IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF NEW JERSEY
`
`BRACCO DIAGNOSTICS INC.,
`
`Case No. 3: l7-cv-13 151-PGS-TJB
`
`Plaintiff,
`
`V. MAIA PHARMACEUTICALS, INC
`
`Defendant.
`
`
`DECLARATION OF PROFESSOR ALEXANDER M. KLIBANOV
`
`IN SUPPORT OF DEFENDANT MAIA PHARMACEUTICALS, INC.’S
`OPENING CLAINI CONSTRUCTION BRIEF
`
`1, Alexander M. Klibanov, Ph.D., declare and state as follows:
`
`1.
`
`I
`
`submit
`
`this
`
`declaration
`
`in
`
`support
`
`of Defendant Maia
`
`Pharmaceuticals, Inc.’s (“Maia”) Opening Claim Construction Brief.
`
`I have
`
`personal knowledge of the matters set forth herein and, if called upon, could and
`
`would testify competently thereto.
`
`I. BACKGROUND AND QUALIFICATIONS
`
`2.
`
`I
`
`am a Professor of Chemistry and Bioengineering at
`
`the
`
`Massachusetts Institute of Technology (“MIT”), where I have been teaching and
`
`conducting research for over 39 years and currently hold the Novartis Endowed
`
`Chair Professorship (which I also held from 2007 to 2012). From 2012 to 2014, I
`
`held the Roger and Georges Finnenich Endowed Chair Professorship in Chemistry.
`
`1
`
`Bracco EX. 2008
`
`Maia V. Bracco
`
`IPR2019-00345
`
`Bracco Ex. 2008
`Maia v. Bracco
`IPR2019-00345
`
`1
`
`
`
`FOR THE DISTRICT OF NEW JERSEY
`
`BRACCO DIAGNOSTICS INC.,
`
`Case No. 3: l7-cv-13 151-PGS-TJB
`
`Plaintiff,
`
`V. MAIA PHARMACEUTICALS, INC
`
`Defendant.
`
`
`DECLARATION OF PROFESSOR ALEXANDER M. KLIBANOV
`
`IN SUPPORT OF DEFENDANT MAIA PHARMACEUTICALS, INC.’S
`OPENING CLAINI CONSTRUCTION BRIEF
`
`1, Alexander M. Klibanov, Ph.D., declare and state as follows:
`
`1.
`
`I
`
`submit
`
`this
`
`declaration
`
`in
`
`support
`
`of Defendant Maia
`
`Pharmaceuticals, Inc.’s (“Maia”) Opening Claim Construction Brief.
`
`I have
`
`personal knowledge of the matters set forth herein and, if called upon, could and
`
`would testify competently thereto.
`
`I. BACKGROUND AND QUALIFICATIONS
`
`2.
`
`I
`
`am a Professor of Chemistry and Bioengineering at
`
`the
`
`Massachusetts Institute of Technology (“MIT”), where I have been teaching and
`
`conducting research for over 39 years and currently hold the Novartis Endowed
`
`Chair Professorship (which I also held from 2007 to 2012). From 2012 to 2014, I
`
`held the Roger and Georges Finnenich Endowed Chair Professorship in Chemistry.
`
`1
`
`Bracco EX. 2008
`
`Maia V. Bracco
`
`IPR2019-00345
`
`Bracco Ex. 2008
`Maia v. Bracco
`IPR2019-00345
`
`1
`
`
`
`Prior to that, I was a Professor of Chemistry and a Professor of Bioengineering at
`
`M.I.T., positions I held from 1988 and 2000, respectively. From 1979 to 1988, I
`
`was an Assistant Professor, then Associate Professor, and thereafter a Full
`
`Professor of Applied Biochemistry in the Department of Applied Biological
`
`Sciences (formerly the Department of Nutrition and Food Science) at M.I.T.
`
`3.
`
`I obtained my M.S. in Chemistry from Moscow University in Russia
`
`in 1971 and Ph.D. in Chemical Enzymology from the same University in 1974.
`
`Thereafter, I was a Research Chemist at Moscow University’s Department of
`
`Chemistry for three years. From 1977 to 1979, following my immigration to the
`
`United States, I was a Post-Doctoral Associate at the Department of Chemistry,
`
`University of California in San Diego.
`
`4.
`
`Over the last 45+ years as a practicing chemist, I have extensively
`
`researched, published, taught, and lectured in many areas of biological, medicinal,
`
`formulation, and polymer chemistry.
`
`5.
`
`I have earned numerous prestigious professional awards and honors.
`
`For example, I was elected to the U.S. National Academy of Sciences (considered
`
`among the highest honors that can be given to an American scientist) and also to
`
`the U.S. National Academy of Engineering (considered among the highest honors
`
`that can be given to an American engineer or applied scientist). I am also a
`
`Founding Fellow of the American Institute for Medical and Biological Engineering
`
`
`
`-2-
`
`2
`
`
`
`and a Corresponding Fellow of the Royal Society of Edinburgh (Scotland’s
`
`National Academy of Science and Letters). In addition, I have received the Arthur
`
`C. Cope Scholar Award, the Marvin J. Johnson Award, the Ipatieff Prize, and the
`
`Leo Friend Award, all from the American Chemical Society, as well as the
`
`International Enzyme Engineering Prize.
`
`6.
`
`I currently serve on the Editorial Boards of over a dozen scientific
`
`journals, including “Open Journal of Pharmacology,” “Applied Biochemistry and
`
`Biotechnology,” ”Nanocarriers,” “Open Access Academic Books in Chemistry,”
`
`“Biotechnology and Bioengineering,” “Journal of Biological Chemistry and
`
`Molecular Pharmacology,” “Recent Patents in Biotechnology,” “Archives of
`
`Medical Biotechnology,”
`
`“Current Pharmaceutical Biotechnology,”
`
`and
`
`“International Journal of Drug Design, Delivery, and Safety.”
`
`7.
`
`I have published over 315 scientific papers in various areas of
`
`chemistry. I am also a named inventor of 25 issued United States patents and of a
`
`number of pending ones. I have given over 370 invited lectures at professional
`
`conferences, universities, and corporations all over the world, many dealing with
`
`formulation, stability, delivery, and biological evaluation of pharmaceutically
`
`active compounds.
`
`8.
`
`In addition to my research and teaching activities at M.I.T., I have
`
`consulted widely for pharmaceutical, medical device, chemical, and biotechnology
`
`
`
`-3-
`
`3
`
`
`
`companies. They have included both innovator and generic pharmaceutical
`
`companies.
`
`9.
`
`I have also founded six pharmaceutical companies and have been on
`
`the scientific advisory boards and/or boards of directors of those companies and of
`
`many others. A number of these consulting, advisory, and directorship activities
`
`have dealt specifically with the formulation, stability, delivery, administration
`
`(including parenteral), and biological evaluation of pharmaceutically active
`
`compounds.
`
`10.
`
`I am being compensated at my standard consulting rate of $950 per
`
`hour. My compensation is in no way dependent on the opinions rendered or the
`
`outcome of this litigation.
`
`11. My curriculum vitae, attached as Exhibit A, summarizes my
`
`education and professional experience, including a list of publications that I have
`
`authored.1
`
`12. During the past four years, I have testified as a technical expert, either
`
`at deposition or trial, as set forth in Exhibit B.
`
`II. MATERIALS CONSIDERED
`
`13. My opinions expressed in this report are based on my review of U.S.
`
`Patent No. 6,803,046 (“the ’046 patent”), its prosecution history, the Declaration of
`
`1
`Exhibits A-C of my declaration are attached hereto. All other exhibits cited
`herein are submitted with the Declaration of Gregory D. Miller, Esq.
`-4-
`
`
`
`4
`
`
`
`Gregory D. Miller, Esq., and exhibits attached thereto, as well as the materials set
`
`forth in Exhibit C hereto and cited in this report. My opinions are further informed
`
`by my professional knowledge and experience in the field of pharmaceutical
`
`formulations (including injectables), which span over 45 years. Based on my
`
`education, research, and other work experience, I believe am competent to provide
`
`the opinions set out in this expert report.
`
`III. SUMMARY OF OPINIONS
`
`14. The plain and ordinary meaning of the claim term “surfactant” to a
`
`person of ordinary skill in the art (“POSA”), reading the ’046 patent at the time of
`
`its invention, would have been “a compound that reduces the tension of the
`
`air/liquid or liquid/solid interface.”
`
`15. The
`
`plain
`
`and
`
`ordinary meaning
`
`of
`
`the
`
`claim
`
`term
`
`“surfactant/solubilizer” to a POSA, reading the ’046 patent at the time of its
`
`invention, would have been “a surfactant that is also a solubilizer.” A “solubilizer”
`
`is “a compound that aids in solubilization, thus preventing or reducing sincalide
`
`denaturation and/or degradation caused by peptide aggregation, precipitation,
`
`surface adsorption, or agitation at air/liquid or liquid/solid interfaces in solution.”
`
`16. The plain and ordinary meaning of the claim term “buffer” to a
`
`POSA, reading the ’046 patent at the time of its invention, would have been “a
`
`compound that stabilizes the pH of a sincalide formulation.”
`
`
`
`-5-
`
`5
`
`
`
`IV. LEGAL PRINCIPLES
`
`17. The following legal principles have been explained to me by counsel
`
`for Maia (“counsel”).
`
`18. The meaning of a patent claim term is ultimately a legal determination
`
`made by the Court. Claim terms are generally given their “plain and ordinary”
`
`meaning that they would have had to a POSA in the relevant art at the time the
`
`patent application was filed.
`
`19. Claims must be read in view of the patent specification, of which they
`
`are a part. In particular, claim terms may be construed outside of their plain and
`
`ordinary meaning when a patentee has acted as his/her own lexicographer and has
`
`clearly provided a different meaning in the specification or when there has been a
`
`clear disavowal of claim scope. However, one must avoid impermissibly
`
`importing limitations from the specification into the claims.
`
`20. The prosecution history of a patent is also part of the “intrinsic
`
`evidence” and can often inform the meaning of the claim language by
`
`demonstrating how the inventor understood the invention.
`
`21.
`
`In addition, the Court may also rely on “extrinsic evidence,” which is
`
`evidence external to the patent and prosecution history, such as expert testimony,
`
`dictionaries, and learned treatises. However, extrinsic evidence may not be used to
`
`alter the meaning of claim terms in a manner inconsistent with the intrinsic
`
`
`
`-6-
`
`6
`
`
`
`evidence.
`
`22. Whenever possible, patent claims should be construed so as to
`
`preserve their validity.
`
`V. LEVEL OF ORDINARY SKILL IN THE ART
`
`23. As noted above, patent claim terms must be interpreted as they would
`
`have been understood by a POSA at the time of the invention. I have been asked
`
`by counsel to assume that the time of the invention claimed in the ’046 patent is
`
`August 16, 2002 (as indicated in section (22) on the cover page of the patent). Ex.
`
`1 at 1.
`
`24.
`
`In my opinion, a POSA in the case of the ’046 patent would have had
`
`background and experience in the design and development of pharmaceutical
`
`formulations, including injectables. Such a person would have had a Ph.D. degree
`
`in chemistry, pharmacy, or a related field, plus about two years of experience
`
`formulating pharmaceuticals. Alternatively, such a person may have had a lower
`
`educational level (such as a M.S. or even a B.S. academic degree) in one of those
`
`fields with commensurately more experience formulating pharmaceuticals.
`
`25.
`
`I understand that Bracco has offered a slightly different definition of
`
`the level of ordinary skill in the art. My claim construction opinions do not change
`
`under Bracco’s proposed level of ordinary skill in the art.
`
`
`
`-7-
`
`7
`
`
`
`VI. TECHNOLOGY OVERVIEW
`
`26.
`
`In order to assist the Court in evaluating how a POSA would have
`
`understood the patent claims in dispute, below I provide a brief tutorial on the
`
`technology at issue in the ’046 patent.
`
`A.
`
`
`Sincalide
`
`27. Sincalide is a cholecystopancreatic-gastrointestinal hormone peptide
`
`for parenteral (i.e., by injection) administration. Ex. 1 (’046 patent), col. 1, ll. 9-
`
`11. Sincalide formulations are used as diagnostic aids for imaging the
`
`hepatobiliary system of a patient. Id., col. 2, ll. 39-50.
`
`28. Sincalide was first introduced commercially in 1976 and provided as a
`
`sterile, non-pyrogenic, lyophilized (i.e., freeze-dried) white powder in a glass vial.
`
`Id., col. 1, ll. 17-19.
`
`B. Drug Formulation
`
`
`29. Active pharmaceutical ingredients (APIs), such as sincalide in the
`
`present case, are rarely administered alone. Instead, an API is typically mixed with
`
`so-called inactive ingredients to improve various aspects of the drug formulation
`
`(e.g., stability or ease of handling). These inactive ingredients are typically
`
`referred to as “excipients.”
`
`30. There are many different types of potential excipients, with each type
`
`intended to serve a specific function in a pharmaceutical formulation. They
`
`
`
`-8-
`
`8
`
`
`
`include, among many others, bulking agents, pH adjusters, tonicity agents,
`
`diluents, colorants, and preservatives. For example, bulking agents are used to
`
`provide bulk and structure to a formulation, which can be useful where the API is
`
`present in small amounts.
`
`31. During drug development, pharmaceutical formulators work to
`
`identify the right excipients in optimal quantities to maximize the drug product’s
`
`stability, efficacy, and safety.
`
`VII. U.S. PATENT NO. 6,803,046
`
`32. The ’046 patent is directed to pharmaceutical formulations of
`
`sincalide for administration by injection. Id., col. 1, ll. 52-53.
`
`33. The claims of the ’046 patent generally recite a formulation for
`
`sincalide. Independent claim 1 is representative and discloses “[a] stabilized,
`
`physiologically acceptable formulation of sincalide” that includes the following
`
`excipients, as defined by
`
`their function: “at
`
`least one stabilizer,” “a
`
`surfactant/solubilizer,” “a chelator,” “a bulking agent/tonicity adjuster,” and “a
`
`buffer.” Id., col. 37, ll. 41-49. The other independent claims are variations of this
`
`basic formulation, claiming the formulation as a kit (claim 40), a method of
`
`making the formulation by mixing the excipients (claim 21), and a method of
`
`imaging a patient by first administering the formulation, followed by imaging the
`
`patient (claims 77 and 104). The dependent claims add limitations regarding the
`
`
`
`-9-
`
`9
`
`
`
`common subclasses and specific compounds within the functional excipient
`
`classes, as well as common techniques for administering the drug and for imaging
`
`the patient.
`
`34. The ’046 patent describes its invention as “sincalide formulations
`
`having improved stability and/or potency over previous formulations.” Id., col. 1,
`
`ll. 37-39; col 3, ll. 38-40. This was reportedly done by the “selection of excipients
`
`that provide certain desired functions.” Id. at col. 3, ll. 35-36.
`
`VIII. PLAIN AND ORDINARY MEANING OF ’046 PATENT CLAIM
`
`TERMS IN DISPUTE
`
`A.
`
`“Surfactant”
`
`35.
`
`A “surfactant” is a well-known term to a POSA. I agree with Maia
`
`(see below) that a POSA would have understood at the relevant time that the ’046
`
`patent’s claim term “a surfactant” means “a compound that reduces the tension of
`
`the air/liquid or liquid/solid interface.”
`
`36. Many claims of the ’046 patent require a “surfactant,” either directly
`
`or through dependency. See, e.g., Ex. 1, claims 7, 18, 27, 38, and 40, as well as the
`
`claims dependent therefrom. Independent claim 40 is representative in this regard:
`
`40. A kit, comprising:
`(i) a powder mixture comprising
`(a) sincalide,
`(b) at least one stabilizer,
`(c) a surfactant,
`(d) a chelator,
`
`
`
`-10-
`
`10
`
`
`
`(e) a bulking agent/tonicity adjuster, and
`(f) a buffer;
`(ii) a container to hold said powder mixture; and
`(iii) optionally, a physiologically acceptable fluid.
`
`’046 patent, col. 39, ll. 53-62 (emphasis added). Several dependent claims further
`
`require a specific type of surfactant to be used (e.g., claim 46 requiring a nonionic
`
`surfactant, namely a polysorbate, and claim 47 requiring a particular polysorbate
`
`like polysorbate 20 (also known to a POSA as Tween® 20)).
`
`37.
`
`The specification of the ’046 patent expressly defines a “surfactant”
`
`in the section entitled “Surfactants/Solubilizers/Surface Active Agents.” Id., col.
`
`11, ll. 26-34. In relevant part, the specification states: “The addition of a nonionic
`
`surfactant, such as [a] polysorbate, to the formulation, may reduce the interfacial
`
`tension [or aid in solubilization thus preventing or reducing denaturation and/or
`
`degradation]2 at air/liquid or liquid/solid interfaces of the product in solution.” Id.,
`
`col. 11, ll. 29-34 (brackets added).
`
`38.
`
`The prosecution history of the ’046 patent does not shed any
`
`additional light on the proper construction of the claim term “surfactant.”
`
`39.
`
`A POSA would have understood, therefore, that a “surfactant” is a
`
`compound that reduces the tension of the air/liquid or liquid/solid interface.
`
`Indeed, various both general and scientific dictionaries define a “surfactant”
`
`2
`The bracketed language references the potential of a nonionic surfactant to
`aid in solubilization, which is distinct from its function as a surfactant and
`discussed below.
`
`
`
`-11-
`
`11
`
`
`
`consistent with this understanding. See, e.g., Ex. 2, Condensed Chemical
`
`Dictionary at 830 (1977) (defining a “surface-active agent (surfactant),” in relevant
`
`part, as “[a]ny compound that reduces surface tension (q.v.) when dissolved in
`
`water or water solutions, or which reduces interfacial tension between two liquids,
`
`or between a liquid and a solid.”); Ex. 4, Webster’s Ninth New Collegiate
`
`Dictionary at 1187 (1985) (defining “surfactant” as “a surface-active substance”
`
`and further defining “surface-active” as “altering the properties and esp[ecially][]
`
`lowering the tension at the surface of contact between phases.”); Ex. 5, McGraw-
`
`Hill Dictionary of Scientific and Technical Terms at 1960 (5th ed., 1994) (defining
`
`a “surface-active agent” “[a]lso known as surfactant” as “[a] soluble compound
`
`that reduces the surface tension of liquids, or reduces interfacial tension between
`
`two liquids or a liquid and a solid.”).
`
`40.
`
`For the Court’s convenience, the following table lists side-by-side
`
`Maia’s and Bracco’s respective competing constructions of the claim term “a
`
`surfactant:”
`
`Bracco’s Proposed Construction
`
`Excipients that “may reduce the
`interfacial tension” and “include, but
`are not limited to, pluronics (e.g.,
`Lutrol F68, Lutrol F127),
`Poloxamers, SDS, Triton-100,
`polysorbates such as TWEEN® 20
`and TWEEN® 80, propylene glycol,
`
`Maia’s Proposed Construction
`
` A
`
` compound that reduces the tension
`of the air/liquid or liquid/solid
`interface.
`
`
`
`-12-
`
`12
`
`
`
`PEG and similar compounds, Brij58
`(polyoxyethylene 20 cetyl ether),
`cremophor EL, cetyl
`trimethylammonium bromide
`(CTAB), dimethylacetamide (DMA),
`NP-40 (Nonidet P-40), and N-
`methyl-2-pyrrolidone (Pharmasolve),
`glycine and other amino acids/amino
`acid salts and anionic surfactants
`containing alkyl, aryl or heterocyclic
`structures, and cyclodextrins.”
`
`
`
`41.
`
`I disagree with Bracco’s proposed construction at least because, in
`
`my opinion, it misapplies the specification of the ’046 patent.
`
`42.
`
`Both Maia and Bracco initially rely on the same portion of the ’046
`
`patent specification (column 11, lines 31-34) to arrive at their respective
`
`constructions of the claim term “surfactant.” There appears to be no dispute that a
`
`“surfactant” functions to reduce the interfacial tension at air/liquid or liquid/solid
`
`interfaces of the product in solution. However, the parties’ proposed constructions
`
`diverge in two important ways.
`
`43.
`
`First, according to Bracco’s construction, surfactants merely “may”
`
`(and hence may not) reduce interfacial tension. Bracco’s inclusion of the
`
`permissive word “may” essentially erases the requirement of a “surfactant” from
`
`the claims. Contrary to Bracco’s construction, however, a surfactant is not
`
`optional in the context of the ’046 patent.
`
`44.
`
`Second, Bracco’s construction of “a surfactant” seeks to read a long
`-13-
`
`
`
`13
`
`
`
`and expressly open-ended list of examples (due to its preamble “include but not
`
`limited to,” as well as numerous phrases therein like “e.g.,” “such as,” “and similar
`
`compounds”) of potential “surfactants/solubilizers” into the claims. However, it is
`
`my opinion that the expressly exemplary and unrestricted list of merely “preferred”
`
`surfactants/solubilizers in the specification does not define the scope of the claim
`
`term “surfactant.”
`
`45.
`
`A POSA would have understood that, in the context of the ’046
`
`patent, the claimed surfactants must exhibit a surfactant effect on sincalide
`
`formulations. Example 3 of the patent is tellingly entitled “Effect of Surfactants on
`
`Sincalide Formulations.” Id., col. 19, l. 53―col. 22, l. 42. In this part of the
`
`specification, the patent explains that surfactants are added to claimed sincalide
`
`formulations of the invention “[t]o minimize sincalide degradation associated with
`
`surface adsorption.” Id., col. 20, ll. 5-9.
`
`46.
`
`In addition, the Abstract, Summary of Invention, and Detailed
`
`Description of the Invention all describe the claimed invention as requiring a
`
`“surfactant” (or, in some cases, a “surfactant/solubilizer”). See, e.g., id., Abstract;
`
`col. 1, l. 56―col. 2, l. 8 (“Summary of the Invention”); col. 4, ll. 8-31 (“Detailed
`
`Description of the Invention”) (requiring a surfactant).
`
`47.
`
`Likewise, all embodiments and descriptions of the claimed invention
`
`of the ’046 patent, as well as all of its 108 claims, recite a “surfactant” (or, in some
`
`
`
`-14-
`
`14
`
`
`
`cases, a "surfactant/solubilizer”). See generally Ex. 1.
`
`48.
`
`Accordingly,
`
`a POSA reading the
`
`’046 patent would have
`
`understood that a “surfactant” is a fundamental feature of the claimed invention
`
`and is not optional.
`
`In other words, the patent requires a surfactant to confer an
`
`actual reduced interfacial tension to practice the claimed invention.
`
`49.
`
`The list of potential
`
`surfactants
`
`that Bracco includes
`
`in its
`
`construction comes from col. 11, 11. 51-62, of the patent specification. However,
`
`that
`
`list
`
`in
`
`the patent
`
`explicitly refers
`
`to
`
`“[e]xamples of preferred
`
`surfactants/solubilizers
`
`.
`
`.
`
`(emphasis
`
`added)—and not all permissible
`
`surfactants, as Bracco apparently believes.
`
`It is worth noting in this respect that,
`
`while Bracco’s list of preferred "surfactants/solubilizers" includes amino acids, its
`
`list of all permissible surfactants conspicuously does not include amino acids.
`
`50.
`
`I also disagree with Bracco’s construction of a “surfactant” because
`
`the list of potential surfactants that Bracco seeks to add to the claim uses excipients
`
`that a POSA would have understood to not function as surfactants in the context of
`
`claimed invention.3
`
`51.
`
`Table l of the ’046 patent specification provides insights to a POSA
`
`
`
`However, because Bracco is proposing a
`
`construction of “surfactant” that explicitly includes amino acids, I provide this
`response, which is limited to information contained in the intrinsic record.
`
`-15-
`
`15
`
`15
`
`
`
`regarding the claimed invention. Table 1 reports “the concentration ranges for
`
`various excipients that were investigated.” Id., col. 4, ll. 32-33. In the second
`
`column in Table 1, under the heading “Function,” the inventors reported the
`
`function of each excipient that they investigated. In particular, Table 1 lists the
`
`function of the following amino acid excipients in the context of the ’046 patent:
`
`methionine, lysine, and arginine.
`
`52.
`
` The amino acid methionine is not identified in Table 1 as
`
`functioning as a surfactant. Rather, methionine’s sole function is listed as a
`
`“Stabilizer.” Id.
`
`53.
`
`Likewise, the amino acid lysine is not reported in Table 1 to function
`
`as a surfactant in the context of the sincalide formulations investigated. Instead,
`
`Table 1 reports that lysine has the following functions in the ’046 patent:
`
`“Stabilizer/Lyoprotectant/Cryoprotectant.” Id. A POSA would have understood
`
`that none of the stated functions for lysine is as a surfactant.
`
`54.
`
`Nor does Table 1 suggest that arginine functions as a surfactant.
`
`Rather, Table 1 reports that arginine has the following functions in the context of
`
`the ’046 patent: “Stabilizer/Lyoprotectant/Cryoprotectant/pH adjuster.” Id. A
`
`POSA would have understood that none of the stated functions for arginine is as a
`
`surfactant.
`
`55.
`
`In stark contrast to these characterizations of the three amino acids,
`
`
`
`-16-
`
`16
`
`
`
`Table 1
`
`lists Tween® 20 as “Non-ionic Surfactant/Solubilizing Agent/Wetting
`
`Agent.”
`
`56.
`
`Viewing Table 1 in the context of the entire patent specification, a
`
`POSA would have understood that, unlike, e.g., Tween® 20,
`
`the amino acids
`
`methionine, lysine, and arginine do not function as surfactants in the context of the
`
`’046 patent. Rather, all three excipients function as “stabilizers” of various kinds.
`
`57.
`
`When methionine, lysine, and arginine are mentioned in the ’046
`
`patent, they are consistently characterized as “stabilizers,” not surfactants.
`
`4 See,
`
`e.g.,
`
`id., col. 2,
`
`11. 4-8 (referring to methionine,
`
`lysine, and arginine as
`
`“stabilizers”); Table 1 (see above); Table 4 (same); col. 10, 11. 54-55 (stating that
`
`various amino acids can be used as “stabilizers” in sincalide formulations); col. 10,
`
`11. 59—61 (“Preferred amino acids for use as stabilizers in the present invention
`
`include methionine, lysine, and arginine”).
`
`In addition, see col. 11, 11. 24-25
`
`(referring to lysine and arginine as “preferred cryoprotectants/lyoprotectants,”
`
`which is consistent with the stated functions for these amino acids in Table 1).
`
`Thus, a POSA would have understood from the ‘046 patent that the amino acids
`
`methionine, lysine, and arginine are not considered “surfactants” in the context of
`
`the claimed invention.
`
`See Ex. 7 at B00109l3.
`
`17
`
`17
`
`
`
`58.
`
`Furthermore, to a POSA the term “stabilizers” certainly would not
`
`have been synonymous with the term “surfactants.” Compare id., col. 11, ll. 29-34
`
`(explaining that surfactants reduce the interfacial tension of the air/liquid or
`
`liquid/solid interface) and col. 20, ll. 5-8 (surfactants are added “[t]o minimize
`
`sincalide degradation associated with surface adsorption”) with col. 10, ll. 10-23
`
`(referring to “stabilizers” as “functional additives for peptide stabilization” against
`
`“oxidation”). The two terms require different functions, as supported by col. 4, ll.
`
`8-20, of the ’046 patent (referring to “stabilizers” and “surfactants” as distinct
`
`types of excipients). Nowhere in the ’046 patent are “stabilizers” described as
`
`“surfactants.”
`
`59.
`
`Table 11 and the text accompanying it further convey to a POSA
`
`that the amino acids methionine, lysine, and arginine are not viewed as surfactants
`
`in the context of the patent. In Table 11, an experiment is reported comparing the
`
`recovery of sincalide in reconstituted formulations with and without TWEEN® 20,
`
`a common pharmaceutical surfactant. Id., col. 21, l. 65—col. 22, l. 1. Of note, the
`
`formulations both with and without TWEEN® 20 contained methionine, lysine, and
`
`arginine. Id., Table 11. Without TWEEN® 20, the average sincalide recovery was
`
`94.8%. Id. In contrast, the ’046 patent discloses that with TWEEN® 20, the
`
`average sincalide recovery was much greater, 99.7%, and that this marked
`
`difference was statistically significant. See id., col. 22, ll. 32–34. Based on these
`
`
`
`-18-
`
`18
`
`
`
`results, the ’046 patent concludes that “the effectiveness of TWEEN® 20,
`
`polyoxyethylene sorbitan monolaurate, as a surfactant was established by
`
`enhancing the sincalide recovery and thus maintaining sincalide potency in the
`
`formulation.” Id., col. 22, ll. 34–38.
`
`60.
`
`A POSA would have understood that the experimental work
`
`reported in Table 11 of the ’046 patent was performed to assess the role of a
`
`particular surfactant, TWEEN® 20, in formulations with and without it. The
`
`formulation lacking TWEEN® 20 was the control, and the formulation containing
`
`TWEEN® 20 was experimental. However, both the control and the experimental
`
`formulations in Table 11 contained the amino acids methionine, lysine, and
`
`arginine. In properly assessing the role of TWEEN® 20 as a surfactant, a POSA
`
`would have understood that the control formulation (i.e., the formulation
`
`containing no TWEEN® 20) is surfactant-free. Consistent with this understanding,
`
`a POSA would have recognized that the amino acids methionine, lysine, and
`
`arginine are not considered surfactants in the context of Table 11.
`
`B.
`
`“Surfactant/Solubilizer”
`
`61.
`
`For the Court’s convenience, the following table lists side-by-side
`
`Maia’s and Bracco’s respective competing constructions of the claim term “a
`
`surfactant/solubilizer:”
`
`
`
`-19-
`
`19
`
`
`
`Bracco’s Proposed Construction
`
`Excipients that “may reduce the
`interfacial tension or aid in
`solubilization” and “include, but are
`not limited to, pluronics (e.g., Lutrol
`F68, Lutrol F127), Poloxamers, SDS,
`Triton-100, polysorbates such as
`TWEEN® 20 and TWEEN® 80,
`propylene glycol, PEG and similar
`compounds, Brij 58 (polyoxyethylene
`20 cetyl ether), cremophor EL, cetyl
`trimethylammonium bromide
`(CTAB), dimethylacetamide
`(DMA), NP-40 (Nonidet P-40), and
`N-methyl-2-pyrrolidone
`(Pharmasolve), glycine and other
`amino acids/amino acid salts and
`anionic surfactants containing alkyl,
`aryl or heterocyclic structures, and
`cyclodextrins.”
`
`
`
`62. While a “surfactant” and a “solubilizer” are commonly used terms in
`
`the art of pharmaceutical formulations, the claim term “surfactant/solubilizer” is
`
`not.
`
`63.
`
`The meaning of the term “surfactant” in the context of the ’046
`
`patent was discussed in section VIII.A above. A POSA would have also
`
`recognized that the plain and ordinary meaning of the term “solubilizer” in the
`
`context of the ’046 patent is a compound that “aid[s] in solubilization, thus
`
`preventing or reducing denaturation and/or degradation at air/liquid or liquid/solid
`
`
`
`-20-
`
`Maia’s Proposed Construction
`
` surfactant that is also a solubilizer.
`
` A
`
` A
`
` solubilizer is a compound that
`aids in solubilization, thus
`preventing or reducing sincalide
`denaturation and/or degradation
`caused by peptide aggregation,
`precipitation, surface adsorption, or
`agitation at air/liquid or liquid/solid
`interfaces in solution.
`
`20
`
`
`
`interfaces in solution.” ’046 patent, col. 11, ll. 30-34.
`
`64.
`
`In my opinion, a POSA would have understood that the plain and
`
`ordinary meaning of “surfactant/solubilizer” in the context of the ’046 patent is “a
`
`surfactant that is also a solubilizer.”
`
`65.
`
`Several claims of the ’046 patent use the claim limitation “a
`
`surfactant/solubilizer.” See, e.g., claims 1, 6, 21, and 26, as well as the claims
`
`dependent therefrom. Claim 1 is representative in this regard and provides:
`
`1. A stabilized, physiologically acceptable formulation of sincalide
`comprising:
`(a) an effective amount of sincalide,
`(b) at least one stabilizer,
`(c) a surfactant/solubilizer
`(d) a chelator,
`(e) a bulking agent/tonicity adjuster, and
`(f) a buffer.
`
`Id., col. 37, ll. 41-49 (emphasis added). Claim 7 directly depends from claim 1 and
`
`provides:
`
`7. The formulation of claim 1, wherein said surfactant is a nonionic
`surfactant
`
`Id., col. 38, ll. 6-7 (emphasis added).
`
`66. A POSA would have recognized that claim 7 depends from claim 1
`
`but adds the further limitation that the surfactant from claim 1 is “nonionic.”
`
`However, claim 1 manifestly does not claim a “surfactant;” rather, the closest thing
`
`to a surfactant claimed in it is a “surfactant/solubilizer.”
`
`
`
`-21-
`
`21
`
`
`
`67. A POSA would have also seen that claims 21 and 27 of the ’046
`
`patent are written in a similar fashion. Compare Claim 21 (claiming, in relevant
`
`part, “(b) a surfactant/solubilizer”) with Claim 27 (“The method of claim 21,
`
`wherein said surfactant is a nonionic surfactant.”).
`
`68. That dependent claims 7 and 27 in the ’046 patent refer to the claim
`
`term “surfactant/solubilizer” as “said surfactant” suggests to a POSA that there are
`
`two possible ways to construe the claim term “surfactant/solubilizer.” One is to
`
`construe it and “surfactant” to be one in the same thing (i.e., interchangeable).
`
`This construction of “surfactant/solubilizer” would effectively erase the word
`
`“solubilizer” from the claims; this is problematic, however, because I understand
`
`from counsel that a claim construction that gives meaning to all the words of the
`
`claim is preferred over one that fails to do so.
`
`69. The second way to construe “surfactant/solubilizer” is to view the
`
`claim term as requiring an excipient that is both a surfactant and a solubilizer (i.e.,
`
`a surfactant that is also a solubilizer). This construction is clearly superior because
`
`it would give meaning to each word in the claim limitation.
`
`70. The term “surfactant/solubilizer” is explicitly used seven times in the
`
`’046 patent: four times in the claims (claims 1, 6, 21, and 26) and three times in the
`
`specification (see col. 11, ll. 26, 35, and 51). However, the patent specification
`
`fails to define the term.
`
`
`
`-22-
`
`22
`
`
`
`71. The specification of the ’046 patent contains a section entitled
`
`“Surfactants/Solubilizers/Surface Active Agents.” ’046 patent, col. 11, ll. 26-63.
`
`That section provides: “The addition of a nonionic surfactant, such as [a]
`
`polysorbate, to the formulation, may reduce the interfacial tension or aid in
`
`solubilization thus preventing or reducing denaturation and/or degradation at
`
`air/liquid or liquid/solid interfaces of the product in solution.” Id., col. 11, ll. 29-
`
`34.
`
`72. Since the foregoing sentence from the specification does not use the
`
`term “surfactant/solubilizer,” a POSA would have understood it to mean that a
`
`nonionic surfactant (which, being a polysorbate like TWEEN 20, happens to be
`
`“most preferred,” see id., col. 11, ll. 62-63) may have dual functions in the context
`
`of the claimed invention.
`
`73. Even if a POSA believed that this language from the ’046 patent
`
`specification was referring to a “surfactant/solubilizer” and not just to a
`
`“surfactant” as stated (because the section
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