Case 1:14-cv-06893-JBS-KMW Document 53 Filed 08/10/15 Page 1 of 25 PageID: 3685
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`______________________________________
`SENJU PHARMACEUTICAL CO., LTD.,
`BAUSCH & LOMB INCORPORATED, and
`BAUSCH & LOMB PHARMA HOLDINGS
`CORP.,
`Plaintiffs,
`v.
`
`LUPIN, LTD. and LUPIN
`PHARMACEUTICALS, INC.,
`
`Defendants.
`
`INNOPHARMA LICENSING, INC.,
`INNOPHARMA LICENSING, LLC,
`INNOPHARMA, INC., INNOPHARMA,
`LLC, MYLAN PHARMACEUTICALS, INC.,
`and MYLAN INC.,
`Defendants.
`______________________________________
`
`DECLARATION OF JAYNE LAWRENCE, PH.D IN SUPPORT OF DEFENDANTS’
`CLAIM CONSTRUCTION BRIEF
`
`I, Jayne Lawrence, Ph.D., declare and state as follows:
`
`I.
`
`INTRODUCTION
`
`1. I am over the age of eighteen (18) and otherwise competent to make this declaration.
`
`2. I have been asked to provide my opinion on the meaning of several claim terms in U.S.
`
`Patents 8,129,431 (“the ’431 patent”) (Ex. 12), 8,669,290 (“the ’290 patent”) (Ex. 13),
`
`8,754,131 (“the ’131 patent”) (Ex. 14), 8,871,813 (“the ’813 patent”) (Ex. 15) and 8,927,606
`
`(“the ’606 patent”) (Ex. 16) (collectively, “the patents in suit”).
`
`3. I am being compensated for my time in connection with this litigation at my standard
`
`consulting rate, which is GBP300 per hour. My compensation is not contingent on the
`
`
`
`UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`
`
`
`Civil Action No.: 1:14-cv-00667-JBS-KMW
`Civil Action No.: 1:14:cv-04149-JBS-KMW
`Civil Action No.: 1:14-cv-05144-JBS-KMW
`Civil Action No.: 1:15-cv-00335-JBS-KMW
`
`
`
`Civil Action No.: 1:14-cv-06893-JBS-KMW
`Civil Action No.: 1:15-cv-03240-JBS-KMW
`
`
`
`Page 1 of 25
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`SENJU EXHIBIT 2250
`LUPIN v. SENJU
`IPR2015-01100
`
`

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`Case 1:14-cv-06893-JBS-KMW Document 53 Filed 08/10/15 Page 2 of 25 PageID: 3686
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`conclusions I reach herein or on the specifics of my testimony. I have no financial stake in the
`
`outcome of this proceeding.
`
`4. I have not testified in any case in the previous four years.
`
`II. QUALIFICATIONS
`
`5. I am an expert in the field of formulation and drug delivery, specifically pharmaceutical
`
`formulation for oral and parenteral use (i.e., non-oral, including intravenous intramuscular,
`
`nasal, respiratory and ophthalmic), including aqueous liquid preparations. I have been an expert
`
`in this field since prior to 2003.
`
`6. I received a BSc with first class (top) honors from Liverpool Polytechnic in 1981, and a
`
`Ph.D. in Pharmacy from Manchester University in 1985. The subject of my PhD studies was
`
`the design, synthesis and physic-chemical characterization of novel non-ionic surfactants1 for
`
`use in aqueous pharmaceutical formulations. I performed my PhD studies under the supervision
`
`of Professors P.H. Elworthy and D. Attwood.
`
`7. From 1984 to the present time I have held full-time, tenured academic positions of
`
`increasing seniority in Pharmacy (Lecturer 1984-1997, Senior Lecturer 1997-1999), Drug
`
`Delivery (Reader 2000-2003) and, most recently Biophysical Pharmaceutics (Professor 2003-to
`
`date) at King’s College London. I note that my professorship at King’s College London is the
`
`United Kingdom equivalent of a full, tenured Professorship in a university in the United States.
`
`In 1993 I spent a 6 month sabbatical working in Respiratory Product Development in Glaxo
`
`
`A surfactant is an amphiphilic molecule which contains a region that is hydrophobic
`1
`(water-hating) and a region that is hydrophilic (water-loving). A non-ionic surfactant is a
`surfactant that does not dissociate into charged ions in solution. As a consequence of their dual
`nature, surfactants collect at surfaces, lowering surface tension as well as self-
`assembling/aggregates in solution. These unique properties make surfactants very attractive
`excipients in pharmaceutical formulations.
`
`
`
`2
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`Group Research (now GSK) concerned with the potential use of surfactants in the new
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`propellant formulations.
`
`8. I am currently Head of the Pharmaceutical Biophysics Group of The Institute of
`
`Pharmaceutical Science, King’s College London and I have held this position since 2002. The
`
`Pharmaceutical Biophysics Group of The Institute of Pharmaceutical Science, King’s College
`
`London currently consists of 6 academics and associated post-doctoral fellows and PhD
`
`students. The work of the group is concerned with securing an understanding at the molecular
`
`level of the physicochemical and biological properties of drug and gene delivery systems,
`
`through the combined application of advanced analytical techniques.
`
`9. Since 2007, I have also held the role of Chief Scientist at the Royal Pharmaceutical
`
`Society on a part-time secondment from King’s College London. At the present time, I equally
`
`divide my time between these two roles. My role at the Royal Pharmaceutical Society involves
`
`me representing it at the highest levels to outside organisations and key stakeholders (including
`
`government and public bodies), acting as its spokesperson on pharmaceutical sciences in the
`
`media and ensuring high quality pharmaceutical science input to policy development and
`
`implementation.
`
`10. My past and current research has been in relation to pharmaceutical formulation and
`
`drug/gene delivery. I have been a principal or co-investigator on many formulation and
`
`drug/gene delivery studies, recent examples of which include the development of novel
`
`microemulsions for parenteral delivery, including for ocular administration; synthesis and
`
`characterisation of novel, non-ionic and zwitterionic surfactants with enhanced drug
`
`solubilisation capacity; the development of novel polymeric surfactants for pulmonary delivery;
`
`
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`3
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`nanoparticles for the targeted delivery of therapeutic agents to the brain; and development of
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`new injectable composites for gene delivery.
`
`11. I have co-authored over 120 full scientific publications, with numerous conference papers
`
`and other scientific outputs such as articles for the scientific magazines. I have given over 150
`
`invited (national and international) presentations. I have also been involved in the organisation
`
`of many pharmaceutical science meetings and conferences including the annual Academy of
`
`Pharmaceutical Sciences conference.
`
`12. As listed in my curriculum vitae, I have also received numerous awards pertaining to my
`
`research and teaching. For example, in 2013 I became a Faculty Fellow of the Royal
`
`Pharmaceutical Society (“FFRPS”), while in 2012 I was awarded an Eminent Fellowship of the
`
`Royal Pharmaceutical Society (“EFAPS”), one of only 20 such Fellowships.
`
`13. I currently hold senior positions in a number of national and international scientific
`
`committees, including the Academy of Pharmaceutical Sciences of Great Britain where I am
`
`currently vice-chair and the Formulation and Pharmaceutical Technology Special Interest Group
`
`of the International Pharmaceutical Federation where I am vice-chair but will become chair next
`
`year.
`
`14. In addition to gaining expertise through educational training, professional experiences,
`
`and research experiences described above, I have kept abreast of the field of drug/gene delivery
`
`and formulation, particularly of aqueous liquid preparations by reading scientific literature,
`
`attending or presenting at scientific conferences, and attending or presenting at academic
`
`symposia. I have also been invited to participate in the peer review process for various scientific
`
`journals, and have reviewed many manuscripts submitted by other scientists relating to drug
`
`delivery, including ocular delivery. Some of the scientific journals for which I have reviewed
`
`
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`4
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`scientific manuscripts include: International Journal of Pharmaceutics, Journal of
`
`Pharmaceutical Science, Langmuir, and Biochim. Biophys. Acta. Furthermore, I have
`
`collaborated with, or have communicated with, many researchers in the field of formulation and
`
`drug/gene delivery. Accordingly, I am an expert in the field of formulation and drug/gene
`
`delivery.
`
`15. In formulating my opinions, I have relied upon my training, knowledge, and experience
`
`in the relevant art.
`
`16. A copy of my current curriculum vitae is provided as Appendix A, and it provides a
`
`comprehensive description of my academic and employment history.
`
`III. MATERIALS REVIEWED
`
`17. In forming my opinions, I have reviewed, among other things, the materials cited in this
`
`report, the ’431 patent, the ’290 patent, the ’131 patent, the ’813 patent, the ’606 patent and
`
`papers filed in the Patent Office in connection with prosecution of each of these patents, which I
`
`understand to constitute the prosecution histories of the patents. A full list of materials I have
`
`considered can be found in Appendix B.
`
`IV. LEGAL STANDARDS
`
`18. I understand that for claim construction purposes, the Court will look to the meaning a
`
`person having ordinary skill in the art at the time of the invention would have ascribed to
`
`disputed claim terms, in view of the specification and prosecution history.
`
`19. With respect to the level of ordinary skill in the art at the relevant times applicable to the
`
`subject patents, I understand that factors such as the education level of those working in the
`
`field, the sophistication of the technology, the types of problems encountered in the art, the prior
`
`art solutions to those problems, and the speed at which innovations are made may help establish
`
`
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`the level of skill in the art. One with ordinary skill has the ability to understand the technology
`
`and make modest adaptations or advances. A person of ordinary skill in the art is also a person
`
`of ordinary creativity, not a robot.
`
`20. In my opinion, a person of ordinary skill in the art at the time of the alleged invention
`
`described in the subject patents would have been a pharmaceutical scientist involved in the
`
`research and development of pharmaceuticals, and would have a Ph.D. and several years of
`
`experience in the field. The amount of post-graduate level experience would depend upon the
`
`level of formal education and particular experience in the field.
`
`21. In determining the qualifications of a person of ordinary skill in the art I considered,
`
`among other factors, the field of the alleged invention and use thereof described in the subject
`
`patents, and my experience with the educational level of practitioners in the fields of drug/gene
`
`formulation, pharmacy, drug/gene delivery, analytical chemistry, organic chemistry, or
`
`chemical engineering. In addition, my opinion is based upon my background, education, and
`
`personal experience in the fields of pharmaceutical development.
`
`22. I consider myself to be an expert in the art of the subject patents at the time of the alleged
`
`inventions claimed therein.
`
`23. I understand that to determine how the skilled person would have understood disputed
`
`claim language, courts first look to the “intrinsic evidence,” the words of the claims themselves,
`
`the patent specification and the prosecution history. I understand that statements in related
`
`patents applications can also be relevant to claim construction.
`
`24. I understand that courts may also consider “extrinsic evidence,” including all evidence
`
`external to the patent and prosecution history, such as dictionaries and learned treatises, and
`
`expert testimony concerning relevant scientific principles, the meaning of technical terms, and
`
`
`
`6
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`the state of the art. I understand that while courts may rely on extrinsic evidence, it is less
`
`significant than the patent and prosecution history in determining the meaning of claim
`
`language. I understand that extrinsic evidence can also be helpful to assist the Court in
`
`understanding what a skilled person would have known at the time that the patent was filed.
`
`25. I understand that a claim term is indefinite, and therefore the claim is invalid, when the
`
`claim read in light of the specification and the prosecution history, fail to inform, with a
`
`reasonable certainty, those skilled in the art about the scope of the claimed invention. I
`
`understand that claims need not provide absolute precision, but they must provide clarity to a
`
`person of ordinary skill in the art the boundaries of what is claimed. I understand that whether a
`
`claim is indefinite is examined from the perspective of the person of ordinary skill in the art at
`
`the time the patent was filed.
`
`26. I have been advised that the relevant time period for conducting my analysis is the
`
`earliest claimed priority date for the patents, or January 21, 2003. Although I note that the
`
`opinions set forth herein would be the same, even if I considered a later time period, through
`
`and including the present day.
`
`V.
`
`SUMMARY OF OPINIONS
`
`27. The phrase “EDTA sodium salt” in the ’431 patent, ’290 patent, ’131 patent, and ’606
`
`patent should be construed to mean “edetic acid tetrasodium salt” or “tetrasodium edetate.”
`
`28. The phrase “sodium edetate” in the 431 patent should be construed to mean “edetic acid
`
`tetrasodium salt” or “tetrasodium edetate.”
`
`29. The phrase “in an amount sufficient to stabilize said first component” in the ’131 patent,
`
`’290 patent, ’813 patent, and ’606 patent is indefinite.
`
`
`
`7
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`30. The phrase “stable” in the ’290 patent, ’131 patent, ’813 patent, and ’606 patent is
`
`indefinite.
`
`31. The phrase “satisfied the preservative efficacy standard of US Pharmacopoeia as follows:
`
`viable cell counts of bacteria (S. aureus, P. aeruginosa) 24 hours and 7 days after inoculation
`
`decreases to not more than 1/10 and not more than 1/1000, respectively, and thereafter, the cell
`
`count levels off or decreases; and viable cell count of fungi (C. albicans, A. niger) 14 days after
`
`inoculation decreases to not more than 1/10, and thereafter, the cell count keeps the same level
`
`as that of 14 days after inoculation” is indefinite.
`
`VI. DETAILED OPINIONS
`
`a. Background and the Patents in Suit
`
`32. The patents in suit2 are generally directed to anti-inflammatory ophthalmic formulations
`
`containing (1) 2-amino-3-(4-bromobenzoyl)phenylacetic acid (also known as bromfenac), a
`
`non-steroidal anti-inflammatory drug (“NSAID”), and (2) tyloxapol, a non-ionic surfactant, and
`
`methods for treating an inflammatory disease by administering such formulations. Claim 1 of
`
`the ’431 patent, and claim 1 of the ’606 are representative.
`
`33. Claim 1 of the ’431 patent is below3:
`
`1. An aqueous liquid preparation consisting essentially of the following two
`components,
`wherein
`the
`first
`component
`is
`2-amino-3-(4-
`bromobenzoyl)phenylaceticacid or a pharmacologically acceptable salt thereof or
`a hydrate thereof, wherein the hydrate is at least one selected from a 1/2 hydrate,
`1 hydrate, and 3/2 hydrate and the second component is tyloxapol, wherein said
`liquid preparation is formulated for ophthalmic administration, and wherein when
`a quaternary ammonium compound is included in said liquid preparation, the
`quaternary ammonium compound is benzalkonium chloride.
`
`
`2 Because of the overlap in subject matter among the patents in suit, and their shared
`specifications, I will refer to the patents, or patents in suit when discussing principles that apply
`to all the patents. When an issue only applies to a single patent, I will indicate as much.
`3 A chart outlining where all the disputed terms occur in each patent claim is attached as
`Appendix C.
`
`
`
`8
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`34. Claim 1 of the ‘606 is below:
`
`the method
`1. A method for treating an inflammatory disease of an eye,
`comprising administering to said eye a stable aqueous liquid preparation that
`comprises: (a) a first component; and (b) a second component; wherein the first
`component
`is
`2-amino-3-(4-bromobenzoyl)phenylacetic
`acid
`or
`a
`pharmacologically acceptable salt
`thereof or a hydrate thereof, wherein the
`hydrate is at least one selected from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate; the
`first component is the sole pharmaceutical active ingredient contained in the
`preparation; the second component is tyloxapol and is present in said liquid
`preparation in an amount sufficient to stabilize said first component; wherein said
`stable liquid preparation is formulated for ophthahnic administration; and wherein
`said liquid preparation is administered to said eye at a dose and a fiequency
`effective to treat said inflammatory disease.
`
`a. A Person of Skill In the Art Would Understand that “Sodium Edetate” and
`
`“EDTA Sodium Salt” Mean Edetic Acid Tetrasodium Salt or Tetrasodium
`
`Edetate
`
`35. EDTA, otherwise known as edetic acid or ethylenediameinetetraacetic acid, has the
`
`following chemical structure:
`
`HO
`
`0
`
`o
`
`N
`
`N
`
`0
`
`Ho{ %
`
`0
`
`OH
`
`36. An acid has a tendency to lose a positively charged proton (Hi), thus resulting in a
`
`negatively charged anion. For example, EDTA may lose a proton from one of its acidic groups,
`
`forming EDTA’ as follows:
`
`Page 9 of 25
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`

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`Case 1:14-cv-06893-JBS-KMW Document 53 Filed 08/10/15 Page 10 of 25 PagelD: 3694
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`HO
`
`O
`
`>/._\ 4>\O,
`
`O
`
`N
`
`N
`
`0
`
`Ho{ \—Q
`
`0
`
`OH
`
`37. Having lost a positively charge proton, EDTA" has a charge of -1.
`
`38. The counterpart of an anion, a cation is an ion having a positive charge. For example, the
`
`sodium cation, Na+, has a charge of +1 .
`
`39. Ions of opposite charge are attracted to each other, and therefore anions and cations can
`
`bind together, forming salts. The principle of charge neutrality requires that a salt be
`
`electrically neutral (i.e., the positive charge of the cation(s) and the negative charge of the
`
`anion(s) cancel each other out). Thus, an EDTA molecule that has lost a single proton (and
`
`therefore has a -1 charge) may bind with a single sodium cation (which has a +1 charge):
`
`HO
`
`O‘ Na*
`
`E O
`
`O
`
`N
`
`_LN 0
`
`O
`
`HO
`
`OH
`
`40. Because EDTA has four acidic groups, it can lose up to four protons, and can therefore
`
`exist as one of four ionic species: EDTA’, EDTA2', EDTA3’, EDTA‘, having charges of -1, -2,
`
`-3, and -4, respectively:
`
`Page 10 of 25
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`10
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`Case 1:14-cv-06893-JBS-KMW Document 53 Filed 08/10/15 Page 11 of 25 Page|D: 3695
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`w» %}
`0
`N
`
`O
`
`»@—er
`or %\ )
`
`H0 L{
`0
`OH
`
` N O
`0
`O
`
`N
`
`Ho
`
`O
`$0
`
` N 0
`0
`0
`
`0
`
`41. Because EDTA may have a charge of -l, -2, -3, or -4, it may form four unique salts with
`
`sodium, having either 1, 2, 3, or 4 sodium cations:4
`
`O Na’ Na‘ 0
`
`:h g N 0%
`0% % 0%
`..Q”%1 QM? .Q“><° 9%:
`
`0 Na’ ~a'o
`
`HO
`
`ON,
`
`42. When present as a salt form, EDTA is generally referred to as an edetate salt. Thus, there
`
`are four different edetate salts consisting of EDTA and sodium: a monosodium, disodium,
`
`trisodium, and tetrasodium edetate salt. EDTA can also form other types of salts with sodium.
`
`For example, EDTA can bind with two sodium ions and a calcium ion (which has a +2 charge).
`
`43. I have reviewed the patents in suit, including the specification and the claims, and have
`
`found the terms “sodium edetate” and “EDTA sodium salt” used, but there is no explanation or
`
`definition or any other indication as to the meaning to the term besides the words themselves.
`
`44. I have reviewed the prosecution histories of the patents in suit and note that during
`
`prosecution of U.S. Patent No. 8,129,431, the Applicants stated, “[n]ote that sodium tetraborate
`
`is also known as borax, and EDTA sodium salt is also known as sodimn edetate.” 03x. 1, ’431
`
`patent prosecution history, Mar. 24, 2010 amendment at 7). This statement suggests that
`
`“EDTA sodium salt” is synonymous with “sodium edetate,” but provides no further clarification
`
`Because the four acidic groups of EDTA are equivalent, the probability of any particular
`4
`group being ionized is equal. I have illustrated only one exemplary conformation for each
`sodium salt.
`
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`of the meaning of these terms. No further statements by the Applicants elucidate the meaning
`
`of these terms.
`
`45. Turning to the extrinsic evidence, a person of skill in the art would have looked to the
`
`Merck Index for understanding the names and definitions of chemicals. The Merck Index is a
`
`highly-regarded, standard reference in the formulation field, and would have been well known
`
`to the person of ordinary skill in the art. The 2001 Merck Index provides an entry for edetic
`
`acid (i.e., ethylenediameinetetraacetic acid or EDTA), as well as entries for several of its salts,
`
`including edetate calcium disodium (sodium calcium edetate), edetate disodium (disodium
`
`edetate), edetate sodium (sodium edetate, tetrasodium edetate, EDTA tetrasodium), and edetate
`
`trisodium (trisodium edetate). (See Ex. 2, THE MERCK INDEX (O’Neil ed., Merck & Co.,
`
`Inc., 13th ed. 2001) at 620-21. LUPIN018902-06.).
`
`46. Accordingly, the nomenclature for the salts of edetic acid distinguishes among them
`
`based upon the number of sodium ions included in the salt. For example, edetate disodium
`
`refers exclusively to the EDTA salt having two sodium ions, while trisodium edetate refers
`
`exclusively to the EDTA salt having three sodium ions. And “edetate sodium” refers
`
`exclusively to tetrasodium edetate or edetic acid tetrasodium salt (i.e., the EDTA salt having
`
`four sodium ions). Notably, “edetate sodium” is also referred to as “sodium edetate.” Thus, a
`
`person of skill in the art would have understood that “sodium edetate” means tetrasodium
`
`edetate or edetic acid tetrasodium salt.
`
`47. Another reference commonly used by a person of skill in the art to identify excipients in
`
`pharmaceutical formulations was The Handbook of Pharmaceutical Excipients (“Kibbe”) by
`
`Arthur H. Kibbe, Ph.D. (“Kibbe”). In Kibbe, the entry for “Edetic Acid” includes a section on
`
`“related substances,” which identifies several salts of edetic acid. Kibbe lists dipotassium
`
`
`
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`edetate, disodium edetate, edetate calcium disodium, sodium edetate, and trisodium edetate.
`
`(Ex. 3, Kibbe, A.H., Editor, HANDBOOK OF PHARMACEUTICAL EXCIPIENTS, Third
`
`Edition, Pharmaceutical Press and American Pharmaceutical Association, London, UK, and
`
`Washington, DC (2000) at 191-94. LUPIN010503-08). The molecular structure of “disodium
`
`edetate” is C10H14N2Na2O8, i.e., the disodium form. By contrast, the molecular structure of
`
`“sodium edetate” is C10H12N2Na4O8, i.e., the tetrasodium form. (Id. at LUPIN010506-07).
`
`Kibbe further identifies “edetic acid tetrasodium salt” and “tetrasodium edetate” as synonyms
`
`for “sodium edetate.” Accordingly, like the Merck Index, Kibbe also shows the term “sodium
`
`edetate” would have meant tetrasodium edetate or edetic acid tetrasodium salt to a person of
`
`skill in the art.
`
`48. I have reviewed Lanigan, Final Report on the Safety Assessment of EDTA, Calcium
`
`Disodium EDTA, Diammonium EDTA, Dipotassium EDTA, Disodium EDTA, TEA-EDTA,
`
`Tetrasodium EDTA, Tripotassium EDTA, Trisodium EDTA, HEDTA, and Trisodium HEDTA,
`
`21 Int’l J. of Toxicology (Supp. 2) 95, 95-96 (2002) (“Lanigan”). (Ex. 4, LUPIN018913-60).
`
`Lanigan lists many EDTA salts, which includes calcium disodium EDTA, dipotassium EDTA,
`
`disodium EDTA, tetrasodium EDTA, tripotassium EDTA, and trisodium. (Id. at
`
`LUPIN018913-15). Lanigan states “Tetrasodium EDTA is also known as Edetate Sodium.”
`
`(Id. at LUPIN018914-15). For disodium EDTA, Lanigan lists several synonyms of disodium
`
`edetate which almost all recite the word disodium. (Id. at LUPIN018914).
`
`49. I have reviewed Lewis’ Dictionary of Toxicology from 1998 (“Lewis”). Ex. 6,
`
`PROLENSA00006189-92). Lewis lists many edetate salts, which includes edetate calcium
`
`disodium, edetate disodium, edetate sodium, and edetate trisodium. Edetate disodium is shown
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`to be the disodium salt, whereas edetate sodium is shown to be the tetrasodium salt.
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`(PROLENSA00006191).
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`50. I have reviewed the Encyclopedia of Food and Color Additives from 1996 by George A.
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`Burdock (“Burdock”). (Ex. 7, PROLENSA00006179-88). Burdock lists “EDTA, disodium,”
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`“EDTA, disodium iron,” and “EDTA, tetrasodium.” (Id. at PROLENSA00006182-88). The
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`synonyms for “EDTA, disodium” includes edetate disodium. (Id. at PROLENSA00006182-83).
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`The synonyms for “EDTA, tetrasodium” includes edetate sodium.” (Id. at
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`PROLENSA00006186-87).
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`51. These documents taken together, show that a person of skill in the art would have
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`understood the terms “sodium edetate” and “EDTA sodium salt” to refer to the tetrasodium
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`form of ethylenediameinetetraacetic. A person of skill in the art would have known that sodium
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`edetate and EDTA disodium salt would not include the other sodium containing edetate salts,
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`such as disodium edetate, trisodium edetate, and calcium disodium edetate. In other words,
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`sodium edetate does not refer to a class of compounds that contain a sodium ion, but instead is
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`specifically referring to tetrasodium edetate.
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`52. Accordingly, it is my opinion that the terms “EDTA sodium salt” and “sodium edetate”
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`in the patents in suit should be construed as “edetic acid tetrasodium salt” or “tetrasodium
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`edetate” in accordance with the ordinary meaning to a person of skill in the art.
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`b. A Person of Skill In the Art Would Not Know What “Stable” or “In an
`Amount Sufficient to Stabilize Said First Component” Means In Light of the
`Intrinsic and Extrinsic Evidence
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`53. It is my opinion that a person of ordinary skill in the art reading the patents in suit would
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`not know what is meant by the terms “stable” and “in an amount sufficient to stabilize said first
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`component,” and therefore would not understand the scope of the claims with reasonable
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`certainty. It is therefore my opinion that these terms are indefinite.
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`54. The phrase “stable” appears in the following claims: claims 1, 7, 8, 10, 13, 14, 19, 20, 22,
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`25 of the ’290 patent; claims 1, 6, 7, 9, 12, 13, 18-22, 24 of the ’131 patent; claims 1, 7, 9, 13,
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`19-21 of the ’813 patent; claims 1, 9, 11, 12, 18, 19, 25, 26 of the ’606 patent. The remaining
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`claims of the ’290, ’131, ’813, and ’606 patents depend from one or more of these claims, and
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`therefore also include the term “stable.”
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`55. Claim 1 of the ‘290 patent is below with the relevant claim term bolded:
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`1. A stable aqueous liquid preparation comprising:
`(a) a first component; and
`(b) a second component;
`wherein the first component is 2-amino-3-(4-bromobenzoyl)phenylacetic acid or a
`pharmacologically acceptable salt thereof or a hydrate thereof, wherein the
`hydrate is at least one selected from a 1/2 hydrate, 1 hydrate, and 3/2 hydrate;
`the first component is the sole pharmaceutical active ingredient contained in the
`preparation;
`the second component is tyloxapol and is present in said liquid preparation in an
`amount sufficient to stabilize said first component; and
`wherein said stable
`liquid preparation
`is
`formulated
`administration.
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`56. Therefore, all of the claims of the ’290, ’131, ’813, and ’606 patents require that the
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`for ophthalmic
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`preparation be “stable.”
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`57. The phrase, “in an amount sufficient to stabilize said first component” appears in claims
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`1 of the ’290, ’131, ’813, and ’606 patents, and, by virtue of their dependency, in those claims
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`dependent thereon.
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`58. As an initial matter, neither “stable” nor “stabilize” have a commonly accepted definition
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`to the person of ordinary skill in the art. For example, the 2000 edition of Remington’s, a
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`reference that would have been well-known to the person of ordinary skill in the art, provides
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`the following definition of stability: “Stability of a pharmaceutical product may be defined as
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`the capability of a particular formulation, in a specific container/closure system, to remain
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`within its physical, chemical, microbiological, therapeutic, and toxicological specifications.”
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`Ex. 8 (Vadas, Stability of Pharmaceutical Products, in Remington: The Science and Practice of
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`Pharmacy 986-94 (Gennaro, ed., 20th ed. 2000)).
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`59. There are thus any number of attributes that one may refer to when using the general
`
`terms, “stable” or “stabilize.” In some contexts, these terms may refer to chemical stability (i.e.,
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`propensity towards chemical degradation); in others, physical stability (i.e., propensity towards
`
`changes in appearance or other physical properties). Furthermore, “stable” and “stabilize” are
`
`merely relative terms which are meaningless in the absence of a defined specification. One
`
`must accordingly specify a particular threshold under particular measurement conditions that
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`permits distinction between formulations that are “stable” or “stabilize[d]” from those that are
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`not, in order to give meaning to the term. Without such a contextual definition, there is simply
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`no way for the person of ordinary skill in the art to understand the meaning of “stable” or
`
`“stabilize.” However, neither the specification nor the prosecution history provides a definition
`
`of these terms.
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`60. There are multiple references in the specification to the word “stable” but none of them
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`clarify the meaning of the term. See e.g., ‘290 application abstract (“An aqueous liquid
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`preparation of the present invention containing 2-amino-3-(4-bromobenzoyl) phenylacetic acid
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`or its pharmacologically acceptable salt or a hydrate thereof, an alkyl aryl polyether alcohol type
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`polymer such as tyloxapol, or a polyethylene glycol fatty acid ester such as polyethylene glycol
`
`monostearate is stable.”); id. at 2:6-12 (“In these prior art references, there is no disclosure that
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`alkyl aryl polyether alcohol type polymers or polyethylene glycol fatty acid esters are able to
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`stabilize an aqueous liquid preparation of 2-amino-3-(4-bromobenzoyl)phenylacetic acid or its
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`pharmacologically acceptable salt, and inhibit decrease in preservative effect of benzalkonium
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`chloride and other quaternary ammonium compounds.”)
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`61. The specification does state that an object of the invention is to provide a formulation that
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`is “stable within a pH range giving no irritation to the eyes” and that the preservative effect
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`“does not substantially deteriorate.” Id. at 2:16-23. However, again, this does not provide any
`
`information to a person of ordinary skill in the art what would qualify as a “stable” formulation,
`
`how stable a formulation would need to be for the preservative effect to not “substantially
`
`deteriorate,” or over what pH range the formulation would need to be stable. None of these
`
`vague descriptions provides a definition for “stable” that would permit the person of ordinary
`
`skill in the art to distinguish a “stable” formulation from an unstable one.
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`62. Experimental Examples 1 and 2, entitled “Stability Test of Sodium 2-amino-3(4-
`
`bromobenzoyl)phenylacetate”, disclose specific conditions under which stability may be
`
`measured. Both of these tests purport to measure stability by the remaining rate in percent,
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`which reflects the amount of bromfenac remaining in the formulation after storage at 60°C for
`
`four weeks. Id. at 8:39-45. In this manner, the specification does suggest that whether a
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`formulation is “stable” depends upon how much bromfenac remains after storage at 60°C for
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`four weeks. However, nothing in the spe