IN THE UNITED STATES DISTRICT COURT
`DISTRICT OF NEW JERSEY
`
`Case No. 3:17—cv—13151—PGS—TJB
`
`)
`)
`)
`)
`)
`
`) )
`
`BRACCO DIAGNOSTICS INC,
`Plaintiff,
`V-
`MAIA PHARMACEUTICALS, INC .,
`Defendant.
`
`MAIA PHARMACEUTICALS, INC.
`Cormterclaimant,
`v
`
`BRACCO DIAGNOSTICS INC.,
`Cormterclaim Defendant.
`
` vvvvvv
`
`—)
`
`
`DECLARATION OF LAIRD FORREST Ph.D.
`
`I, Laird Forrest, PhD, declare as follows:
`
`1.
`
`I make this declaration concerning the Opening Markman Claim Construction
`
`Submission of Bracco Diagnostics Inc. (“Bracco”) and the subject matter of United States
`
`Patent No. 6,803,046 (the “’046 Patent”), which is Exhibit 1 attached to the Declaration of
`
`Donald L. Rhoads.
`
`2.
`
`I have reviewed the specification and claims of the ‘046 Patent, which is
`
`entitled “Sincalide Formulations.” I have also reviewed the prosecution history of the ‘046
`
`Patent. Exhibit 67. I am an expert in this subject matter. I have been asked by counsel for the
`
`Plaintiff to express my opinions regarding the meaning of certain terms in the claims of the
`
`‘046 Patent.
`
`3.
`
`I am currently a Professor in the Department of Pharmaceutical Chemistry at
`
`the University of Kansas in Lawrence, Kansas, a position I have held since 2017. I am also
`
`Professor in the Bioengineering Center, a position I have held since 2011, and Professor in the
`
`Bracco EX. 2006
`
`Maia v. Bracco
`
`IPR20 1 9-003 45
`
`Bracco Ex. 2006
`Maia v. Bracco
`IPR2019-00345
`
`

`

`Department of Medicinal Chemistry, a position I have held since 2015, both also at the
`
`University of Kansas. I have been a faculty at the University of Kansas since 2007.
`
`4.
`
`I received a Bachelor of Science in Chemical Engineering from Auburn
`
`University in 1998, a Master of Science in Chemical Engineering from the University of
`
`Illinois in 2001, and a Ph.D. in Chemical and Biomolecular Engineering from the University
`
`of Illinois in 2003. I was a Postdoctoral Fellow in the Division of Pharmaceutical Sciences at
`
`the University of Wisconsin, Madison, from 2004 to 2006. In 2006, I became Adjunct
`
`Assistant Professor in the Department of Pharmaceutical Sciences at Washington State
`
`University, a position I held until 2011. In 2007, I accepted a position as Assistant Professor
`
`in the Department of Pharmaceutical Chemistry at the University of Kansas. I was promoted
`
`to Associate Professor at the University of Kansas in 2013. I was then promoted to the rank of
`
`Professor in 2017.
`
`5.
`
`Since 2009, I have been a Member of the Scientific and Medical Advisory
`
`Board of Exogenesis Corporation, which develops nanoscale surface modifications for
`
`implantable medical devices. I am the co-founder of HylaPharm LLC, founded in 2011,
`
`which specializes in reformulation of anti-cancer chemotherapeutics by modification of the
`
`delivery route and pharmacokinetics. Also, I am a co-founder of Hafion LLC, founded in
`
`2016, which specializes in development of vaccines, and Aerobyx LLC, founded in 2017,
`
`which specializes in the development of medications for treatment of neurological and
`
`metabolic disease. In addition, I am a co-founder of Vesarex LLC, founded in 2018, which
`
`specializes in ultrasound-based imaging and treatment of vein thrombosis. My research
`
`toward drug formulation has been competitively funded by multiple awards from the National
`
`Institutes of Health and the National Cancer Institute, the National Institute of Allergy and
`
`
`
`2
`
`
`

`

`Infectious Disease, the National Institute on Aging, the National Heart, Lung and Blood
`
`Institute, the American Cancer Society, the Department of Defense, the Susan G. Komen
`
`Race for the Cure, and the Pharmaceutical Research and Manufacturers of America
`
`Foundation ("PhRMA"), among others. In addition, I have been funded by the Food and
`
`Drug Administration ("FDA") to develop methodologies for the in vitro determination of
`
`bioequivalence in follow-on complex botanical and biosimilar drug formulations.
`
`6.
`
`I have received many awards and honors, including the Baxendale Innovation
`
`Award (2016), the University of Kansas Leading Light award (2014), the Japan Society for
`
`Promotion of Science Visiting Scholar Fellow (2010), the American Cancer Society Research
`
`Scholar (2008 to 2012), the American Association of Colleges of Pharmacy, New
`
`Investigators Award (2007), and the PhRMA Foundation Postdoctoral Fellow (2006), among
`
`others.
`
`7.
`
`I am currently or have been in the past a member of various professional
`
`societies, including the American Association for Cancer Research, the American Association
`
`of Pharmaceutical Scientists, and the American Institute of Chemical Engineers. I serve
`
`currently or have served recently on numerous scientific review panels for the National
`
`Institutes of Health and the American Cancer Society, and the Association for International
`
`Cancer Research (United Kingdom).
`
`8.
`
`I have authored more than 85 peer-reviewed journal articles and 5 book
`
`chapters. I have also edited 2 special journal issues on drug delivery and formulation and a
`
`book on drug delivery and formulation.
`
`9.
`
`I have taught drug formulation and biopharmaceutics, including all aspects of
`
`drug excipient choice and the effects of excipient modification on drug pharmacokinetics,
`
`
`
`3
`
`
`

`

`drug chemical stability, drug dissolution, and drug absorption, to clinical pharmacy students
`
`and graduate students studying pharmaceutical sciences since 2007.
`
`10.
`
`I have experience in all aspects of parenteral and oral drug formulation,
`
`stability testing and formulation analysis, and pharmacokinetics testing through my research
`
`and teaching. Additionally, as part of my work with HylaPharm, Exogenesis Inc., Atrin
`
`Pharmaceutics, and Akari Therapeutics Inc., I have worked on pharmaceutical formulations
`
`for intramuscular, subcutaneous, intravenous, topical, and oral formulation.
`
`11.
`
`In the past six years, I have testified in the following litigations:
`
`Medac Pharma, Inc., et al. v. Antares Pharma Inc., et al., Civ. No. 1:14-cv-01498-JBB (D.
`
`NJ); Par Pharmaceutical, Inc., et al. v. Breckenridge Pharmaceutical, Inc., et al., Civ. No.
`
`1:15-cv-00486-SLR (D. DE); Merck Sharp & Dohme Corp. v. Savior Lifetec Corp., Civ. No.
`
`5:15-cv-415 (E.D.N.C); Mylan Pharmaceuticals Inc. v. Astrazeneca AB; PTAB IPR2016-
`
`01326; PTAB IPR2016-01325; PTAB IPR2016-01324; PTAB IPR2016-01316; Horizon
`
`Pharma, Inc., Horizon Pharma USA, Inc. and Pozen Inc. v. Mylan Pharmaceuticals Inc.,
`
`Mylan Laboratories Limited, and Mylan Inc; Civ. No. 3:15-cv-03327-MLC-DEA, 3:16-cv-
`
`04921 (D. NJ); joint Horizon Pharm, Inc., Horizon Pharma USA, Inc., and Pozen Inc. v. Dr.
`
`Reddy’s Laboratories, Inc. and Dr. Reddy’s Laboratories; Civ. No. 3:15-cv-03324 (D. NJ),
`
`3:16-cv-04918 (D. NJ), 3:16-cv-09035 (D.NJ); joint Horizon Pharm, Inc., Horizon Pharma
`
`USA, Inc., and Pozen Inc. v. Lupin Ltd. and Lupin Pharmaceuticals Inc.; Civ. No. 3:15-cv-
`
`03326 (D. NJ), 3:16-cv-04920 (D.NJ); and Halozyme, Inc. v. Joseph Matal (on behalf of
`
`USPTO), Civ. No. 1:16-cv-1580 (E.D. Va) (2017).
`
`12.
`
`I am being compensated for my time at my standard consulting rate of
`
`$550/hour. In addition, Thomson Reuters receives a fee for case management and billing.
`
`
`
`4
`
`
`

`

`Neither the amount of my compensation nor the fact that I am being compensated has altered
`
`the opinions that I have given in this Declaration. My compensation is in no way dependent
`
`on the outcome of this proceeding. My curriculum vitae is attached hereto as Appendix A.
`
`13.
`
`I have been asked to render my expert opinion on the construction of the
`
`claims of the ‘046 Patent. A list of my opinions, and a summary and the subject matter of my
`
`opinions, as well as subject matter I will rely on in rendering those opinions, were identified
`
`in “Plaintiff’s Identification of Opposing Intrinsic and Extrinsic Evidence Concerning Claim
`
`Construction,” the “Joint Claim Construction and Prehearing Statement,” “Plaintiff’s First
`
`Amendment to Plaintiff’s Disclosure of Infringement Contentions,” “Plaintiff’s First
`
`Amendment to Plaintiff’s Identification of Opposing Intrinsic and Extrinsic Evidence
`
`Concerning Claim Construction and the Joint Claim Construction and Prehearing Statement,”
`
`and the “Amended Joint Claim Construction and Prehearing Statement.” I incorporate these
`
`documents into this declaration.
`
`Standards
`
`14.
`
`In rendering my opinions, I was informed that claim terms “are generally given
`
`their ordinary and customary meaning” to a person of skill in the art: I should consider “those
`
`sources available to the public that show what a person of skill in the art would have
`
`understood the disputed claim language to mean.” The “ordinary” meaning of a claim term is
`
`that meaning to a person of skill in the art.
`
`15.
`
`The sources I should consider include, first, the intrinsic record, which is
`
`composed of the claims, the specification and the prosecution history. Second, and perhaps to
`
`be given less weight, it is all evidence external to the patent and prosecution history, including
`
`expert and inventor testimony, dictionaries, and learned treatises.
`
`
`
`5
`
`
`

`

`16.
`
`I reviewed the description of the person of skill in the art provided in
`
`“Plaintiff’s Responses to Invalidity Contentions,” which I have reviewed (pages 46-50, in
`
`particular) and agree with. I am informed that it was prepared with Dr. Bowen. I used this
`
`person of skill in the art description in rendering my opinions and analysis in this declaration.
`
`17.
`
`I understand that the person of skill in the art is a hypothetical person that is
`
`presumed to have known the relevant art at the time of the invention, here, August 16, 2002,
`
`when the application that led to the ‘046 Patent was filed. I have been informed that factors
`
`that may be considered in determining the level of skill in the art may include: (a) type of
`
`problems encountered in the art; (b) prior art solutions to those problems; (c) rapidity with
`
`which innovations are made; (d) sophistication of the technology; and (e) educational level of
`
`active workers in the field. I have been informed that in a given case, every factor may not be
`
`present, and one or more factors may predominate.
`
`18.
`
`Here, the type of problem is formulating drugs, and, for this invention in
`
`particular, peptide drugs. Protein drug formulation is also relevant, but proteins may provide
`
`different problems than peptides, depending on the proteins and peptides being considered.
`
`19.
`
`Prior art solutions were, for example, the original Kinevac® formulation
`
`before the ‘046 Patent was filed (i.e., sincalide with NaCl salt). There is considerable
`
`evidence that innovations were not made rapidly. For example, Kinevac® was first marketed
`
`in 1976, and as described in the patent at col. 1, the original Kinevac® formulation stayed the
`
`same for 30 years before the ‘046 Patent was filed.
`
`20.
`
`The sophistication of the technology in formulating peptide drugs is relatively
`
`high compared to other fields of science because the formulation of such drugs for use in
`
`humans is regulated by the FDA, which adds additional sophistication and knowledge to the
`
`
`
`6
`
`
`

`

`hypothetical person of skill in the art. It is also rather high because peptide and protein drugs
`
`are relatively difficult to formulate; for example, peptide drugs are often relatively unstable
`
`and more subject to degradation and instability compared to small molecule drugs, e.g. aspirin.
`
`The educational level of active workers in the field are people with about two years of
`
`experience in formulating drugs and at least a B.S. or equivalent undergraduate degree in
`
`chemistry or a related field.
`
`21.
`
`The field was, at the time of the filing date, somewhat unpredictable. It is still
`
`unpredictable today to some extent. This unpredictability is described in the following
`
`references: Waterman (MAIA004986, 4991, 4995), Arakawa (p. 308, 323), Wang 1999 (p.
`
`175, 178), Li 1995 (p. 498), Wang 1988 (p. S8, S22), Wang 2000 (pp. 50-51), Bayol (col. 2,
`
`lines 54-64), Audhya (pp. 5-7)), De Filippis 2003 (¶14), Prior 1990 (1:20-2:15), Schneider
`
`2011 (pg. 7447). See, e.g., Exhibits 3-14.
`
`Background Information
`
`22.
`
`The ‘046 Patent is entitled “Sincalide Formulations.” It was filed as an
`
`application on August 16, 2002 as is indicated on the first page of the patent. The ‘046 patent
`
`does not claim priority to any earlier application, so I understand that this is the critical date
`
`for my opinion concerning the construction of the patent claims. The ‘046 Patent has 108
`
`claims. They are generally directed to formulations (e.g., claims 1-20 and 106), methods for
`
`making formulations (e.g., claims 21-39), kits containing formulations (e.g., claims 40-55 and
`
`107-108), and methods for using formulations (e.g., claims 56-105).
`
`23.
`
`Claim 1 is an example of the claims. It has six claim terms, (a) through (f). For
`
`the Markman claim construction submission, I am informed that the parties are requesting that
`
`the Court construe three terms of the ‘046 Patent claims. These are, specifically, “a buffer,” “a
`
`
`
`7
`
`
`

`

`surfactant/solubilizer,” and “a surfactant.” Claim 1 states:
`
`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.
`
`The parts of the claim include the preamble, which states “A stabilized, physiologically
`
`acceptable formulation of sincalide.” In addition to an effective amount of sincalide, Claim 1
`
`also lists 5 excipients or components of the formulation, including a stabilizer, a
`
`surfactant/solubilizer, a chelator, a bulking agent/tonicity adjuster, and a buffer. These
`
`excipients or components are described in the ‘046 Patent claims and specification at, for
`
`example, claims 3, 6 and 44, and ‘046 Patent, col. 3, lines 30-39 and col. 4, lines 8-31.
`
`24.
`
`The patent makes it clear that one excipient or component can perform more
`
`than one function in a particular formulation. This is stated in the specification at col. 4, lines
`
`22-31: “a single excipient may perform more than one function ... e.g., amino acids may
`
`function as bulking agents, stabilizers and/or buffers.” Furthermore, “Amino acids have also
`
`been used as stabilizers or co-stabilizers of peptides to … improve solubility or rehydration,
`
`inhibit isomerization, reduce surface adsorption, or act as chelating agents” (10:42-47). It is
`
`also stated at col. 13, lines 24-28: “a component in a formulation kit can also serve more than
`
`one function.” A comparison of Tables 1, 2, 4, 16 and 17, also shows that in different
`
`formulations, an excipient or component can do or perform different functions. For example,
`
`
`
`8
`
`
`

`

`Table 1 shows preferred sincalide formulations where arginine is a
`
`“stabilizer/lyoprotectant/cryoprotectant/pH adjuster”
`
`25.
`
`The inclusion of multi-function/result excipients or components is also set
`
`forth in the claims. For example, “amino acids” are included as a “buffer” in claim 3, a
`
`“surfactant/solubilizer” in claim 6, a “surfactant” in claim 44, and examples of amino acids,
`
`particularly “L-arginine monohydrochloride, L-methionine, [and] L-lysine
`
`monohydrochloride”, are included as a “stabilizer” in claim 14.
`
`“Buffer” Term Construction
`
`
`26.
`
`All 108 claims of the ‘046 Patent include an embodiment of the “buffer” claim
`
`term. These include independent claims (claims 1, 21, 40, 77 and 104), dependent claims that
`
`identify a group of specific, preferred embodiments of the “buffer” claim term (claims 3, 23,
`
`41, 60, and 87), or additional claims that identify even more specific, preferred embodiments.
`
`I am informed that the parties’ competing claim constructions for this term are below:
`
`9
`
`
`Defendant’s claim
`construction
`Plain and ordinary meaning:
`
` a
`
` compound that stabilizes
`the pH of a sincalide
`formulation.
`
`Plaintiff’s Claim Construction
`
`Claim
`Term
`“a buffer” Excipients that “stabilize the pH” and
`“include, but are not limited to, phosphoric
`acid, phosphate (e.g. monobasic or dibasic
`sodium phosphate, monobasic or dibasic
`potassium phosphate, etc.), citric acid, citrate
`(e.g. sodium citrate, etc.), sulfosalicylate,
`acetic acid, acetate (e.g. potassium acetate,
`sodium acetate, etc.), methyl boronic acid,
`boronate, disodium succinate hexahydrate,
`amino acids, including amino acid salts (such
`as histidine, glycine, lysine, imidazole),
`lactic acid, lactate (e.g. sodium lactate, etc.),
`maleic acid, maleate, potassium chloride,
`benzoic acid, sodium benzoate, carbonic
`acid, carbonate (e.g. sodium carbonate, etc.),
`bicarbonate (e.g. sodium bicarbonate, etc.),
`boric acid, sodium borate, sodium chloride,
`succinic acid, succinate (e.g. sodium
`
`
`
`

`

`succinate), tartaric acid, tartrate (e.g. sodium
`tartrate, etc.), tris(hydroxymethyl)-
`aminomethane, biological buffers (such as
`N-2-hydroxyethylpiperazine, N’-2-
`ethanesulfonic acid (HEPES), CHAPS and
`other ‘Good’s’ buffers), and the like.” ‘046
`patent, col. 9, lines 45-65.
`
`
`
`Intrinsic Evidence Concerning The “Buffer” Claim Term
`
`27.
`
`Buffers have a wide variety of uses in many different products, including
`
`specialized and particular uses in drug formulations. The buffers that are relevant to the ‘046
`
`Patent claims are those that are relevant to peptide and protein drug formulations (e.g., claim
`
`1), kits for using them (e.g., claim 40) and the processes of making (e.g., claim 21) and using
`
`them (e.g., claim 56).
`
`28.
`
`The first part of the construction is from column 9, line 45, “[b]uffering agents
`
`are employed to stabilize the pH.” A person of skill in the art would understand after reading
`
`the claims and specification that a buffer would be an excipient that stabilizes pH. Neither the
`
`claim nor the specification limits the buffer to stabilizing the pH for any particular
`
`formulation, at any particular time or in any particular way. Thus, a buffer could be a
`
`component that stabilizes the pH (a) in the process of compounding the drug product, after all
`
`of the components are added together and the pH is adjusted, (b) in the process of formulating
`
`a drug product, in an intermediate form, such as a lyophilized form used for storage, or (c) in
`
`a final form where the product has been reconstituted with sterile water prior to injection into
`
`a patient, as just some examples that would fit the claims.
`
`29.
`
`Similarly, after reading the claims and the specification, a person of skill in the
`
`art would understand that the buffer does not need to achieve any specified benefit or
`
`advantage to meet the claims terms. In particular, it does not need to increase the stability of
`
`
`
`10
`
`
`

`

`the peptide drug ingredient or reduce degradation under all or any particularly specified
`
`limiting conditions to meet the claim terms.
`
`30.
`
`The second part of the construction starting with the words, “[buffering agents]
`
`include, but are not limited to, phosphoric acid …,” (9:49-65) gives a non-limiting list of
`
`preferred embodiments. The items on this list would indeed be recognized as buffers relevant
`
`to the formulation of peptide and protein drugs by a person of skill in the art. Some items on
`
`the list would not be single “compounds” per se, but instead would be two or more related
`
`compounds that may form in response to their chemical environment, e.g. “sodium chloride”
`
`is not itself a buffer, but sodium chloride may be a component of “sodium lactate” or that
`
`forms in a chemical environment with the addition of other buffer and non-buffer components.
`
`For example, adding arginine hydrochloride and sodium phosphate together to form a
`
`combined buffer will result in the production of sodium chloride in addition to various
`
`arginine and phosphate species. This list also appears in a slightly different (but materially the
`
`same) form in the claims (e.g., claims 3 and 23). The list from claim 3 is recited below:
`
`“..buffers selected from the group consisting of phosphoric acid, phosphate, citric acid,
`
`citrate, sulfosalicylate, acetic acid, acetate, methyl boronic acid, boronate, disodium
`
`succinate, hexahydrate, one or more amino acids, lactic acid, lactate, maleic acid,
`
`maleate, potassium chloride, benzoic acid, sodium benzoate, carbonic acid, carbonate,
`
`bicarbonate, boric acid, borate, sodium chloride, succinic acid, succinic acid, succinate,
`
`tartaric acid, tartrate, tris-(hydroxymethyl)aminomethane, and biological buffers.”
`
`(emphasis added)
`
`31.
`
`I understand that the correct construction of patent claims should generally
`
`(with some exceptions where there is, for example, a clear disavowal of them) be construed to
`
`
`
`11
`
`
`

`

`include or encompass the exemplified and otherwise preferred embodiments that are disclosed
`
`in the specification.
`
`32.
`
`There is additional information on the buffer in the patent. This includes a
`
`description of the possible benefits, advantages or results of using a buffer, at column 9, lines
`
`46-47, such as to “reduce the risk of chemical stability at extreme pH values”. Even if this
`
`description of a possible function or benefit of buffers were read to limit the extent of the
`
`term’s meaning, no limitations were placed on the pH range or capacity of a buffer, nor does
`
`it require that the buffer offer a specific or particular benefit related to stabilizing the pH. In
`
`essence, the person of skill in the art would understand that a formulation component could
`
`instill chemical stability to a formulation at an extreme pH without directly affecting the
`
`buffering capacity or pH of the formulation. There is also information concerning particular
`
`buffers, including a phosphate buffer, which is a particularly preferred embodiment at, for
`
`example, column 9, line 65 to column 10, line 9, and in Example 1. I have not included this
`
`other information in the claim construction because it was not included specifically in the
`
`claims, such as claim 1, and it describes possible benefits, advantages, results and specific
`
`embodiments, but not the full scope of the claim term that a person of skill in the art would
`
`understand to be what was disclosed and claimed.
`
`Extrinsic Evidence Concerning The “Buffer” Claim Term
`
`33.
`
`I examined the extrinsic evidence concerning the buffer claim term with
`
`respect to the construction provided in the table above. This evidence confirmed that the
`
`construction was correct.
`
`34.
`
`A particular issue in this action is whether amino acids can meet the “buffer”
`
`claim term. I examined the extrinsic evidence for this point, looking at (a) specific
`
`
`
`12
`
`
`

`

`formulations of sincalide that contained amino acids, to determine whether the amino acids
`
`would function as buffers using calculations available before the filing date of the patent on
`
`August 16, 2002, (b) relevant articles fiom before the filing date of the patent on August 16,
`
`2002, and (c) relevant articles after the filing date to see if anything had changed. In my
`
`opinion, amino acids meet the “buffer” claim term as used in claims such as claim 1 and claim
`
`3, in the specification (e.g., column 9, lines 49-65), and as taught in the extrinsic evidence. I
`
`have included immediately below a table of the structures and abbreviations used for common
`
`amino acids. In addition, there are some less common amino acids and amino acids that result
`
`from post-translational modification of other amino acids, such as sulfotyrosine produced by
`
`sulfation of tyrosine, that I have not listed.
`
`Amino acid Structure
`
`Single
`and three
`letter
`codes
`
`Single
`and three
`letter
`codes
`
`Amino acid Structure
`
`Ala (A)
`
`alanine
`
`Cys (C)
`
`cysteine
`
`ASP (D)
`
`aSpaI'th acid
`
`Glu (E)
`
`ghltamic acid
`
`Phe (F)
`
`phenylalanine
`
`"'"HIH'w"
`CH3
`
`"'""T"°°'
`(I:Hz
`SH
`
`"-M‘l-(|:H-OO--
`Hzc—C—OH
`4
`
`“him-0°"
`H’c_gz'c_°H
`3
`
`"‘T'm"
`Hp
`0
`
`Met 0V1) methionine
`
`Asn (N)
`
`aSpaIagine
`
`Pro (P)
`
`proline
`
`61]] (Q)
`
`glutamine
`
`Arg (R)
`
`arginine
`
`---NH—(|:H—co-_
`Hzc—gz-s—CH3
`
`"'NH-CH-co--
`Hzc—c—NH2
`3
`
`'--/N—C\H-CO--
`Hzc\ /CH2
`32
`
`m—TH-co-
`Hzc—gz—c—NH2
`g
`
`--«n_¢l:n.:o--
`WC—CZ-CH,
`..il.
`
`13
`
`

`

`Gly (G)
`
`glycine
`
`His (H)
`
`histidine
`
`He (1)
`
`isoleucine
`
`LYS (K)
`
`lysine
`
`Leu (L)
`
`leucine
`
`"'""'T”'°°"
`H
`
`"M'TH'M"
`H20
`H
`m
`
`"'""‘°"'°°"
`HC—gz-CHQ
`L.
`
`"MT—0°"
`”20—32-012
`'
`"'""'°"'°°"
`|
`H
`Hzc—9—CH,
`013
`
`Haw—cu.
`
`Ser (S)
`
`serine
`
`Thr (T)
`
`threonine
`
`Val (V)
`
`valine
`
`TIp (W)
`
`tryptophan
`
`Tyr (Y)
`
`tyrosine
`
`"'"”'T'"°°"
`Hzc—gz-OH
`
`"‘""'°|"'°°“
`Hc—OH
`t.
`
`"'"""|’"'°°“
`HC—CH;
`g,
`
`"'""“|’"'°°“
`”20
`or:
`---NH-cn-co--
`|
`Hzc—Q—on
`
`”N
`
`Figure: Common amino acids, the abbreviations commonly used in the art, and their
`chemical structures (conjugated at N and C termini, as in a peptide).
`
`(a) Calculation 0f Buffering By Amino Acids
`
`35.
`
`In my opinion, the hypothetical person of ordinary skill in the art as I have
`
`defined them above would have the skill and knowledge to calculate the buffering ability of
`
`amino acids in sincalide formulations, using references such as Butler (1998)(Exhibit 15).
`
`36.
`
`I have provided a discussion and examples of such calculations in Appendix B
`
`hereto. These calculations show that amino acids used in relevant formulations, including a
`
`formulation disclosed in the ‘046 Patent (e.g., claim 106), have substantial buffering capacity
`
`over a broad range of pH, including around a pH of 7.0. This confirms a claim construction
`
`for the “buffer” term that includes amino acids.
`
`(b) Before The Filing Date
`
`37.
`
`Nema et al., “Excipients and Their Use in Injectable Products,” PDA Journal
`
`of Pharmaceutical Science and Technology 51 (1997), p. 166-171 (“Nema”). Exhibit 16.
`
`Nema was cited as relevant prior art by the Defendant, Maia (MAIA0004762-4769), and it is
`
`14
`
`

`

`a review article and survey of the excipients used in pharmaceutical products as reported in
`
`the Physicians’ Desk Reference. Nema also was considered by the Examiner, cited by Bracco,
`
`and not used to reject the ‘046 Patent claims during the prosecution history. Therefore, the
`
`claims of the ‘046 Patent were allowed to issue by the Examiner and the United States Patent
`
`and Trademark Office (“USPTO”) over the Nema reference. Nema states (at p. 169) that
`
`arginine may be used as a buffer in formulations:
`
`“Table VII lists additives which are used to modify osmolality, and as bulking or
`lyo-cryo protective agents. Dextrose and sodium chloride are used to adjust
`tonicity in the majority of formulations. Some amino acids, glycine, alanine,
`histidine, imidazole, arginine, asparagine, aspartic acid, are used as bulking agents
`for lyophilization and may serve as stabilizers for proteins or peptides and as
`buffers.”
`
`Nema also states (at p. 169) that lysine may be used as a buffer in formulations:
`
`“Lysine and glycine are amino acids which function as buffers and stabilize
`protein and peptide formulations. These amino acids are also used as lyo-
`additives and may prevent cold denaturation.”
`
`38. Wang, “Instability, Stabilization, and Formulation of Liquid Protein
`
`Pharmaceuticals,” International Journal of Pharmacy, 185 (1999), pp. 129-88 (“Wang 1999”).
`
`Exhibit 5. Wang 1999 was cited by Maia (MAIA0004686-4745) as prior art and it relates to
`
`the stability of protein drugs. Wang 1999 (at 175) recognizes arginine as a buffer component
`
`in protein formulations. It states:
`
`“Multiple excipients are often required in a liquid protein formulation, although a
`single-excipient protein formulation may be sufficient, such as tPA, which is
`formulated in 0.5 M arginine-phosphate buffer (pH 7.3) (Overcashier et al., 1997).”
`
`39.
`
`Stoclet, FR2468366A1, which published on May 8, 1981 (“Stoclet”), is
`
`relevant to these claim terms. For example, it shows a lysine buffer for anti-glaucoma
`
`formulation at a pH of about 7 to 9 (e.g., B0018483; claims 1-4). Exhibit 17. Stoclet states in
`
`the specification that arginine also may be useful to buffer the solution between 7 and 9
`
`
`
`15
`
`
`

`

`(B0018482).
`
`40. Malecki, GB915429A, which published on January 9, 1963 (“Malecki”), is
`
`relevant to these claim terms. Exhibit 18. For example, it shows a lysine buffer for a vegetable
`
`product at a pH of about 8.5 to 9.7 (e.g., claims 11 and 12; Example 4). B0018489.
`
`41.
`
`George et al., WO2000056273A2, US6239088B1, which published on
`
`September 28, 2000, (“George”), is relevant to these claim terms. Exhibit 19. For example, it
`
`shows an arginine buffer for a lachrymal fluid formulation at a pH of 6 to 8 (e.g., US col. 3,
`
`line 60 – col. 4, line 2; claims 12 and 19; Example 1). B0018909, 19111.
`
`42.
`
`Prior et al., WO 90/06764, which published on June 28, 1990, is relevant to
`
`these claim terms. Exhibit 13. For example, it states that basic amino acids, including arginine
`
`and lysine, may behave as buffers in the formulation of immunoglobulins (7:5-16 and 7:35-
`
`8:6).
`
`43.
`
`Susumu et al., Japan JPS60158105A, which published on August 19, 1985, is
`
`relevant to these claim terms. Exhibit 20. For example, lists arginine as a buffer for a skin
`
`rinse agent (claim 2).
`
`
`
`44.
`
`(c) After The Filing Date
`
`The Handbook of Pharmaceutical Excipients, Seventh Edition (2012)
`
`(B0020730-34), characterizes lysine hydrochloride and methionine, two amino acids, as
`
`“Buffering agent,” as their “Functional Category.” The MSDS (Material Safety Data Sheet)
`
`and related literature for lysine hydrochloride, methionine, and arginine hydrochloride shows
`
`that the amino acid solutions spontaneously reach an equilibrium pH of between about 5 and 7.
`
`E.g., B0020735-49. See also MAIA0001176-87, 1252-53, 1278. Exhibits 21 and 22.
`
`45.
`
`Patel et al., WO201575743A1, US20160250295A1, which published on May
`
`
`
`16
`
`
`

`

`28, 2015 (“Patel”), is relevant to these claim terms. Exhibit 23. For example, it shows an
`
`arginine buffer for a gonadotropin formulation in the range of pH 5.0 to 9.0 (e.g., from US
`
`[0013], [0064], and claim 30). Arginine can also be used as a stabilizer or antioxidant (e.g.,
`
`from US [0032] and claim 38). B0018765, 19498.
`
`46.
`
`DeFelippis et al., US20030104983A1, which published on June 5, 2003
`
`(“DeFelippis”) is relevant to these claim terms. Exhibit 11. It states at [0040] that insulin
`
`analog formulations “comprising TRIS buffer or L-arginine buffer at pH 7.4 remain stable
`
`against aggregation for markedly longer periods of time than do formulations comprising a
`
`phosphate buffer.” See also [0048], Table 2, claim 1, Examples 2 and 5. B0018637.
`
`47.
`
`Nishida et al., US20040132689A1, which published on July 8, 2004
`
`(“Nishida”), is relevant to these claim terms. Exhibit 24. For example, it shows an arginine
`
`buffer for a colloid formulation at various pH, including a formulation with arginine buffer at
`
`about pH 6.5 having high buffer capacity (e.g., [0018], [0036]; claim 11; Example 1).
`
`B0018646.
`
`48.
`
`Nagai et al., “Temperature Dependence of the Dissociation Constants of
`
`Several Amino Acids,” Journal Chemical Engineering Data, 2008, 53, pp. 619-627 (“Nagai”),
`
`is relevant to these claim terms. Exhibit 25. For example, it shows that lysine and arginine have
`
`suitable pKa’s for buffering of pharmaceuticals at conditions relevant to the formulation,
`
`manufacture or testing of sincalide formulations described and claimed in the ‘046. B0020650.
`
`49.
`
`Friedl et al., WO2009121945A2, US9415016B2, which published on October
`
`8, 2009 (“Friedl”), is relevant to these claim terms. Exhibit 26. For example, it shows an
`
`arginine buffer for a DPP-4 inhibitor formulation (e.g., col. 6, lines 18-25), and describes
`
`embodiments using arginine or lysine buffers (e.g. col 8, lines 7-12, claim 5). B0019058,
`
`
`
`17
`
`
`

`

`19378.
`
`50.
`
`Gastner, US20100056633A1, which published on March 4, 2010, (“Gastner”),
`
`shows an arginine buffer and a lysine buffer for a creatine formulation at a pH of about 8 to
`
`12 (e.g., claims 20 and 38, Figure 1, Example 1). B0018655. Exhibit 27.
`
`51.
`
`Prior et al., WO 90/06764 (“Prior”), is relevant to these claim terms. Exhibit 13.
`
`For example, it shows that basic amino acids such as arginine and lysine were preferred amino
`
`acids (e.g., B00206027-28; B0020631) that were used to solubilize immunoglobulins and
`
`related polypeptides (e.g., claims 1, 3, 5, 7, 9, 12). Prior also states that “the basic amino acid
`
`itself, with proper pH adjustment, behaves as a buffer”, and thus arginine can have a dual role
`
`as both a solubilizer and buffering agent (7:32 to 8:1). B0020623-41.
`
`52. Wang et al., US20110135615A1, US8642029B2, w