238,239 to Jiang et al.
`Issue Date: October 27, 2015
`Title: Levothyroxine Formulations
`Case: IPR2017-00644
`_____________________
`
`
`
`DECLARATION OF JAMES E. KIPP, PH.D
`
`
`
`
`
`Mylan Ex 1004, Page 1
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`

`

`
`
`I.
`
`II.
`
`TABLE OF CONTENTS
`
`Introduction ................................................................................................. 1
`
`Background and Qualifications .................................................................... 2
`
`III.
`
`List of Materials Considered ........................................................................ 8
`
`IV.
`
`Legal Standards ..........................................................................................11
`
`V.
`
`Summary of Opinions .................................................................................15
`A.
`Claims 1-21 of the ’289 Patent Would Have Been Obvious ..............15
`B.
`Claims 1-30 of the ’238 patent Would Have Been Obvious ..............15
`C.
`Claims 1-15 of the ’239 patent would have been obvious .................16
`
`VI.
`
`The Jiang Patents ........................................................................................17
`
`VII. Level of Ordinary Skill in the Art ...............................................................23
`
`VIII. The Subject Matter of Claims 1-21 of the ’289 Patent, Claims 1-30 of
`the ’238 Patent, and Claims 1-15 of the ’239 Patent Would Have Been
`Obvious ......................................................................................................25
`A.
`Scope and Content of the Prior Art ...................................................25
`i.
`Levothyroxine Sodium Compositions .....................................25
`ii.
`Instability of Levothyroxine Sodium Compositions ................26
`iii. Mannitol was the Most Commonly Used Bulking Agent
`and was Used in Lyophilized Levothyroxine Sodium
`Compositions ..........................................................................34
`iv. Mannitol’s Degradation of Moisture-Sensitive
`Compounds .............................................................................37
`Obviousness Based on the Abbott Label, Brower, Baheti, and
`Collier ...............................................................................................45
`i.
`Independent Claims of the Jiang Patents .................................45
`a.
`Independent Claims 1 and 14 of the ’289 Patent ...........45
`b.
`Independent Claims 1, 11, and 21 of the ’238
`Patent ............................................................................47
`Independent Claim 1 of the ’239 Patent ........................49
`It Would Have Been Obvious to Use 100
`Micrograms of Levothyroxine Sodium .........................49
`
`c.
`d.
`
`B.
`
`i
`
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`

`

`ii.
`
`iii.
`
`iv.
`
`
`
`C.
`
`e.
`
`b.
`c.
`
`d.
`
`e.
`
`f.
`
`b.
`c.
`d.
`e.
`
`f.
`
`g.
`h.
`
`i.
`
`It Would Have Been Obvious to Reduce the
`Amount of Mannitol Below 10 Milligrams ...................50
`Dependent Claims of the ’289 Patent ......................................74
`a.
`Amount of Levothyroxine Sodium: Claims 2 and 3 ......74
`b.
`Amount of Mannitol: Claims 2, 3, and 15 .....................74
`c.
`Phosphate Buffer and Amount: Claims 4, 9, and 16 ......75
`d.
`Lyophilization Process: Claim 5, 10, and 17 .................79
`e.
`Amount of Levothyroxine Sodium Converted to
`Liothyronine: Claims 6–8, 11–13, and 18–21 ...............80
`Dependent Claims of the ’238 Patent ......................................88
`a.
`Amount of Levothyroxine Sodium Converted to
`Liothyronine: Claims 2, 3, 12, 13, 22, and 23 ...............88
`Amount of Mannitol: Claim 4, 14, and 24 .....................90
`Pharmaceutically Acceptable Liquid Carrier:
`Claims 5, 15, and 25 .....................................................90
`Concentration of Levothyroxine in Pharmaceutical
`Solution: Claims 6, 16, and 26 ......................................91
`Method of Providing Levothyroxine to a Patient in
`Need: Claims 7, 17, and 27 ...........................................92
`Dosage of Levothyroxine Sodium: Claims 8, 9, 18,
`19, 28, and 29 ...............................................................92
`Phosphate Buffer: Claim 10, 20, and 30 ........................93
`g.
`Dependent Claims of the ’239 Patent ......................................94
`a.
`Amount of Levothyroxine Sodium Converted to
`Liothyronine: Claims 2-5 ..............................................94
`Amount of Mannitol: Claim 6 .......................................99
`Phosphate Buffer and/or Amount: Claims 7 and 8 ...... 100
`Levothyroxine Sodium: Claim 9 ................................. 100
`Pharmaceutically Acceptable Liquid Carrier:
`Claim 10 ..................................................................... 101
`Concentration of Levothyroxine in Pharmaceutical
`Solution: Claim 11 ...................................................... 101
`pH of the Solution: Claim 12 ...................................... 101
`Method of Providing Levothyroxine to a Patient in
`Need: Claim 13 ........................................................... 108
`Dosage of Levothyroxine Sodium: Claims 14 and
`15 ................................................................................ 108
`Obviousness Based on the APP Label, Brower, Baheti, and
`Collier ............................................................................................. 109
`i.
`Independent Claims of the Jiang Patents ............................... 109
`
`ii
`
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`

`

`
`
`ii.
`
`iii.
`
`iv.
`
`a.
`b.
`
`c.
`d.
`
`b.
`c.
`
`d.
`
`e.
`
`f.
`
`Independent Claims 1 and 14 of the ’289 Patent ......... 109
`Independent Claims 1, 11, and 21 of the ’238
`Patent .......................................................................... 111
`Independent Claim 1 of the ’239 Patent ...................... 112
`It Would Have Been Obvious to Reduce the
`Amount of Mannitol Below 10 Milligrams ................. 113
`Dependent Claims of the ’289 Patent .................................... 120
`a.
`Amount of Levothyroxine Sodium: Claims 2 and 3 .... 120
`b.
`Amount of Mannitol: Claims 2, 3, and 15 ................... 120
`c.
`Phosphate Buffer and Amount: Claims 4, 9, and 16 .... 121
`d.
`Lyophilization Process: Claim 5, 10, and 17 ............... 123
`e.
`Amount of Levothyroxine Sodium Converted to
`Liothyronine: Claims 6–8, 11–13, and 18–21 ............. 123
`Dependent Claims of the ’238 Patent .................................... 124
`a.
`Amount of Levothyroxine Sodium Converted to
`Liothyronine: Claims 2, 3, 12, 13, 22, and 23 ............. 124
`Amount of Mannitol: Claim 4, 14, and 24 ................... 125
`Pharmaceutically Acceptable Liquid Carrier:
`Claims 5, 15, and 25 ................................................... 125
`Concentration of Levothyroxine in Pharmaceutical
`Solution: Claims 6, 16, and 26 .................................... 126
`Method of Providing Levothyroxine to a Patient in
`Need: Claims 7, 17, and 27 ......................................... 127
`Dosage of Levothyroxine Sodium: Claims 8, 9, 18,
`19, 28, and 29 ............................................................. 127
`Phosphate Buffer: Claim 10, 20, and 30 ...................... 128
`g.
`Dependent Claims of the ’239 Patent .................................... 128
`a.
`Amount of Levothyroxine Sodium Converted to
`Liothyronine: Claims 2-5 ............................................ 128
`Amount of Mannitol: Claim 6 ..................................... 130
`Phosphate Buffer and/or Amount: Claims 7 and 8 ...... 130
`Levothyroxine Sodium: Claim 9 ................................. 131
`Pharmaceutically Acceptable Liquid Carrier:
`Claim 10 ..................................................................... 131
`Concentration of Levothyroxine in Pharmaceutical
`Solution: Claim 11 ...................................................... 131
`pH of the Solution: Claim 12 ...................................... 132
`Method of Providing Levothyroxine to a Patient in
`Need: Claim 13 ........................................................... 132
`
`b.
`c.
`d.
`e.
`
`f.
`
`g.
`h.
`
`iii
`
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`

`

`
`
`D.
`
`ii.
`
`iii.
`
`iv.
`
`i.
`
`b.
`c.
`
`d.
`
`e.
`
`f.
`
`b.
`c.
`d.
`e.
`
`f.
`
`g.
`h.
`
`Dosage of Levothyroxine Sodium: Claims 14 and
`15 ................................................................................ 132
`Obviousness Based on the Abbott Label, APP Label, Brower,
`Baheti, and Collier .......................................................................... 133
`i.
`Independent Claims of the Jiang Patents ............................... 133
`a.
`It Would Have Been Obvious to Reduce the
`Amount of Mannitol Below 10 Milligrams ................. 134
`Dependent Claims of the ’289 Patent .................................... 135
`a.
`Amount of Levothyroxine Sodium: Claims 2 and 3 .... 135
`b.
`Amount of Mannitol: Claims 2, 3, and 15 ................... 135
`c.
`Phosphate Buffer and Amount: Claims 4, 9, and 16 .... 136
`d.
`Lyophilization Process: Claim 5, 10, and 17 ............... 137
`e.
`Amount of Levothyroxine Sodium Converted to
`Liothyronine: Claims 6–8, 11–13, and 18–21 ............. 137
`Dependent Claims of the ’238 Patent .................................... 139
`a.
`Amount of Levothyroxine Sodium Converted to
`Liothyronine: Claims 2, 3, 12, 13, 22, and 23 ............. 139
`Amount of Mannitol: Claim 4, 14, and 24 ................... 139
`Pharmaceutically Acceptable Liquid Carrier:
`Claims 5, 15, and 25 ................................................... 140
`Concentration of Levothyroxine in Pharmaceutical
`Solution: Claims 6, 16, and 26 .................................... 140
`Method of Providing Levothyroxine to a Patient in
`Need: Claims 7, 17, and 27 ......................................... 141
`Dosage of Levothyroxine Sodium: Claims 8, 9, 18,
`19, 28, and 29 ............................................................. 141
`Phosphate Buffer: Claim 10, 20, and 30 ...................... 142
`g.
`Dependent Claims of the ’239 Patent .................................... 143
`a.
`Amount of Levothyroxine Sodium Converted to
`Liothyronine: Claims 2-5 ............................................ 143
`Amount of Mannitol: Claim 6 ..................................... 144
`Phosphate Buffer and/or Amount: Claims 7 and 8 ...... 144
`Levothyroxine Sodium: Claim 9 ................................. 145
`Pharmaceutically Acceptable Liquid Carrier:
`Claim 10 ..................................................................... 145
`Concentration of Levothyroxine in Pharmaceutical
`Solution: Claim 11 ...................................................... 146
`pH of the Solution: Claim 12 ...................................... 146
`Method of Providing Levothyroxine to a Patient in
`Need: Claim 13 ........................................................... 147
`
`iv
`
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`
`
`i.
`
`Dosage of Levothyroxine Sodium: Claims 14 and
`15 ................................................................................ 147
`Secondary Considerations ............................................................... 148
`i.
`No unexpected results ........................................................... 148
`No other evidence of non-obviousness ............................................ 152
`
`E.
`
`F.
`
`IX. Conclusion ................................................................................................ 152
`
`
`
`v
`
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`
`
`I.
`
`Introduction
`
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of Petitioner for the
`
`above captioned inter partes reviews (“IPRs”). I am being compensated for my
`
`time in connection with these IPRs at my standard consulting rate, which is $350
`
`per hour for consulting and $500 per hour for deposition. No part of my
`
`compensation is contingent upon the outcome of this case, any issue in it, or the
`
`positions or opinions that I express.
`
`3.
`
`I understand that the petitions for inter partes review involve 3 patents:
`
`U.S. Patent No. 9,006,289 (“the ’289 patent”) (EX1001), issued on April 14, 2015
`
`from U.S. Appl. No. 13/597,884 (“the ’884 application”); U.S. Patent No. 9,168,238
`
`(“the ’238 patent) (EX1002), issued on October 27, 2015 from U.S. Appl. No.
`
`14/641,426 (“the ’426 application”); and U.S. Patent No. 9,168,239 (“the ’239
`
`patent”) (EX1003), issued on October 27, 2015 from U.S. Appl. No. 14/658,058
`
`(“the ’058 application”).
`
`4.
`
`All patents name John Zhiqiang Jiang, Arunya Usayapant, and George
`
`Monen as the purported inventors. I understand that the ’426 application and the
`
`’058 application, which issued as the ’238 patent and ’239 patent, respectively, are
`
`continuations of the ’884 application, which issued as the ’289 patent. The ’289
`
`1
`
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`
`
`patent claims priority to U.S. Provisional Appl. No. 61/529,084 (“the ’084
`
`provisional”), which was filed on August 30, 2011. It is my understanding that the
`
`earliest possible priority date of the ’289 patent, ’238 patent, and ’239 patent
`
`(collectively, “the Jiang Patents”) is August 30, 2011, i.e., the filing date of the ’084
`
`provisional application. I further understand that the Jiang Patents are assigned to
`
`Fresenius Kabi USA, LLC (“Fresenius,” “the Patentee,” or “the Patent Owner”).
`
`5.
`
`As explained below, my opinion is that all claims of the Jiang Patents
`
`would have been obvious. Degradation of lyophilized levothyroxine sodium
`
`compositions was known and all the purported inventors did was reduce the amount
`
`of mannitol, which was a known way to improve stability of moisture-sensitive
`
`compounds, such as levothyroxine sodium.
`
`II. Background and Qualifications
`
`6.
`
`I am an expert in the field of pharmaceutical sciences. Specifically, I
`
`specialize in drug formulation development and targeted delivery of therapeutics,
`
`including development of lyophilized and injectable products, and I have been an
`
`expert in this field prior to August 30, 2011. Throughout this declaration, I will
`
`refer to the field of injectable formulations which includes lyophilized drug
`
`compositions, as the relevant field or the relevant art. I have relied upon my
`
`training, knowledge, and experience in the relevant art to form my opinions. A
`
`copy of my current curriculum vitae is provided as EX1005.
`
`2
`
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`
`
`7.
`
`I am currently an independent consultant with my own business
`
`providing technical review and advice in matters involving pharmaceutical
`
`technology, research and design (“R&D”), and the development of new drugs and
`
`new pharmaceutical products. I have over 32 years of experience in the field of
`
`parenteral formulation, principally in the development of injectable pharmaceutical
`
`products.
`
`8. My areas of expertise broadly encompass synthetic and physical
`
`organic chemistry and pharmaceutical
`
`sciences;
`
`the development of
`
`pharmaceutical solution products; the development of new drug delivery
`
`technology; lyophilization, and physical science of freezing; research and
`
`development of nanoparticulate pharmaceutical dosage forms; market surveillance
`
`and evaluation of new technology opportunities; data modeling and mining; and
`
`molecular modeling for prediction of bulk physical and chemical properties.
`
`9.
`
`I received a Bachelor of Arts degree in Chemistry, Cum Laude, from
`
`Albion College (Albion, Michigan) in 1975, and while attending Albion College, I
`
`spent one year of academic study at the University of Leiden in The Netherlands.
`
`10.
`
`I attended the University of Michigan from 1975-1983, and obtained
`
`both a Master of Science degree and a Ph.D. in Chemistry (organic chemistry). My
`
`Ph.D. dissertation was directed at the development of new organic synthesis of
`
`unstable molecules, bridgehead alkenes, and the study of their chemical behavior.
`
`3
`
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`
`
`11. After graduate school, starting in July 1983, I worked for more than 28
`
`years at Baxter Healthcare Corporation, formerly Baxter Travenol Laboratories. I
`
`am intimately familiar with process development in aqueous formulations and the
`
`effects of freezing on formulation chemistry. For example, I directed (and was the
`
`technical leader for) Baxter in the formulation development of vancomycin
`
`hydrochloride, a frozen premix antibiotic in Baxter’s GALAXY frozen plastic
`
`container system (PL 2040).
`
`12.
`
`I am also intimately familiar with lyophilized formulations, including
`
`the properties of compounds commonly used in lyophilization (such as mannitol
`
`and lactose) and with the lyophilization process itself. I have developed two novel
`
`lyophilization methods for the preparation of nanosuspensions using dispersion
`
`lyophilization. I am a named inventor on two patents (U.S. Patents 6,835,396 and
`
`8,722,091) resulting from this work.
`
`13. While at Baxter, I spearheaded development and was lead inventor of
`
`a method for stabilizing pharmaceutical agents in frozen aqueous media by adding
`
`vitrifying (“glass-forming”) additives that included disaccharides. This research
`
`led to U.S. Patent Nos. 8,183,233, for which I am a named inventor.
`
`14. From 1983 to 1984, I was a synthetic organic chemist for Baxter
`
`Travenol Laboratories (now Baxter) and directed synthesis and isolation of new
`
`4
`
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`
`
`molecules that were possible degradation products
`
`in Baxter’s Tagamet
`
`(cimetidine) premix infusion product.
`
`15. Among my other accomplishments at Baxter was the development of
`
`quantitative structure-property relationship (QSPR) methods for predicting
`
`chemical and physical properties of pharmaceuticals in solution, such as their
`
`solubility in various solvents and binding constants to polysaccharides, namely
`
`cyclodextrins. I also developed computational methods for prediction of ionic
`
`equilibria and pH in pharmaceutical formulations, as well as estimating the effects
`
`of temperature on ionic equilibria. The techniques I developed were applied in
`
`subsequent product development at Baxter, and were published and presented at
`
`prominent scientific meetings. While at Baxter, I also developed new, time-saving
`
`methods to test the stability of pharmaceutical formulations. For example, I
`
`developed a non-isothermal method of testing and assessing formulation stability,
`
`and applied this method to clindamycin-2-phosphate and caspofungin. By using
`
`an accelerated linear heating ramp, the long-term stability of these drug
`
`formulations could be estimated in only one day.
`
`16. Many R&D projects I led have resulted in commercial products,
`
`including products for intravenous delivery and delivery by other routes. Products
`
`include premix solutions for intravenous infusion of clindamycin phosphate,
`
`nitroglycerin, fluconazole, and vancomycin.
`
`5
`
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`
`
`17.
`
`I was also a lead inventor of Baxter’s nanoparticle drug delivery
`
`platform, NANOEDGE™. This technology used formulation tools that enabled
`
`the manufacture of water insoluble drugs as solid, sub-micron particles. In a joint-
`
`venture with Dr. Howard Gendelman’s research group at the University of
`
`Nebraska Medical Center, we were able to produce small particles in a size range
`
`recognizable by macrophages and other immunocytes, which could then
`
`phagocytize and traffic the drug to desired drug targets. This “Trojan horse”
`
`approach used the patient’s own macrophages to bypass the blood-brain barrier and
`
`enter sites of active inflammation and disease in the brain and has been used
`
`experimentally to treat gliomas and HIV-1 encephalitis (HIVE).
`
`18. Baxter was contracted by the National Aeronautics and Space
`
`Administration (through NASA contractor Krug International) to develop a method
`
`for mixing and delivering injectable pharmaceutical agents in zero gravity. This
`
`development was constrained by a passive system requirement, utilizing only water
`
`pressure from a sterile water generator onboard the Space Shuttle and International
`
`Space Station (ISS) to provide the mixing. In connection with this contract, I
`
`spearheaded development of a flow-through fluid reconstitution system for
`
`emergency preparation of intravenous formulations, which were to be prepared
`
`from sterile concentrates, or powders. For this achievement, I was awarded two
`
`6
`
`Mylan Ex 1004, Page 12
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`

`

`
`
`Certificates of Recognition
`
`from
`
`the National Aeronautics and Space
`
`Administration in 1993.
`
`19.
`
`In total, I am a named inventor on 22 issued patents, and over 35 patent
`
`applications. I have been published in numerous peer-reviewed journals, written
`
`two book chapters, and have taught courses in chemical kinetics and ionic
`
`equilibria at the University of Illinois in Chicago. I have been a member of the
`
`American Association of Pharmaceutical Sciences (AAPS) for about 20 years, have
`
`presented many papers at AAPS meetings, and have taught a short course at AAPS
`
`in the field of pharmaceutical formulation (AAPS, Baltimore, 2004). I have also
`
`been a member of the American Chemical Society for about 40 years. I have
`
`received over 30 corporate and departmental technical awards at Baxter, the
`
`recognition awards from NASA cited above, and have been the lead Baxter
`
`scientist in bringing at least 5 drugs successfully to market, including a liquid
`
`formulation for aerosolized pulmonary delivery (Tobramycin for Inhalation,
`
`TOBI®).
`
`20. At the end of 2011, I retired from Baxter, and have since then run my
`
`own consulting business, addressing the concerns of pharmaceutical product
`
`development. In private practice, I have consulted for several medium to large
`
`pharmaceutical firms, and have assisted in regulatory file preparation, new product
`
`surveillance, vendor facility quality inspection, and research design for new drug
`
`7
`
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`

`
`
`product development. Between 2012 and now I have served as an expert witness
`
`in at least seven cases, having been deposed twice.1
`
`III. List of Materials Considered
`
`21.
`
`I have reviewed the Jiang Patents and their respective prosecution
`
`histories. In forming my opinions, I have relied upon my experience and expertise
`
`in the relevant art. I have also considered the viewpoint of a person of ordinary skill
`
`in the art (“POSA”) as defined below as of August 30, 2011. I have considered all
`
`documents cited in this Declaration and all documents cited in the Petitions for Inter
`
`Partes Review of the Jiang Patents, including documents cited in the exhibit list,
`
`which is reproduced below:
`
`Exhibit #
`1001
`
`
`
`1002
`
`1003
`
`1004
`1005
`1006
`1007
`1008
`
`Description
` U.S. Patent No. 9,006,289 to Jiang et al., “Levothyroxine
`Formulations”
`U.S. Patent No. 9,168,238 to Jiang et al., “Levothyroxine
`Formulations”
`U.S. Patent No. 9,168,239 to Jiang et al., “Levothyroxine
`Formulations”
`Declaration of James E. Kipp, Ph.D.
`Curricula Vitae of James E. Kipp, Ph.D.
`Abbott Synthroid® Prescribing Information
`APP Levothyroxine Sodium for Injection Prescribing Information
`Rowe et al., “Mannitol,” Handbook of Pharmaceutical
`Excipients, 5th Ed. (2006) pp. 449-453
`
`
`1 I reserve the right to further explain my background and qualifications in deposition
`
`if needed.
`
`8
`
`Mylan Ex 1004, Page 14
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`

`

`
`
`Exhibit #
`1009
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`1019
`
`1020
`1021
`1022
`1023
`1024
`1025
`
`Description
`Collier et al., “Influence of Formulation and Processing Factors
`on Stability of Levothyroxine Sodium Pentahydrate,” APPS
`PharmSiTech 11(2), 2010, 818-825
`Baheti et al., Excipients Used in Lyophilization of Small
`Molecules, J. Excipients and Food Chem. 1 (1), 41-54 (2010)
`U.S. Patent App. Pub. No. 2012/0190748 to Haren Treasurer,
`“Greater Utility with Thyroid hormone”
`Markman Opinion in Fresenius Kabi USA, LLC v. Fera
`Pharmaceuticals, LLC, et al., No. 15-cv-3654-KM-MAH, ECF
`No. 327 (D.N.J. Sep. 20, 2016)
`Declaration of Arunya Usayapant dated December 23, 2014 filed
`in U.S. Patent App. No. 13/597,884
`Declaration of Jiang et al., dated August 7, 2013 filed in U.S.
`Patent App. No. 13/597,884
`Declaration of Leonard J. Chyall dated June 5, 2014 filed in U.S.
`Patent App. No. 13/597,884
`Shah et al., Stability Indicating Validated HPLC Method for
`Quantification of Levothyroxine with Eight Degradation Peaks in
`the Presence of Excipients, International Journal of
`Pharmaceutics 360 (2008) 77–82
`Chong Min Won, Kinetics of Degradation of Levothyroxine in
`Aqueous Solution and in Solid State, Pharm. Res. Vol. 9 No.,
`131–137 (1992)
`Brower et al., Determination of Sodium Levothyroxine in Bulk,
`Tablet, and Injection Formulations by High-Performance Liquid
`Chromatography, J. Pharm. Sci. 73:1315-1317 (1984)
`Glass et al., Stability Considerations in Liquid Dosage Forms
`Extemporaneously Prepared from Commercially Available
`Products, J Pharmacy & Pharma. Sci. 9 (3): 398-426 (2006)
`Reserved
`Physician’s Desk Reference, 25th Ed., 1971, p. 716
`Reserved
`Reserved
`Reserved
`Carpenter et al., Rational Design of Stable Lyophilized Protein
`Formulations: Some Practical Advice, Pharm. Research, Vol. 14,
`No. 8, 1997
`
`9
`
`Mylan Ex 1004, Page 15
`
`

`

`
`
`Exhibit #
`1026
`
`1027
`1028
`1029
`1030
`1031
`1032
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`1041
`1042
`
`1043
`
`1044
`
`1045
`
`1046
`
`Description
`Amendment and Response dated December 23, 2014 filed in U.S.
`Patent App. No. 13/597,884
`U.S. Provisional Application No. 61/529,084
`Reserved
`Reserved
`Reserved
`Reserved
`Reserved
`Byrn et al., Chemical Reactivity in Solid-State Pharmaceuticals:
`Formulation Implications, Advanced Drug Delivery Reviews 48
`(2001) 115-136
`Prescribing Information of Levothyroxine Sodium, Fresenius
`Kabi USA, LLC (December 2013)
`Amendment and Response dated June 6, 2014 filed in U.S. Patent
`App. No. 13/597,884
`Richard J. Lewis, Sr., Hawley’s Condensed Chemical Dictionary
`15th Ed. (2007) 1153-1154
`Amendment and Response dated August 9, 2013 filed in U.S.
`Patent App. No. 13/597,884
`Sznitowska et al., The Physical Characteristics of Lyophilized
`Tablets Containing a Model Drug in Different Chemical Forms
`and Concentrations, Drug Research, Vol. 62 No. 1 pp. 25-29
`(2005)
`Richard J. Lewis, Sr., Hawley’s Condensed Chemical Dictionary
`15th Ed. (2007) 1035-1036
`Reserved
`Reserved
`Michael J. Akers, Sterile Drug Products, Formulation, Packaging,
`Manufacturing, and Quality, Informa Healthcare (2010) 138-139,
`154-168
`U.S. Patent No. 6,399,101 to Frontanes et al., “Stable Thyroid
`Hormone Preparations and Method of Making Same”
`Amendment and Response dated July 13, 2015 filed in U.S.
`Patent App. No. 14/658,058
`Rowe et al., “Sodium Phosphate,” Handbook of Pharmaceutical
`Excipients, 5th Ed. (2006) pp. 693-698
`Merck Index 14th Ed. (2006) pp. 1488-1489
`
`10
`
`Mylan Ex 1004, Page 16
`
`

`

`
`
`Exhibit #
`1047
`
`1048
`
`1049
`
`1050
`
`1051
`
`1052
`
`1053
`
`1054
`
`1055
`1056
`
`1057
`
`Description
`Appeal Brief of Defendants-Appellants filed in Fresenius Kabi
`USA, LLC v. Fera Pharmaceuticals, LLC, et al., No. 2017-1099,
`ECF No. 24 (Fed. Cir. Dec. 27, 2016)
`Kim et al., The Physical State of Mannitol after Freeze-Drying:
`Effects of Mannitol Concentration, Freezing Rate, and a
`Noncrystallizing Cosolute, 87 J. Pharm. Sci. 931-935 (1998)
`Yu et al., Existence of a Mannitol Hydrate during Freeze-Drying
`and Practical Implications, 88 J. Pharm. Scis. 196-198 (1999)
`Torrado et al., Characterization of Physical State of Mannitol
`after Freeze-Drying: Effect of Acetylsalicylic Acid as a Second
`Crystalline Cosolute, Chem. Pharm. Bull. 50(5) 567-570 (2002)
`Synthroid, Announcements: Postgraduate Medicine, 1969 Vol.
`46, No. 4, p. 18
`U.S. Patent No. 6,284,277 to Bouloumie et al., “Stable Freeze-
`Dried Pharmaceutical Formulation”
`Bedford Laboratories, Levothyroxine Sodium for Injection Rx
`Only
`Herman et al., The Effect of Bulking Agent on the Solid-State
`Stability of Freeze-Dried Methylprednisolone Sodium Succinate,
`Pharm. Res., 11:1467-1473 (1994)
`Reserved
`Smith R.M., Martell A.E., Critical Stability Constants, Vol. 4:
`Inorganic Complexes, Springer Science, New York, 1976, pp. 56-
`74
`Brown T.L., Lemay H.E. Jr., Bursten B.E., Chemistry, the Central
`Science 8th Rev. Ed., Prentice-Hall, Inc., New Jersey, 2002, pp.
`644-647, 650
`
`
`IV. Legal Standards
`
`22.
`
`In this section, I describe my understanding of certain legal standards.
`
`I have been informed of these legal standards by the Petitioner’s attorneys. I have
`
`applied these legal standards in forming my opinions.
`
`23.
`
`I have been instructed by counsel that the priority date for the purposes
`
`of the Jiang Patents is August 30, 2011, which is the date U.S. Provisional Appl. No.
`
`11
`
`Mylan Ex 1004, Page 17
`
`

`

`
`
`61/529,084 was filed. EX1001 at 1. I understand that a patent or other publication
`
`must first qualify as prior art before it can be used as part of any invalidity analysis.
`
`In forming my opinions, I have applied a POSA’s understanding as it would have
`
`existed as of August 30, 2011.
`
`24.
`
`I understand that the first step in determining whether a patent claim
`
`would have been obvious is to construe the claims to determine claim scope and
`
`meaning. I understand that in Inter Partes Review proceedings the claim terms are
`
`generally given the broadest reasonable interpretation (“BRI”), i.e., their ordinary
`
`and customary meaning as would have been understood by a POSA at the time, in
`
`the context of the entire patent disclosure.
`
`25.
`
`I have been instructed by counsel on the law regarding obviousness,
`
`and understand that a patent claim will be unpatentable if the differences between
`
`the claimed subject matter 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 a POSA with a
`
`reasonable expectation of success.
`
`26. When determining if a claimed invention would have been obvious to
`
`a POSA, it is my understanding that this determination includes consideration of the
`
`following factors: (i) the scope and content of the prior art; (ii) differences between
`
`the prior art and the claims at issue; (iii) the level of ordinary skill in the pertinent
`
`12
`
`Mylan Ex 1004, Page 18
`
`

`

`
`
`art; and (iv) the existence of secondary considerations of non-obviousness. I
`
`understand these are also sometimes referred to as the Graham factors.
`
`27.
`
`I also understand that obviousness can be established by combining or
`
`modifying the teachings of the prior art. A claimed invention can be obvious when,
`
`for example, there is some teaching, suggestion, or motivation in the prior art that
`
`would have led a POSA to modify the prior art reference or to combine prior art
`
`reference teachings to arrive at the claimed invention.
`
`28.
`
`I also understand that the prior art references themselves do not have to
`
`provide an explicit teaching, suggestion, or motivation to combine prior art reference
`
`teaching; rather, the analysis may rely on interrelated teachings, market demands,
`
`the background knowledge possessed by a POSA, and/or common sense. Put
`
`another way, the motivation to combine prior art references can come from any
`
`reason to do so, and is not limited to the reasons that may have motivated the
`
`patentee.
`
`29.
`
`I am also informed that a combination of familiar elements according
`
`to known methods is likely to be obvious when it does no more than yield predictable
`
`results. I also understand that when a person of ordinary skill would have reached
`
`the claimed invention through routine experimentation, the invention may be
`
`deemed obvious.
`
`13
`
`Mylan Ex 1004, Page 19
`
`

`

`
`
`30.
`
`I understand that various rationales are utilized to determine whether a
`
`claim
`
`is obvious,
`
`including, among others:
`
`(i) simple substitution or
`
`interchangeability of one known element for another to obtain predictable results;
`
`(ii) use of known techniques to improve similar methods or products in the same
`
`way; (iii) applying a known technique to a known method or product ready for
`
`improvement to yield predictable results; (iv) “obvious to try”—cho