UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`_____________________________
`
`MYLAN PHARMACEUTICALS INC. & MYLAN LABORATORIES LIMITED,
`Petitioners,
`
`v.
`
`BAXTER INTERNATIONAL INC.,
`Patent Owner.
`
`_____________________________
`
`Patent No. 6,310,094
`
`_____________________________
`
`DECLARATION OF ROBERT J. LINHARDT, PH.D.
`
`MYLAN ET AL. - EXHIBIT 1002
`
`

`
`TABLE OF CONTENTS
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`QUALIFICATIONS...............................................................................................1
`QUALIFICATIONS ............................................................................................. .. 1
`
`SCOPE OF WORK ...............................................................................................3
`
`SCOPE OF WORK ............................................................................................. ..3
`
`III. OVERVIEW OF THE ’094 PATENT.......................................................................3
`
`OVERVIEW OF THE ’O94 PATENT ..................................................................... ..3
`
`III.
`
`IV.
`
`IV.
`
`V.
`
`VI.
`
`VI.
`
`FILE HISTORY OF THE ’094 PATENT..................................................................6
`
`FILE HISTORY OF THE ’O94 PATENT ................................................................ ..6
`
`LEGAL STANDARDS ..........................................................................................7
`
`LEGAL STANDARDS ........................................................................................ ..7
`
`LEVEL OF ORDINARY SKILL AND RELEVANT TIME ...........................................9
`
`LEVEL OF ORDINARY SKILL AND RELEVANT TIME ......................................... ..9
`
`VII. CLAIM CONSTRUCTION...................................................................................10
`
`CLAIM CONSTRUCTION ................................................................................. .. 10
`
`VII.
`
`VIII. THE STATE OF THE ART ..................................................................................12
`
`THE STATE OF THE ART ................................................................................ .. 12
`
`VIII.
`
`IX.
`
`CERTAIN REFERENCES DISCLOSE OR SUGGEST EACH OF THE CLAIMED
`
`IX. CERTAIN REFERENCES DISCLOSE OR SUGGEST EACH OF THE CLAIMED
`FEATURES OF THE ’094 PATENT......................................................................27
`
`FEATURES OF THE ’O94 PATENT .................................................................... ..27
`
`X.
`
`CONCLUDING STATEMENTS ............................................................................65
`
`CONCLUDING STATEMENTS .......................................................................... ..65
`
`XI. APPENDIX – LIST OF EXHIBITS........................................................................66
`
`APPENDIX — LIST OF EXHIBITS ...................................................................... ..66
`
`XI.
`
`-i-
`
`

`
`I, Robert J. Linhardt, declare as follows:
`QUALIFICATIONS
`
`I.
`
`1.
`
`My name is Robert J. Linhardt. I am currently the Ann and John H.
`
`Broadbent Senior Constellation Chair in Biocatalysis and Metabolic Engineering,
`
`and a Professor in the Departments of Chemistry and Chemical Biology, Biology,
`
`Chemical and Biological Engineering, and Biomedical Engineering at Rensselaer
`
`Polytechnic Institute (RPI). I have been a member of the faculty at RPI since
`
`2003. I am also an Adjunct Professor in the Orthopaedics Department at Mount
`
`Sinai School of Medicine as well as an Adjunct Professor of Pharmaceutical
`
`Sciences at Albany College of Pharmacy. Prior to joining the faculty at RPI, I was
`
`a member of the faculty in the College of Pharmacy at the University of Iowa for
`
`21 years, starting in 1982.
`
`2.
`
`I received a B.S. in Chemistry from Marquette University in 1975,
`
`and an M.A. and a Ph.D. in Organic Chemistry from The Johns Hopkins
`
`University in 1977 and 1979, respectively. I received additional, post-doctoral
`
`training in Biochemical Engineering at Massachusetts Institute of Technology.
`
`3.
`
`My current research program at RPI focuses on the study of bioactive
`
`carbohydrates, particularly the polysaccharide heparin, an anticoagulant which is
`
`administered parenterally, often continuously, due to its short half-life. I am
`
`currently using bioengineered Chinese hamster ovary cell lines to develop a
`
`biosynthetic pathway to produce a bioengineered heparin product. In addition to
`
`my studies on heparin, my research program also involves the determination of the
`
`therapeutic utility of proteoglycans and other glycoconjugates to determine new
`
`1
`
`

`
`pathways for drug development. I have extensive experience with pharmaceutical
`
`formulations, including the sterilization of parenteral formulations via autoclave.
`
`4.
`
`My research has been funded by such organizations as the National
`
`Institute of Health and the National Science Foundation, as well as other
`
`government agencies and foundations, and I have also served as an Industrial
`
`Consultant in the areas of biocatalysis, biopolymers, carbohydrate chemistry, and
`
`drug delivery since 1981. I also serve, or have served, on the editorial board of 20
`peer-reviewed journals such as the Journal of Biological Chemistry, Applied
`
`Biochemistry and Biotechnology, and the Journal of Carbohydrate Chemistry.
`
`5.
`
`I have authored or co-authored more than 700 scientific publications,
`
`the vast majority of which are peer-reviewed journal articles. I have also authored
`
`6 book chapters and been listed as an inventor on 65 issued patents. I have given
`
`over 130 invited seminars at scientific symposia and educational institutions.
`
`6.
`
`I have received numerous honors and awards, including being named
`
`one of the Scientific American 10, an honor bestowed upon ten individuals who
`
`“demonstrated outstanding commitment to assuring that the benefits of new
`
`technologies and knowledge will accrue to humanity.” I also received the USP
`
`Award for an Innovative Response to a Public Health Challenge, numerous
`
`accolades from the American Chemical Society, as well as the Volweiler Research
`
`Achievement Award in Pharmaceutical Sciences.
`
`7.
`
`A summary of my education, experience, publications, awards and
`
`honors, patents, publications, and presentations is provided in my CV, a copy of
`
`which is submitted separately. Ex. 1003.
`
`-2-
`
`

`
`II.
`
`SCOPE OF WORK
`
`8.
`
`I understand that a petition is being filed with the United States Patent
`
`and Trademark Office for Inter Partes Review of U.S. Patent No. 6,310,094
`
`(hereinafter “the ’094 patent,” Ex. 1001). I have been retained by the Petitioner as
`
`a technical expert to provide analysis and opinions regarding the ’094 patent. I
`
`have reviewed the ’094 patent and relevant sections of its prosecution history in the
`
`United States Patent and Trademark Office. Ex. 1004. I have also reviewed and
`
`considered various other documents in arriving at my opinions, and cite them in
`
`this declaration. For convenience, documents cited in this declaration are listed in
`
`the Appendix in Section XI.
`
`9.
`
`I am compensated at the rate of $600/hour for my work. I have no
`
`financial interest in the outcome of this matter.
`III. OVERVIEW OF THE ’094 PATENT
`
`10.
`
`The ’094 patent is entitled “Ready-To-Use Esmolol Solution.” The
`
`first page of the patent states that an application for the ’094 patent was filed on
`
`January 12, 2001.
`
`11.
`
`The ’094 patent is generally directed to pharmaceutical compositions
`
`of the drug esmolol hydrochloride, and methods of making thereof. Claim 1 of the
`
`’094 patent recites the following:
`
`1. An injectable, aqueous pharmaceutical composition for the
`treatment of cardiac conditions, having a pH between 3.5 and 6.5 and
`comprising
`
`-3-
`
`

`
`a. 0.1-100 mg/ml methyl-3-[4-(2-hydroxy-3-isopropylamino)
`propoxy] phenylpropionate hydrochloride (esmolol
`hydrochloride),
`b. 0.1-5.0 mg/ml buffering agent, and
`c. 1-100 mg/ml osmotic-adjusting agent.
`
`12. Claims 2 and 3 depend from claim 1 and recite further limitations to
`
`the composition. Claim 2 recites that the buffering agent comprises at least one of
`
`acetate, glutamate, citrate, tartrate, benzoate, lactate, gluconate, phosphate, and
`
`glycine. Claim 3 recites that the osmotic-adjusting agent comprises at least one of
`
`sodium chloride, dextrose, sodium bicarbonate, calcium chloride, potassium
`
`chloride, sodium lactate, Ringer’s solution, and lactated Ringer’s solution.
`
`13. Claim 4 of the ’094 patent is an independent claim to a method for
`
`preparing a pharmaceutical composition, and recites the following:
`
`4. A method for preparing a sterile, injectable aqueous
`pharmaceutical composition for the treatment of cardiac conditions,
`comprising forming an aqueous composition having a pH between 3.5
`and 6.5 comprising methyl-3-[4-(2-hydroxy-3-
`isopropylamino)propoxy] phenylpropionate hydrochloride (esmolol
`hydrochloride), a buffering agent, and an osmotic-adjusting agent in a
`sealed container, and autoclaving for a period of time sufficient to
`render the composition sterile.
`
`14. Claims 5-9 depend either directly or indirectly from claim 4 and recite
`
`further limitations to the method. Claim 5 recites that the composition comprises
`
`0.1-100 mg/ml esmolol hydrochloride, 0.1-5.0 mg/ml buffering agent, and 1-100
`
`-4-
`
`

`
`mg/ml osmotic-adjusting agent. Claim 6 recites that the composition is autoclaved
`
`at a temperature ranging from 115 to 130 °C for a period of time ranging from 5 to
`
`40 minutes. Claim 7 recites that the container is a flexible polymeric container free
`
`from polyvinyl chloride (PVC). Claim 8 recites that the method further comprises
`
`providing the container with a moisture barrier. Claim 9 recites that the moisture
`
`barrier is an aluminum overpouch.
`
`15.
`
`In the Background of the Invention of the ’094 patent, the applicants
`
`describe esmolol hydrochloride as “a short-acting beta-blocker used for treatment
`
`or prophylaxis of cardiac disorders in mammals.” Ex. 1001, col. 1, ll. 14-16. The
`
`applicants further describe instability of the drug in aqueous solutions without
`
`identifying a source for this information: “Esmolol hydrochloride contains an
`
`ester functional group . . . [that is] unstable in an aqueous environment because of .
`. . extreme susceptibility to hydrolytic degradation.” Id. at col. 1, ll. 24-33.
`
`16. Referring to prior art formulations of esmolol hydrochloride, the
`
`applicants state:
`
`The stability of esmolol in water is mediated by the rate of acid/base
`hydrolysis of the labile aliphatic methyl ester group. In the past, the
`rate of degradation of esmolol hydrochloride has been reduced by
`the use of acetate as a buffer, maintaining the pH as close to 5.0 as
`possible, minimizing the concentration of esmolol in the solution, and
`minimizing the concentration of buffer used. Prior art formulations
`maintain a reasonably long shelf-life, however, they are packaged in
`glass vials or ampules, and suffer from severe degradation upon
`autoclaving. As a result, prior art formulations are prepared
`aseptically. C.f. U.S. Pat. No. 4,857,552. However, terminal
`
`-5-
`
`

`
`sterilization is typically preferred by regulatory authorities as a way
`of reducing microbiological burden and to ensure the safety of the
`finished product.
`
`Id. at col. 1, ll. 34-48 (emphasis added).
`
`17.
`
`Thus, according to the ’094 patent, prior art formulations of esmolol
`
`hydrochloride contained acetate as a buffer, and had a pH of about 5.0. The
`
`applicants cite one reference related to esmolol hydrochloride, U.S. Patent No.
`4,857,552 to Rosenberg et al. (filed Jun. 8, 1988) (hereinafter “Rosenberg ’552,”
`
`Ex. 1012). As discussed in detail below in “The State of the Art,” I can find no
`
`teaching or suggestion that the injectable, aqueous pharmaceutical compositions of
`esmolol hydrochloride disclosed by Rosenberg ’552 (see Ex. 1012) “suffer from
`
`severe degradation upon autoclaving” as is asserted in the ’094 patent. Ex. 1001,
`
`col. 1, ll. 42-43.
`IV. FILE HISTORY OF THE ’094 PATENT
`
`18.
`
`It is my understanding that during prosecution of the ’094 patent, no
`
`information disclosure statements were filed by the applicants, and no Office
`actions were issued by the examiner. See Ex. 1004. Each of the originally filed
`
`claims was allowed by the examiner, without amendment, in a Notice of
`Allowance mailed on June 7, 2001. Id. at 0028. According to the examiner,
`
`original claims 1-9 were allowed because “the prior art fails to teach or suggest the
`
`inclusion of an osmotic agent.” Id.
`
`19. As discussed in detail below, compositions of esmolol hydrochloride
`
`containing osmotic-adjusting agents were described in publications that are prior
`
`-6-
`
`

`
`art to the ’094 patent. The only prior art reference marked as considered by the
`
`examiner was Rosenberg ’552 (Ex. 1012), which was mentioned in the
`
`Background of the Invention of the ’094 patent. Ex. 1001, col. 1, ll. 34-48.
`V.
`LEGAL STANDARDS
`
`20.
`
`I understand that a claim is not patentable under 35 U.S.C. §102, for
`
`lack of novelty, if each and every element of the claim is described, either
`
`expressly or inherently, in a single prior art reference.
`
`21.
`
`I have been informed that a claimed invention is not patentable under
`
`35 U.S.C. §103, for obviousness, if the differences between the invention 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 person having ordinary skill in the art to which
`
`the subject matter pertains.
`
`22.
`
`I have been instructed that, a determination of obviousness requires
`
`inquiries into (i) the scope and content of the art when the invention was made; (ii)
`
`the differences between the art and the claims at issue; (iii) the level of ordinary
`
`skill in the pertinent art when the invention was made; and, to the extent they exist,
`
`any secondary considerations.
`
`23.
`
`I understand that a claim can be found to be obvious if all the claimed
`
`elements were known in the prior art and one skilled in the art could have
`
`combined the elements as claimed by known methods with no change in their
`
`respective functions, and the combination would have yielded nothing more than
`
`predictable and expected results to one of ordinary skill in the art.
`
`-7-
`
`

`
`24.
`
`I understand that hindsight must not be used when comparing the
`
`prior art to the invention for obviousness. Thus, a conclusion of obviousness must
`
`be firmly based on the knowledge and skill of a person of ordinary skill in the art at
`
`the time the invention was made, without the use of post-filing knowledge.
`
`25.
`
`I understand that in order for a claimed invention to be considered
`
`obvious, there must be some supporting rationale for combining cited references as
`
`proposed.
`
`26.
`
`I have been informed that obviousness may also be shown by
`
`demonstrating that it would have been obvious to modify what is taught in a single
`
`piece of prior art to create the patented invention. Obviousness may be
`
`demonstrated by showing that it would have been obvious to combine the
`
`teachings of more than one item of prior art. In determining whether a piece of
`
`prior art could have been combined with other prior art or with other information
`
`within the knowledge of one of ordinary skill in the art, the following are examples
`
`of approaches and rationales that may be considered: combining prior art elements
`
`according to known methods to yield predictable results; simple substitution of one
`
`known element for another to obtain predictable results; use of a known technique
`
`to improve similar methods or products in the same way; applying a known
`
`technique to a known method or product ready for improvement to yield
`
`predictable results; applying a technique or approach that would have been
`
`“obvious to try” (choosing from a finite number of identified, predictable solutions,
`
`with a reasonable expectation of success); known work in one field of endeavor
`
`may prompt variations of it for use in either the same field or a different one based
`
`-8-
`
`

`
`on design incentives or other market forces if the variations would have been
`
`predictable to one of ordinary skill in the art; or some teaching, suggestion, or
`
`motivation in the prior art that would have led one of ordinary skill to modify the
`
`prior art reference or to combine prior art reference teachings to arrive at the
`
`claimed invention.
`
`27.
`I also understand that “secondary considerations” may be considered
`when in evidence to rebut a conclusion of prima facie obviousness where
`
`appropriate.
`
`28.
`
`I understand that such secondary considerations include: (i)
`
`commercial success of a product due to the merits of the claimed invention; (ii) a
`
`long-felt, but unsatisfied need for the invention; (iii) failure of others to find the
`
`solution provided by the claimed invention; (iv) deliberate copying of the invention
`
`by others; (v) unexpected results achieved by the invention; (vi) praise of the
`
`invention by others skilled in the art; (vii) lack of independent simultaneous
`
`invention within a comparatively short space of time; and (viii) teaching away
`
`from the invention in the prior art. Secondary considerations are relevant where
`
`there is a connection, or relationship, between the evidence and the claimed
`
`invention.
`VI. LEVEL OF ORDINARY SKILL AND RELEVANT TIME
`
`29.
`
`I have been advised that “a person of ordinary skill in the relevant
`
`field” is a hypothetical person who is presumed to have known the relevant art at
`
`the time of the invention. A person of ordinary skill in the art is also a person of
`
`ordinary creativity. I have been advised that the relevant timeframe for assessing
`
`-9-
`
`

`
`validity of claims of the ’094 patent is the time prior to January 12, 2001. Unless
`
`otherwise specifically noted, all of my opinions expressed herein regarding a
`
`person of ordinary skill in the art apply to a person of ordinary skill in the art prior
`
`to January 12, 2001.
`
`30. By virtue of my education, experience, and training, I am familiar with
`
`the level of skill in the art of the ’094 patent prior to January 12, 2001. In my
`
`opinion, a person of ordinary skill in the relevant field as of January 12, 2001
`would typically have an advanced degree (e.g., a Ph.D.) in organic chemistry,
`
`pharmaceutical chemistry, medicinal chemistry, pharmaceutics, physical
`
`pharmacy, or a related field, or could have less education but considerable
`
`professional experience in one or more of these fields.
`
`31.
`
`In particular, one of ordinary skill in the art would likely have some
`
`combination of the following skills and experience: (i) knowledge of sterilization
`
`methods for pharmaceutical products; (ii) experience with autoclaving; (iii)
`
`experience designing and preparing liquid drug formulations intended for
`
`parenteral administration; (iv) experience designing and preparing formulations of
`
`drugs that are unstable in water; (v) the ability to understand results and findings
`
`presented or published by others in the field, including the publications discussed
`
`in this declaration.
`VII. CLAIM CONSTRUCTION
`
`32.
`
`I have been advised that, in the present proceeding, the ’094 patent
`
`claims are to be given their broadest reasonable interpretation in view of the
`
`specification and this standard differs from the standard used in district court
`
`-10-
`
`

`
`patent litigation proceedings. I also understand that, at the same time, absent some
`
`reason to the contrary, claim terms are typically given their ordinary and
`
`accustomed meaning as would be understood by one of ordinary skill in the art. I
`
`have followed these principles in my analysis throughout this declaration.
`
`33.
`
`I understand “an injectable, aqueous pharmaceutical composition” as
`
`recited, e.g., in claim 1 of the ’094 patent, to mean “a pharmaceutical composition
`
`containing water, and suitable for injection into a patient.”
`
`34. Claim 4 of the ’094 patent recites “forming an aqueous composition [.
`
`. .] in a sealed container [. . .]” According to the specification, “[c]ompositions
`
`according to the present invention are packaged in suitable sealed containers,
`
`which may be either glass or polymer-based.” Ex. 1001, col. 2, ll. 38-40. The ’094
`
`patent describes preparing an aqueous composition “. . . in a calibrated
`
`compounding tank. . .” which is “then filled into . . . flexible bags . . . These bags
`are sealed in aluminum foil overpouches.” See id. at col. 3, l. 48 - col. 4, l. 5. In
`
`view of these disclosures and the specification of the ’094 patent as a whole, I
`
`understand “forming an aqueous composition [. . .] in a sealed container” to mean
`
`“forming an aqueous composition . . . and then placing the aqueous composition in
`
`a container and sealing the container.”
`
`35. Claim 8 of the ’094 patent recites “a moisture barrier.” According to
`
`the specification, “[t]he polymeric containers can further be provided with a
`
`moisture barrier as a secondary packaging system to prevent the loss of water
`during storage. . .” Id. at col. 2, ll. 44-46. In view of this disclosure and the
`
`-11-
`
`

`
`specification of the ’094 patent as a whole, I understand “a moisture barrier” to
`
`mean “an outer container suited to prevent the loss of water during storage.”
`
`36. Claim 9 of the ’094 patent recites that the moisture barrier of claim 8
`
`is “an aluminum overpouch.” According to the specification, “[a] preferred
`moisture barrier is an aluminum overpouch.” Id. at col. 2, ll. 47-48. The
`
`specification further discloses bags containing esmolol hydrochloride in solution
`that are “. . . sealed in aluminum foil overpouches.” Id. at col. 4, ll. 4-5. In view of
`
`these disclosures and the specification of the ’094 patent as a whole, I understand
`
`“an aluminum overpouch” to mean “an outer container composed of aluminum,
`
`including aluminum foils.”
`
`37.
`
`I have followed these definitions in my analysis throughout this
`
`declaration.
`VIII. THE STATE OF THE ART
`
`38. Below I describe some of the relevant aspects of what was generally
`
`known in the art as of January 12, 2001.
`
`39.
`
`Esmolol hydrochloride, an intravenous beta blocker employed for the
`
`treatment of cardiac events such as supraventricular tachyarrhythmias, ischemic
`
`heart disease, and hypertension, was approved by the U.S. Food and Drug
`Administration (FDA) in 1988 under the trade name Brevibloc® Injection. See
`Brevibloc® Injection Label, Center for Drug Evaluation and Research, 1988
`(hereinafter “Brevibloc® Label,” Ex. 1009). With regard to the structure and use of
`esmolol hydrocholride, L. Blanski et al., Esmolol, the first ultra-short-acting
`intravenous beta blocker for use in critically ill patients, 17 HEART LUNG, 80
`
`-12-
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`

`
`(1988) (hereinafter “Blanski,” Ex. 1010) teaches, “Esmolol (Brevibloc), a new
`
`short-acting intravenous cardioselective β-blocker . . . is similar to other β-blockers
`
`except for the ester linkage responsible for its short elimination half-life (9
`
`minutes).” Ex. 1010 at 81. The structure of esmolol hydrochloride is shown below.
`
`Formulations of esmolol hydrochloride were known in the art prior to
`40.
`January 12, 2001. The Brevibloc® Label teaches two formulations of the
`Brevibloc® Injection. The first is a concentrate, described as a “. . . sterile,
`nonpyrogenic solution for intravenous infusion after dilution,” with an appropriate
`intravenous fluid such as, e.g., sodium chloride solutions, dextrose solutions, or
`
`lactated Ringer’s solutions. Ex. 1009 at 0001, 0004; see also, Ex. 1010 at 87. The
`second formulation described in the Brevibloc® Label is a 10 mL “Single Dose
`Vial,” which did not require additional dilution. Ex. 1009 at 0001; see also, Ex.
`
`1010 at 87. Thus, esmolol hydrochloride was known in the art to be an FDA-
`
`approved pharmaceutical for the treatment of a range of cardiac events, and was
`
`supplied as both a concentrated solution, as well as a ready-to-use injection well
`
`prior to January 12, 2001.
`
`41.
`
`The concentrated formulation of esmolol hydrochloride was known to
`
`have caused severe complications when it was erroneously administered directly,
`
`without dilution into an isotonic intravenous fluid. A 1996 letter to the editor by
`
`-13-
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`

`
`Dr. D.J. Pearce, Brevibloc drug errors, 43 CAN. J. ANESTH. 419 (1996) (hereinafter
`
`“Pearce,” Ex. 1011) describes the “routine administration of Brevibloc” to a patient
`
`resulting in “brady-asystolic arrest requiring full resuscitation measures. The
`
`patient developed severe cardiogenic shock and was further treated with
`
`vasopressors and monitored in the ICU.” Ex. 1011 at 419. The prescribing doctor
`
`later came to realize, “the discarded Brevibloc vial contained the . . . concentrat[e]
`rather than the [ready-to-use] 10 mg • ml-1 concentration used in the bolus
`containers. The containers are so similar, that this mistake is likely to recur.” Id.
`Thus, the public literature cautioned that the Brevibloc® concentrate, when
`administered directly, resulted in life-threatening complications, and that its
`
`container and label were easily mistaken for the ready-to-use injection formulation.
`
`42.
`
`In addition to being safer to administer than concentrated solutions,
`
`ready-to-use preparations of esmolol hydrochloride were also appreciated in the art
`
`as being more stable. Rosenberg ’552 teaches factors affecting the stability of an
`
`injectable, aqueous pharmaceutical composition of esmolol hydrochloride:
`
`[T]he rate of degradation of esmolol can be reduced by: (1) use of
`acetate as the buffer, (2) maintaining the pH as near to pH = 5.0 as
`possible, (3) minimizing the concentration of esmolol in solution,
`and (4) minimizing the concentration of buffer used. If these four
`conditions can be met, then it is possible to formulate esmolol in a
`totally aqueous solution with an acceptable shelf life.
`
`Ex. 1012, col. 2, ll. 42-51 (emphasis added).
`
`-14-
`
`

`
`Thus, the art recognized that dilute solutions of esmolol hydrochloride resulted in
`
`more stable formulations, with decreased rates of degradation, and consequently
`
`longer shelf lives.
`
`43. Rosenberg ’552 also teaches that a pH “as near to pH = 5.0 as
`
`possible,” is an important parameter in the stability of esmolol hydrochloride
`
`formulations. Rosenberg ’552 describes the relative stability of esmolol
`
`hydrochloride for a range of pH values from 0-12, and discloses, “[t]he pH
`
`showing maximum stability [of esmolol] was found to be pH = 5.0±0.50.” Ex.
`
`1012, col. 2, l. 68 – col. 3, 1. 1. Rosenberg ’552 also teaches an inherent self-
`
`buffering capability of esmolol, which allows for the reduction of buffer necessary
`
`to hold esmolol hydrochloride compositions at a pH close to 5.0:
`
`[Esmolol] degrad[es] in aqueous solution to produce 3-[4-(3-propionic
`acid)-phenoxy]-1-isopropylamino-2-propanol (degradation product),
`said degradation product having a pK in the pH range of the
`composition to thereby act as a secondary buffer to increase the buffer
`capacity and minimize the change in pH and thereby maximize the
`stability of esmolol in aqueous composition.
`
`Ex. 1012, col. 1, l. 64 – col. 2, l. 3.
`
`44. Rosenberg ’552 notes that the esmolol degradation product, which
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`forms via the hydrolysis of the methyl ester, has a pK of 4.8, which is “just below
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`the initial pH (i.e. the pH of maximum stability). This . . . reduces the change in
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`pH due to degradation. The stability and shelf life of esmolol in an aqueous
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`formulation is thereby increased.” Ex. 1012, col. 3, ll. 56-61. Thus esmolol
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`hydrochloride is taught by Rosenberg ’552 to be stabilized by its own hydrolysis
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`degradation product, and aqueous formulations of esmolol hydrochloride are
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`described as being more stable due to this self-buffering phenomenon.
`
`45. As esmolol hydrochloride was an established drug product that was
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`marketed and sold prior to January 12, 2001, multiple formulations of the
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`pharmaceutical were known. Ex. 1012, col. 2, ll. 35-41; see also, ¶ 40 above
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`discussing Ex. 1009. Regarding these multiple known formulations, Rosenberg
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`’552 teaches:
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`Current esmolol formulations use alcohol and propylene glycol to
`minimize the concentration of water in the formulation and therefore,
`slow [the] degradation pathway. As an alternative to the mixed
`organic/aqueous formulation, work has been done in totally aqueous
`solutions.
`
`Ex. 1012, col. 2, ll. 36-41.
`
`Thus, esmolol hydrochloride solutions which did not contain propylene glycol,
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`ethanol, or other organic solvents are described.
`
`46. Rosenberg ’552 teaches that the elimination of organic solvents such
`
`as alcohols and propylene glycol from the drug preparation has notable benefits:
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`“[An] advantage of the totally aqueous formulation is that there are no ‘extra’
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`routes of degradation possible. The only possible competing reaction, in the totally
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`aqueous formulation of esmolol, is the recombination of the degradation product
`and methanol to reform esmolol.” Id. at col. 3, ll. 61-66. Thus, the art recognized
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`that the formulation of esmolol hydrochloride as a totally aqueous solution had
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`benefits over mixed organic/aqueous formulations.
`
`47. Rosenberg ’552 provides a table summarizing the results of a shelf
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`life stability study of an injectable, aqueous composition of esmolol hydrochloride.
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`Ex. 1012, col. 9, ll. 37-61. The prepared esmolol hydrochloride solutions, which
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`also contained an acetate buffer and were adjusted to a pH of about 5.0, were
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`placed in vials which were sealed, and then tested for stability by storing the vials
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`“in the inverted position which is an aggressive test because of the solution to
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`stopper contact,” at a range of temperatures from room temperature (15 to 30 °C)
`to 75 °C for a time period of one to nine months. Id. at col. 9, ll. 1-23. Over the
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`course of the months-long shelf stability assay, the aqueous esmolol samples
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`exhibited degradation ranging from 0.5% to 54%. Rosenberg ’552 notes this test
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`was designed to be “aggressive” due to the position of the vials and also, as “[w]ith
`time, most drugs will begin to degrade in solution.” Id. at col. 4, ll. 1-2. Thus,
`
`Rosenberg ’552 teaches a shelf stability study showing esmolol hydrochloride
`
`degradation, using months as units of time. Rosenberg ’552 does not teach a
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`stability study of esmolol hydrochloride at temperatures above 75 °C or for a time
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`period of less than one month, nor does Rosenberg ’552 make predictions as to the
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`stability of esmolol hydrochloride at higher temperatures or for shorter durations.
`
`48.
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`The inclusion of osmotic adjusting agents in parenteral drug
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`formulations was well known in the art prior to January 12, 2001. Chapters 36 and
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`84, REMINGTON’S 19TH EDITION: THE SCIENCE AND PRACTICE OF PHARMACY (A.
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`Gennaro, ed. 1995) (hereinafter “Remington’s,” Ex. 1013) describes the
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`undesirable effects of a parenteral formulation without proper osmotic adjusting
`
`agents, resulting in a dosage with abnormal osmoticity:
`
`Osmoticity is of great importance in parenteral injections, its
`effects depending on the degree of deviation from tonicity, the
`concentration, the location of the injection, the volume injected, the
`speed of the injection, the rapidity of dilution and diffusion, etc.
`When formulating parenterals, solutions otherwise hypotonic usually
`have their tonicity adjusted by the addition of dextrose or sodium
`chloride . . . Hypotonic and hypertonic solutions usually are
`administered slowly in small volumes . . . Solutions that differ from
`the serum in tonicity generally are stated to cause tissue irritation, pain
`on injection and electrolyte shifts.
`
`Excessive infusion of hypotonic fluids may cause swelling of red
`blood cells, hemolysis and water invasion of the body’s cells in
`general. When this is beyond the body’s tolerance for water, water
`intoxication results, with convulsions and edema, such as pulmonary
`edema.
`
`Ex. 1013 at 0007 (bold added; italics in original).
`
`49.
`
`Thus, Remington’s teaches that parenteral drugs must be formulated
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`with osmotic adjusting agents such as sodium chloride and dextrose if they are to
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`be safely administered in large volumes.
`
`50.
`
`It was known in the art that esmolol hydrochloride was stable when
`
`diluted with intravenous fluids to yield a ready-to-use solution with appropriate
`osmoticity. D. M. Baaske et al., Stability of esmolol hydrochloride in intravenous
`solutions, 51 AM. J. HOSP. PHARM. 2693 (1994) (hereinafter “Baaske,” Ex. 1014).
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`Baaske provides a shelf life stability study, which teaches the stability of esmolol
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`hydrochloride combined with intravenous solutions of osmotic adjusting agents
`
`such as, e.g., sodium chloride, dextrose, lactated Ringer’s injection, sodium
`
`bicarbonate, and potassium chloride, in concentrations of 10 mg/mL. Baaske
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`concluded: “With one exception [of sodium bicarbonate], esmolol hydrochloride
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`was stable in all the i