IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`PATENT TRIAL AND APPEAL BOARD
`
`ADAMIS PHARMACEUTICALS CORPORATION
`Petitioner
`
`v.
`
`BELCHER PHARMACEUTICALS, LLC
`Patent Owner
`
`_____________________
`
`CASE: IPR2019-01021
`U.S. PATENT NO. 9,283,197
`_____________________
`
`DECLARATION OF JAMES KIPP, PH.D. IN SUPPORT OF PETITION
`FOR INTER PARTES REVIEW OF U.S. PATENT 9,283,197
`
`Page A
`
`ADAMIS EXHIBIT 1002
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`

`

`CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION .................................................................................. 1
`
`QUALIFICATIONS AND BACKGROUND ........................................ 3
`
`III. OVERVIEW OF THE TECHNOLOGY ................................................ 7
`
`A.
`
`B.
`
`C.
`
`Epinephrine Compound ................................................................ 7
`
`Epinephrine Injections .................................................................. 8
`
`Racemization and Oxidation Processes ..................................... 10
`
`D. Adrenalone and Other Impurities ............................................... 12
`
`THE ‘197 PATENT .............................................................................. 14
`
`LEVEL OF SKILL IN THE ART ........................................................ 16
`
`IV.
`
`V.
`
`VI. CLAIM CONSTRUCTION ................................................................. 18
`
`VII. SUMMARY OF OPINIONS ................................................................ 20
`
`VIII. OVERVIEW OF PRIOR ART ............................................................. 24
`
`A.
`
`Stepensky .................................................................................... 24
`
`B. USP ............................................................................................. 29
`
`C. Gupta .......................................................................................... 31
`
`D.
`
`E.
`
`F.
`
`G.
`
`Bruss ........................................................................................... 33
`
`Fyllingen ..................................................................................... 35
`
`Zeleznick .................................................................................... 36
`
`Szulczewski ................................................................................ 37
`
`IX. DETAILED ANALYSIS ...................................................................... 39
`
`A.
`
`Prior Art Showing Motivation to Minimize Degradation in Sterile
`Liquid Injectable Pharmaceutical Formulations of l-Epinephrine
` .................................................................................................... 40
`
`i
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`B.
`
`Prior Art Showing How to Manufacture the Said Liquid
`Pharmaceutical Formulation ...................................................... 41
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Said Liquid Pharmaceutical Formulation Having a pH
`Between 2.8 and 3.3 ......................................................... 42
`
`Said Injectable Liquid Pharmaceutical Formulation
`Compounded in an Aqueous Solution as 1.0 to 1.06 mg/mL
`L-Epinephrine, and Further Including a Tonicity Agent . 43
`
`Said Liquid Pharmaceutical Formulation Including no More
`Than About 6% D-Epinephrine and no More Than About
`0.5% Adrenalone at Release ............................................ 45
`
`Said Liquid Pharmaceutical Formulation Including no More
`Than About 12% D-Epinephrine and no More Than About
`0.5% Adrenalone Over a Shelf-Life of at Least 12 Months
` .......................................................................................... 46
`
`Said Liquid Pharmaceutical Formulation Having a
`Concentration of 1 mg per mL L-Epinephrine ................ 49
`
`X. COMBINATIONS .............................................................................. 49
`
`C.
`
`D.
`
`E.
`
`F.
`
`G.
`
`H.
`
`Stepensky and USP .................................................................... 50
`
`Stepensky and Gupta .................................................................. 52
`
`Bruss and USP and Fyllingen ..................................................... 53
`
`Gupta and Fyllingen and Zeleznick ........................................... 54
`
`Szulczewski and Fyllingen ......................................................... 55
`
`Szulczewski and Fyllingen and Gupta ....................................... 56
`
`XI.
`
`SECONDARY CONSIDERATIONS ............................................... 56
`
`ii
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`I, James Kipp, Ph.D., do hereby declare and say:
`I.
`
`INTRODUCTION
`
`1.
`
`I am over the age of twenty-one (21) and competent to make this
`
`declaration. I am also qualified to give testimony under oath. The facts and
`
`opinions listed below are within my personal knowledge.
`
`2.
`
`I have been engaged in this matter to provide my independent analysis
`
`of certain issues I understand arise in connection with the Inter Partes Review of
`
`U.S. Patent No. 9,283,197 (which I refer to as the ‘197 Patent). (Ex. 1001). I am
`
`being compensated for my time in connection with this IPR at my standard
`
`consulting rates. I have received no compensation for this declaration beyond my
`
`normal hourly rate for time spent on this matter, and I will not receive any added
`
`compensation based on the outcome of any proceeding related to the ‘197 Patent.
`
`3.
`
`I have been asked to review certain documents, including the ‘197
`
`Patent (Ex. 1001), and to provide my opinions on how those of skill in the art (as
`
`defined herein) would understand those documents. For purposes of this
`
`declaration, the documents I was asked to review include:
`
`Ex. 1001
`
`U.S. Patent No. 9,283,197 (“‘197 Patent”)
`
`Ex. 1004
`Ex. 1005
`
`File History of U.S. Patent No. 9,283,197
`Stepensky, D., Long-Term Stability Study of L-Adrenaline Injections:
`Kinetics of Sulfonation and Racemization Pathways of Drug
`Degradation, Journal of Pharmaceutical Sciences, Vol. 93 No. 4,
`published in April 2004 (“Stepensky”)
`
`1
`
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`

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`Ex. 1006
`
`Ex. 1007
`
`Ex. 1008
`
`Ex. 1009
`
`Ex. 1010
`Ex. 1011
`
`Ex. 1012
`
`Ex. 1013
`Ex. 1014
`
`U.S. Patent Application Publication No. 2008/0269347 to Bruss et al.
`(“Bruss”)
`Fyllingen, G., Racemisation and oxidation in adrenaline injections,
`Acta Pharm. Nord. 2(5) 1990 (“Fyllingen”)
`Vidal-Ollivier, E., Assay for epinephrine and its impurities using
`reversed-phase high-performance liquid chromatography, Journal of
`Chromatography 1987 (“Vidal”)
`Kerddonfak, S., The Stability and Sterility of Epinephrine Prefilled
`Syringe, Asian Pacific Journal of Allergy and Immunology, 2010
`(“Kerddonfak”)
`U.S. Patent No. 5,002,973 to Zeleznick et al. (“Zeleznick”)
`International Patent Publication No. WO 2014/127015 to Gupta et al.
`(“Gupta”)
`Connors, K.A. Chemical Stability of Pharmaceuticals: A Handbook
`for Pharmacists, 2nd Edition, published in 1986 (“Connors”)
`2004 United States Pharmacopeia Monograph for Epinephrine
`2009 United States Pharmacopeia Monograph for Epinephrine
`(“USP”)
`2014 United States Pharmacopeia Monograph for Epinephrine
`Analytical Profiles of Drug Substances, 7, Epinephrine by Dale H.
`Szulczewski et al., published in 1978 (“Szulczewski”)
`
`Ex. 1017 Moed H.D. et al., Synthesis of beta-phenyl-ethylamine derivatives III
`Bronchodilators, Rec. Trav. Chim. 74, 1955 (“Moed”)
`
`IMS Product Information
`Claim Construction Order in Case No. 17-775-LPS, Belcher
`Pharmaceuticals, LLC v. Hospira, Inc
`Belcher Initial Infringement Contentions in Case No. 8:18-cv-02379-
`WFJ-AAS, Adamis Pharmaceuticals Corp. v. Belcher
`Pharmaceuticals, LLC
`Goodman, L.S., The Pharmacological Basis of Therapeutics, 5th
`Edition, (“Goodman”) published in 1975
`Belcher Expert Report in Case No. 17-775-LPS
`
`Ex. 1015
`Ex. 1016
`
`Ex. 1018
`Ex. 1019
`
`Ex. 1020
`
`Ex. 1022
`
`Ex. 1023
`
`2
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`
`
`4.
`
`I provide my conclusions regarding
`
`the disclosures of
`
`these
`
`documents below.
`
`5.
`
`I was asked to provide opinions about what those of skill in the art
`
`would have understood is disclosed by the prior art. In this regard, I was asked to
`
`provide opinions about whether or not what is claimed in the ‘197 Patent is
`
`disclosed or taught by the prior art. I was also asked to provide opinions about the
`
`relevant state of the art. I have offered my opinions on these issues where asked.
`
`6.
`
`I am not offering any conclusions as to the ultimate determinations
`
`that I understand the Patent Trial and Appeal Board will make in this proceeding. I
`
`am simply providing my opinion on the technical aspects of the documents and on
`
`the concepts disclosed in the documents from a technical perspective.
`
`II. QUALIFICATIONS AND BACKGROUND
`7.
`I am an expert in the field of pharmaceutical sciences. I hold an
`
`undergraduate degree in chemistry. In addition, I hold a master’s degree and Ph.D.
`
`in chemistry. I have over 34 years of experience in the field of pharmaceutical
`
`chemistry. Specifically, I specialize in drug formulation development and targeted
`
`delivery of therapeutics.
`
`8.
`
`I received my Bachelor of Arts degree in chemistry, cum laude, from
`
`Albion College in 1975. I received my master’s degree in chemistry from the
`
`3
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`University of Michigan in 1977. I received my doctorate in chemistry from the
`
`University of Michigan in 1983. 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.
`
`9. While in graduate school, I taught courses in organic chemistry and
`
`qualitative organic chemical analysis.
`
`10. After graduate school, beginning in July 1983 until my retirement at
`
`the end of 2011, I worked at Baxter Healthcare Corporation (“Baxter”), formerly
`
`Baxter Travenol Laboratories.
`
`11.
`
` From 1983 to 1985, I worked as a senior research associate for Baxter
`
`where I focused on organic synthesis, isolation, identification, and characterization
`
`of degradation products from product formulations.
`
`12. From 1985 to 2011, I held various positions at Baxter, beginning as a
`
`research scientist and finally a principal scientist.
`
`13. 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
`
`4
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`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.
`
`14. 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.
`
`15.
`
`I was the technical leader at Baxter in the development of successfully
`
`marketed injectable products such as clindamycin phosphate, nitroglycerin,
`
`fluconazole, and vancomycin. I also worked on the development of well over 100
`
`injectable formulations, including catecholamines of same class as epinephrine—
`
`dopamine, for example.
`
`16.
`
`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 more than 20 years,
`
`have presented many papers at AAPS meetings, and have taught a short course at
`
`5
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`AAPS in the field of pharmaceutical formulation (AAPS, Baltimore, 2004). I have
`
`also been a member of the American Chemical Society for over 40 years. I
`
`received over 30 corporate and departmental technical awards at Baxter and was
`
`the lead Baxter scientist in bringing at least 5 drugs successfully to market.
`
`17. From 2012 to the present, I have acted as a consultant in the
`
`pharmaceutical field. 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 product
`
`development.
`
`18. For these reasons and because of my technical experience and training
`
`as outlined in my curriculum vitae (Ex. 1003), I believe I am qualified to offer
`
`technical opinions regarding the ‘197 Patent and the other documents I have
`
`reviewed as part of my work in this matter.
`
`19.
`
`In forming my opinions, I have relied upon my experience and
`
`expertise in the relevant art.
`
`6
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`III. OVERVIEW OF THE TECHNOLOGY
`A. Epinephrine Compound
`
`20. Epinephrine is among the earliest hormones discovered and applied to
`
`the treatment of disease.1 Epinephrine is one of the neural hormones responsible
`
`for the regulation of the heart, blood pressure, airway resistance, and energy
`
`metabolism. (Ex. 1006 at [0004]). It is classified as a sympathomimetic drug,
`
`acting on both alpha and beta receptors. (Id.).
`
`21. Epinephrine generates an inotropic effect, wherein it increases the
`
`heart rate, the force of contraction of the heart, narrows the blood vessels thus
`
`increasing blood pressure, reduces airway resistance to make it easier to breathe,
`
`and raises blood glucose and blood fatty acid levels to supply the body with energy
`
`during stress. (Id.).
`
`22. Epinephrine is a catecholamine compound. (Ex. 1005 at 969). The
`
`full chemical name of epinephrine is 4-[1-hydroxy-2-(methylamino)ethyl]-1,2-
`
`benzenediol. (Ex. 1012 at 438). The structure of epinephrine is shown below:
`
`
`1 While epinephrine is sometimes referred to as adrenalin or adrenaline, I will
`
`refer to it throughout this Declaration as epinephrine for consistency. The
`
`compounds are identical in chemical structure, differing in name only.
`
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`
`
`(Id.).
`
`23. The chemistry of epinephrine is well-known. Epinephrine shares
`
`similar chemical features with many other catecholamines, such as norepinephrine
`
`(noradrenaline), and dopamine. All of these molecules share a common catechol
`
`(3,4-dihydroxybenzene) moiety.
`
`B.
`
`Epinephrine Injections
`
`24. Epinephrine is available in a variety of formulations suited for
`
`different clinical indications and routes of administration, for example, by
`
`injection, by inhalation, or topically. It is used to treat allergic shock, asthma
`
`attacks, reducing nasal congestion, and/or performance aid in emergency
`
`situations. (Ex. 1006 at [0004]). Epinephrine is commonly applied by intravenous
`
`injection in emergency medicine due to its effects on the cardiovascular system.
`
`(Ex. 1005 at 969).
`
`25. When compounded for use in a pharmaceutical drug application,
`
`epinephrine injections must comply with governing standards from United States
`
`Pharmacopeia (“USP”), which outlines requirements for identity, potency, purity,
`
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`and performance of pharmaceutical compounds. To the extent a prescribed
`
`medication has “USP,” it must be compliant with USP standards for that particular
`
`drug. For example, International Medication Systems, Limited’s (“IMS”)
`
`epinephrine injection is labeled with “USP.” (Ex. 1018 at 1).
`
`26. USP requirements for epinephrine are well-settled. I reviewed three
`
`iterations of USP Monograph for both raw epinephrine and epinephrine injections,
`
`dated 2004, 2009, and 2014. USP disclosure relevant to the issues discussed in this
`
`Declaration are consistent throughout each iteration, so I have only cited to the
`
`2009 version throughout this Declaration.
`
`27. Epinephrine solutions are generally sterilized by filtration or by
`
`heating. (Ex. 1012 at 445). Additionally, antioxidants such as sodium bisulfite or
`
`sodium metabisulfite may be added to increase stability. (Id.).
`
`28. The first modern epinephrine autoinjector, the EpiPen, was invented
`
`in
`
`the mid-1970s and approved for marketing by
`
`the FDA
`
`in 1987.
`
`https://en.wikipedia.org/wiki/Epinephrine_autoinjector. As another example, IMS
`
`Epinephrine injections, compliant with USP, consisting of sterile 1 mg/ml
`
`epinephrine solution in water for injections with the use of a tonicity agent have
`
`been commercially available since at least the 1990s. (See e.g., Ex. 1005; Ex.
`
`1007; Ex. 1018).
`
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`C. Racemization and Oxidation Processes
`
`29. Epinephrine in solution can undergo racemization and oxidation, both
`
`of which reduce the pharmacological efficacy of epinephrine. (Ex. 1005 at 977–
`
`978). Both reactions should be minimized in pharmaceutical formulations in order
`
`to maximize the amount of active l-epinephrine delivered to the patient. (Id.).
`
`30. Racemization refers to the enantiomeric conversion of l-epinephrine
`
`into its less biologically active dextrorotatory isomer, d-epinephrine. (Id.). The
`
`degradation chemistry in sulfite-free aqueous media is shown below in a diagram I
`
`created:
`
`
`31. D-epinephrine is not desirable since it has less pharmacological
`
`activity than l-epinephrine. (Id. at 969). Thus, in creating epinephrine for
`
`pharmaceutical use, one of skill in the art would understand that it is desirable to
`
`maximize the content of l-epinephrine in solution and decrease the likelihood of
`
`racemization.
`
`32.
`
`In addition to degradation through racemization, epinephrine is also
`
`easily subject to oxidation, which results in a colored solution. (Ex. 1012 at 439).
`
`The final product of oxidation is adrenolutin as shown in the figure below:
`
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`
`
`(Ex. 1008 at Fig. 1; Ex. 1012 at 440).
`
`33. Thus, in a pharmaceutical preparation of l-epinephrine, it is known to
`
`use certain techniques to limit the oxidation process. For example, ampoules of
`
`epinephrine solution are usually packed under nitrogen, rather than air. (Ex. 1012
`
`at 441).
`
`34. One known way to impact both the rate of racemization and oxidation
`
`is through adjustments to the pH of the solution. Interestingly, the rate of
`
`oxidation increases with a higher pH, while the rate of racemization decreases with
`
`a higher pH. (Ex. 1012 at 441; Ex. 1007 at 361). Because both of these processes
`
`are undesirable, there is an optimum pH at which racemization and oxidation can
`
`be balanced to minimize loss of intact drug by these two routes. (Ex. 1012 at 441).
`
`Most studies demonstrate that optimal stability is achieved by maintaining the pH
`
`between 2.8 and 4.0. (Ex. 1012 at 441 (optimum pH of 3.0 to 3.8); Ex. 1006 at
`
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`[0014] (optimum pH of 3.0 to 4.0); Ex. 1010 at 2:55–57 (optimum pH of 2.8 to
`
`3.5); Ex. 1009 (optimum pH range of 2.8–3.6); Ex. 1005 at 977 (optimum pH of 3
`
`to 3.8)).
`
`35. Additionally, the permissible pH range for an epinephrine injection as
`
`stated in USP is between 2.2 and 5.0. (Ex. 1014 at 2261).
`
`D. Adrenalone and Other Impurities
`
`36.
`
`It should come as no surprise that in compounding an epinephrine
`
`formulation, by-product impurities in the starting drug substance (raw material)
`
`should be limited. One such impurity is adrenalone and the limits of adrenalone
`
`permissible in epinephrine raw material are laid out in USP. (Id. at 2260).
`
`37. Under “Limit of Adrenalone,” USP:2
`
`Its absorptivity (see Spectrophotometry and Light-scattering <851>)
`at 310 nm, determined in a solution in dilute hydrochloric acid (1 in
`200) containing 2 mg per mL, is not more than 0.2.
`
`(Id.).
`
`38. Absorptivity, α, as defined in USP <851> is the absorbance (A)
`
`normalized to the product of the sample concentration, c (in grams/L), times path
`
`length, l (usually assumed to be 1 cm):
`
`
`2 The adrenalone limit of 0.5% pertains to the raw material meaning that this
`
`limit is carried through to the solution.
`
` 
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`(cid:2009)(cid:3404)(cid:1827)(cid:1855) (cid:1864)
`
`So based on analyte weight, the absorbance (A) equals αcl. Setting l=1 cm, A is
`
`0.2 x 2 g/L, or 0.4.
`
`39. Absorbance (A) is equal to molar absorptivity, ε, times molar
`
`(cid:1827)(cid:3404)(cid:2013)(cid:1839)(cid:1864)
`
`concentration of analyte (M, in mol/L), times the light path length, l.:
`
`The path length is usually set to 1 cm. Since the molar absorptivity is 7300 M-1
`
`cm-1 (from Moed (Ex. 1017) at 923), one calculates the molar concentration of
`
`adrenalone to be about 0.4/7300, or 5.5 x 10-5 M. 2 g/L of epinephrine at a molar
`
`concentration of 0.011 mol/L, 2 g/L, 183.2 g/mol.
`
`
`
`40. This represents a molar percentage of:
`
`(5.5 x 10-5 / 0.011) x 100 = 0.5% adrenalone
`
`41. Therefore, using a test sample concentration of 2 mg epinephrine per
`
`mL and assuming that the molar absorptivity of adrenalone is 7300 M-1 cm-1, the
`
`upper limit of permissible adrenalone in a pharmacologically viable injection of
`
`epinephrine is 0.5%. This would be the same using a test sample concentration of
`
`1 mg epinephrine per mL.
`
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`IV. THE ‘197 PATENT
`42.
`I have been asked to assume (and I have assumed) for purposes of my
`
`analysis that the ‘197 Patent has a priority date of August 15, 2014. (Ex. 1001). I
`
`therefore offer my opinions in this declaration through the eyes of one of skill in
`
`the art (as defined below in Paragraphs 53 and 54) as of that date.
`
`43. The ‘197 Patent discloses a pharmaceutical formulation of l-
`
`epinephrine along with methods of producing and using the formulation. As the
`
`specification describes, epinephrine has a long history of pharmaceutical use that
`
`spans many decades since it was first synthesized at the turn of the twentieth
`
`century. (Ex. 1001 at 1:15–18).
`
`44. The background of the ‘197 Patent acknowledges that epinephrine
`
`formulations are plagued by two major problems, racemization and oxidation, as I
`
`discussed above. (Id. at 1:55–58).
`
`45. The background of the ‘197 Patent also describes that past solutions
`
`of epinephrine have included a microbial preservative in order to assure the
`
`sterility of the drug product and reduce oxidation. (Id. at 2:15–20). The ‘197
`
`Patent alleges these sulfites can cause severe allergic reactions in patients who are
`
`sensitive to sulfites. (Id. at 2:23–40).
`
`46. The ‘197 Patent purports to reduce these problems by creating a liquid
`
`formulation of l-epinephrine that is both preservative-free and sulfite-free, with
`
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`minimal overage, if any, and minimal levels of degradants, including d-
`
`epinephrine. (Id. at 2:47–59).
`
`47. The ‘197 Patent asserts that “[i]nadvertently, increasing the in-process
`
`pH to 2.8–3.3, unexpectedly reduced the racemization of l-epinephrine to d-
`
`epinephrine at release by approximately two-thirds, from 14% to 5%, respectively.
`
`To the contrary, these results led to the discovery that in a preservative-free,
`
`sulfite-free, l-epinephrine solution, racemization was a more significant problem
`
`than expected, even more so than oxidation. This discovery led to new methods of
`
`manufacturing sulfite-free, l-epinephrine solution with an in-process pH of 2.8 to
`
`3.3, approximately 3.0, which was a nonobvious solution to the problem of
`
`racemization.” (Id. at 4:48–58).
`
`48. Although the ‘197 Patent discusses the need for a preservative-free
`
`and sulfite-free formulation, Claim 6 and Claim 7 of the ‘197 Patent do not require
`
`that the formulation be preservative-free or sulfite-free.
`
`49. Claim 6 of the ‘197 Patent is reproduced below.
`
`An injectable liquid pharmaceutical formulation of l-epinephrine
`sterile solution; said liquid pharmaceutical formulation having a pH
`between 2.8 and 3.3; said injectable liquid pharmaceutical formulation
`compounded in an aqueous solution as 1.0 to 1.06 mg/mL l-
`epinephrine, and further including a tonicity agent; said liquid
`pharmaceutical formulation including no more than about 6% d-
`epinephrine and no more than about 0.5% adrenalone at release, and
`no more than about 12% d-epinephrine and no more than about 0.5%
`adrenalone over a shelf-life of at least 12 months.
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`50. Claim 7 further requires that the formulation of Claim 6 has a
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`concentration of 1 mg per mL l-epinephrine.
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`51. As discussed above, racemization and oxidation were known
`
`problems in the potency of epinephrine prior to the filing of the ‘197 Patent.
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`Moreover, it was known as of August 15, 2014, that a pH in the range of 2.8 to 3.3
`
`was necessary to reduce racemization and oxidation. For example, Connors
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`disclosed in 1986 that the need to minimize both epimerization and oxidation were
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`critical stability goals achieved by setting the pH appropriately: “The rate of
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`oxidation increases with increased pH, and since the rate of racemization decreases
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`with increased pH, there is an optimum pH at which racemization and oxidation
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`can be balanced to minimize loss of intact drug by these two routes: this is
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`approximately pH 3.0–3.8, which is consistent with USP”. (Ex. 1012 at 441).
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`52. Thus, in my opinion, both the ‘197 Patent’s identified problem and its
`
`identified solution of a pH between 2.8 and 3.3 were known in the art well before
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`August 15, 2014. In fact, the ‘197 Patent merely recites injectable liquid
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`pharmaceutical formulations
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`in accordance with known USP epinephrine
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`standards.
`
`V. LEVEL OF SKILL IN THE ART
`53.
`I was asked to provide my opinion about the experience and
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`background a person of ordinary skill in the art of the ‘197 Patent would have had
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`as of August 15, 2014. In my opinion, such a person of skill in the art would have
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`at least an advanced degree in in one of the fields of chemistry, pharmacy, or
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`pharmaceuticals. This person would have several years of experience in his or her
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`pertinent field, including areas of physical chemistry, organic chemistry, medicinal
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`chemistry, pharmaceutics, and chemical engineering. This person would have
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`additional experience in the pharmaceutical industry, specifically in dealing with
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`injectable formulations, which include the means and methods for packaging and
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`sterilizing parenteral products, knowledge of organic chemistry and common
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`modes of drug decomposition, knowledge of use of pH adjustment and other
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`means such as the use of excipients for optimizing drug solubility and stability, and
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`the physical and chemical aspects of drug-container interactions.
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`54. A person of ordinary skill in the art would be familiar with the
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`amounts of active pharmaceutical ingredients and additives used for injectable
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`formulations as well as the need for maintaining clinically acceptable osmolality
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`and pH.
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`55.
`
`I believe that I was a person of ordinary skill in the art as of August
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`15, 2014. Furthermore, I believe that I can provide an opinion today regarding
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`what those of skill in the art would have known and understood as of August 15,
`
`2014.
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`VI. CLAIM CONSTRUCTION
`56.
`I understand that claim terms are typically given their ordinary and
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`customary meanings, as would have been understood by a person of ordinary skill
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`in the art at the time of the alleged invention, which I understand is August 15,
`
`2014. In considering the meaning of the claims, however, I understand that one
`
`must consider the language of the claims, the specification, and the prosecution
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`history of record.
`
`57.
`
`I further understand that certain claim terms of the ‘197 Patent were
`
`construed in Case No. 17-775-LPS, Belcher Pharmaceuticals, LLC v. Hospira,
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`Inc., currently pending in the District of Delaware.3 (Ex. 1019). Those terms are
`
`shown in the table below:
`
`Claim Term
`compounded in an aqueous solution as
`1.0 to 1.06 mg/mL l-epinephrine
`
`said injectable liquid pharmaceutical
`formulation compounded
`
`in an aqueous solution
`
`District Court’s Construction
`having 1.0 to 1.06 mg/mL l-epinephrine
`in an aqueous solution after the
`compounding step has been completed
`
`the injectable liquid pharmaceutical
`formulation formed by combining the
`active ingredients and excipients
`
`in a homogenous mixture of one or
`more substances dissolved in a solvent
`that is mainly water
`
`
`3 I understand that Petitioner is not a party to the Delaware action.  
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`Claim Term
`as 1.0 to 1.06 mg/mL I-epinephrine
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`District Court’s Construction
`the concentration of 1-epinephrine in the
`compounded solution being within the
`range of 1.0 to 1.06 mg/mL
`
`and further including a tonicity agent
`
`no construction necessary
`
`58.
`
`In my opinion, the constructions applied by the District Court above
`
`are consistent with my understanding of the plain and ordinary meaning of each
`
`claim term of the ‘197 Patent. Therefore, I have applied the above constructions in
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`my analysis.
`
`59.
`
`I further understand the Court’s rationale that “after the compounding
`
`step has been completed” means that Claim 6 covers an “injectable liquid
`
`pharmaceutical formulation” at any point “after the compounding step has been
`
`completed.” That is, the limitations in Claim 6, including the l-epinephrine and pH
`
`ranges, are “after the compounding step has been completed.” (Ex. 1019). This is
`
`consistent with Patent Owner’s Infringement Contentions against Petitioner where
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`Patent Owner assets that the term “having a pH between 2.8 and 3.3” refers to the
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`final product, which is at a point “after the compounding step has been completed.”
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`(Ex. 1020 at 3) (“[T]he plain language of the claim states that ‘said liquid
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`pharmaceutical formulation’ has the stated pH range which logically and
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`grammatically refers to the final product.”).
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`60. For all other terms in the challenged claims of the ‘197 Patent, I have
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`applied the plain and ordinary meaning as understood by one of skill in the art.
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`VII. SUMMARY OF OPINIONS
`61.
`In my opinion, the pharmaceutical formulation of Claims 6 and 7 of
`
`the ‘197 Patent was known in the prior art.
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`62. My review of the documents referenced in the preceding and
`
`following sections comports with my experience that those of skill in the art prior
`
`to August 2014 knew that a pH of 2.8–3.3 would reduce racemization and
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`oxidation and result in a liquid pharmaceutical formulation according to Claims 6
`
`and 7 of the ‘197 Patent. Moreover, there is nothing novel or nonobvious about
`
`using a pH of 2.8–3.3 because it falls within the permissible pH levels described in
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`USP and one of skill in the art would routinely test various pH levels when
`
`formulating epinephrine injections.
`
`63.
`
`In particular, Stepensky describes an epinephrine
`
`injection
`
`in
`
`accordance with USP, that is nearly identical to Claims 6 and 7 of the ‘197 Patent.
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`The injection includes 1.03 mg of epinephrine per mL, 1 mg/mL of sodium
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`metabisulfite, 8 mg/mL of sodium chloride, and water for injection with a
`
`measured pH ranging from 3.25–3.7. (Ex. 1005 at 971 and 973). At a storage time
`
`of 0.2 years, the identified epinephrine samples had a d-epinephrine content of
`
`about 2%, with overall epinephrine content of about between 1.0 and 1.1 mg/mL
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`and l-epinephrine content of about between 1.0 and 1.03 mg/mL. (Id. at 975, Fig.
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`44). The batches were tested again between 1 and 2 years of storage. At that time,
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`the identified epinephrine samples had a d-epinephrine content of less than 12%, or
`
`about 3% and 6% at 1 and 2 years, respectively, with overall epinephrine content
`
`of about between 1.0 and 1.1 mg/mL. The upward trend of d-epinephrine with
`
`time is consistent with known acid-catalyzed racemization. One of skill in the art
`
`would further understand t