IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`
`
`BRACCO DIAGNOSTICS INC.,
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`Case No. 3:17-cv-13151-PGS-TJB
`
`Plaintiff,
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`v.
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`MAIA PHARMACEUTICALS, INC.,
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`Defendant.
`
`
`CONFIDENTIAL – SUBJECT TO
`DISCOVERY CONFIDENTIALITY
`ORDER
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`
`
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`DEFENDANT MAIA PHARMACEUTICALS, INC.’S INVALIDITY CONTENTIONS
`PURSUANT TO L. PAT. R. 3.3 AND 3.6(c)-(d)
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`Pursuant to Local Patent Rules 3.3 and 3.6(c)–(d), Defendant/Counterclaimant Maia
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`Pharmaceuticals, Inc. (hereinafter “Maia”) hereby provides Plaintiff Bracco Diagnostics Inc.
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`(hereinafter “Bracco” or “Plaintiff”) with Maia’s Invalidity Contentions as to U.S. Patent
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`No. 6,803,046 (“the ’046 patent” or “the patent-in-suit”). Pursuant to L. Pat. R. 3.6(d), and
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`subject to the reservation of rights outlined herein, concurrently with service of these
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`contentions, Maia is also producing the documents and things it currently intends to rely on in
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`support of its Invalidity Contentions.
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`A.
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`GENERAL STATEMENTS
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`Discovery is just beginning and is ongoing. Maia bases these Invalidity Contentions, in
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`part, upon the positions taken by Bracco in its Complaint and the information in Maia’s
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`possession as of the date of these Invalidity Contentions. Maia anticipates that the subject matter
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`of these Invalidity Contentions will be the subject of further extensive fact and expert discovery.
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`Additionally, expert discovery has not started and Maia reserves the right to amend or
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`supplement these Invalidity Contentions and accompanying document production as a result of
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`new information disclosed through discovery, including through the parties’ experts.
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`Bracco Ex. 2003
`Maia v. Bracco
`IPR2019-00345
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`1
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`These Invalidity Contentions are based on information available to Maia at this time.
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`These Invalidity Contentions are necessarily preliminary and may require subsequent
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`amendment, alteration or supplementation.
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`Maia reserves the right to amend, alter or supplement these contentions based on further
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`investigation, fact or expert discovery, any claim construction ruling, or as a result of Bracco’s
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`Infringement Contentions and/or any amendments or supplements thereto. Maia’s contentions
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`may be in the alternative and do not constitute any concession by Maia for purposes of claim
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`construction or infringement.
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`Furthermore, these Invalidity Contentions are provided without prejudice to the rights of
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`Maia to introduce at trial any subsequently discovered evidence or expert opinions relating to
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`currently known facts and to produce and introduce at trial all evidence, whenever discovered,
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`relating to the proof of subsequently-discovered facts. Moreover, facts, documents and things
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`now known may be imperfectly understood and, accordingly, such facts, documents and things
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`may not be included in the following Invalidity Contentions. Maia reserves the right to conduct
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`discovery with reference to, or offer into evidence at the time of trial, any and all facts, expert
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`opinion testimony, documents and things notwithstanding the Invalidity Contentions herein.
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`To the extent that Maia inadvertently discloses information that may be protected from
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`discovery under the attorney-client privilege, the attorney work product immunity, the common
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`interest privilege or any other applicable privilege or immunity, such inadvertent disclosure does
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`not constitute a waiver of any such privilege or immunity.
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`The information set forth below is provided without in any manner waiving: (1) the right
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`to object to the use of any statement for any purpose, in this action or any other actions, on the
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`grounds of privilege, relevance, materiality, or any other appropriate grounds; (2) the right to
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`object to any request involving or relating to the subject matter of the statements herein; or (3)
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`the right to revise, correct, supplement or clarify any of the statements provided below at any
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`time.
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`Maia reserves the right to supplement or amend these Invalidity Contentions to the full
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`extent consistent with the Court’s Rules and Orders, including Local Rules, as additional
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`information becomes available through discovery or otherwise.
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`1. Asserted Claims
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`Plaintiff asserts that Maia infringes claims 1–108 of the ’046 patent (“the Asserted
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`Claims”). These Invalidity Contentions address all claims of the ’046 patent, for which Maia
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`seeks declaratory judgment of invalidity and non-infringement.
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`2. Claim Construction
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`The Court has not yet construed the Asserted Claims. Maia’s position on the invalidity of
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`particular claims will depend on how those claims are construed by the Court. The Invalidity
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`Contentions Maia presents herein are based, at least in part, on Maia’s current understanding of
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`the Asserted Claims. To the extent that these Invalidity Contentions reflect constructions of
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`claim terms that may be consistent with or implicit in Bracco’s construction of the claim terms,
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`no inference is intended, nor should any inference be drawn, that Maia agrees with such claim
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`constructions. Any statement herein describing or tending to describe any claim element is
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`provided solely for the purpose of understanding the relevant prior art. Maia expressly reserves
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`the right to propose any claim construction it considers appropriate and/or contest any claim
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`construction it considers inappropriate.
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`In part, because of the uncertainty of claim construction, the Invalidity Contentions may
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`be made in the alternative and are not necessarily intended to be consistent with each other, and
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`should be viewed accordingly. Further, Maia’s inclusion of prior art that would render a claim
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`obvious based on a particular scope or construction of the claim is not, and should in no way be
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`seen as, an adoption or admission as to the accuracy of such scope or construction. Maia
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`reserves all rights to further supplement or modify the positions and information in these
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`Invalidity Contentions, including without limitation, the prior art and grounds of invalidity set
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`forth herein, after the Court has construed the claims of the patent-in-suit.
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`B.
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`PRIOR ART
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`In addition to all of the prior art references found on the face of the patent-in-suit, which
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`Maia incorporates fully herein, Maia identifies the following items of prior art which, separately
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`or in any reasonable combination, render obvious one or more of the claims of the patent-in-suit
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`under 35 U.S.C. § 103. Maia further incorporates by reference, in full, all references cited in the
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`following prior art references and their prosecution histories, where applicable. Maia further
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`incorporates by reference, in full, any prior art or other supporting references cited in Maia’s
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`Non-Infringement Contentions. The citations provided are representative of the references and
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`are not exhaustive. To the extent that similar claim limitations occur in one or more claims, the
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`disclosures below should be read to apply to all similar claim limitations. Moreover, many of the
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`references discussed herein are representative of additional prior art references in the relevant
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`field. Persons of ordinary skill in the art at the time of the filing of the patent-in-suit knew or
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`read references as a whole, and in the context of other publications, literature and the general
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`knowledge in the field. Maia may rely on all such information, including other portions of the
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`prior art references listed herein and other publications and expert testimony, to provide context
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`and as aids to understanding and interpreting the listed references, or to establish that it would
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`have been obvious for a person of ordinary skill in the art to modify or combine any of the cited
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`references. Maia reserves the right to modify these Invalidity Contentions to add additional prior
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`art references in light of the information gained through discovery, expert discovery, arguments
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`or positions advanced by Bracco, or the Court’s claim construction rulings.
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`U.S. Patent No. 3,937,819 to Ondetti et al., entitled “Method of Stabilizing an Injectable
`Composition of a Cholecystokinin Active Octapeptide” (“Ondetti”)
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`Ondetti issued on February 10, 1976, more than one year prior to the earliest priority date
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`of the ’046 patent, and therefore qualifies as prior art under 35 U.S.C. § 102(b). Ondetti
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`discloses a lyophilized pharmaceutical composition of the sulfated octapeptide sincalide. See
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`Ondetti at 1:24–36, 50–55. Ondetti discloses that the composition of sincalide is obtained by
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`lyophilizing an aqueous solution of the octapeptide and NaCl (a stabilizer/tonicity agent). Id. at
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`Abstract. Ondetti discloses a sincalide solution prepared by adding 2500 mcg of sincalide and
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`21.42 g of NaCl to 900 mL of water for injection, adjusting the pH to between 5.50 and 6.50, and
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`creating a solution of approximately 1 liter. Id. at 2:33–47. The solution is filled into vials and
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`lyophilized. Id. at 2:47–57. Ondetti discloses that this enhances “the stability of the octapeptide
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`against degradation upon storage.” Id. at 2:60–66. Ondetti further discloses that the “lyophilized
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`material is readily reconstituted for injection by the addition of sterile water for injection,”
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`preferably in a quantity “that forms an isotonic solution.” Id.at 2:18–23. Ondetti discloses that
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`each vial of lyophilized composition contains 5.25 mcg of sincalide and 45.0 mg of sodium
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`chloride. Id. at 2:14–16. The lyophilized composition “is reconstituted by addition of 5 ml of
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`sterile water for injection.” Id. at 2:57–58.
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`Bracco Diagnostics, Kinevac® Sincalide for Injection (1994) (“Kinevac Label”)
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`
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`Kinevac Label published in 1994, more than one year prior to the earliest priority date of
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`the ’046 patent, and therefore qualifies as prior art under 35 U.S.C. § 102(b). Kinevac Label
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`discloses Kinevac®, also known as Sincalide for Injection. Kinevac Label at page 1. Kinevac
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`Label discloses that each vial of sincalide provides a sterile vial of lyophilized white powder
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`containing 5 mcg of sincalide with 45 mg of sodium chloride as a tonicity agent. Id. Sincalide,
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`when injected, produces a substantial reduction in gallbladder size. Id. The evacuation of bile
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`that results is similar to that which occurs in response to endogenous cholecystokinin. Id. “Like
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`cholecystokinin, sincalide stimulates pancreatic secretion.” Id. Kinevac Label discloses that
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`Kinevac® is to be stored at room temperature prior to reconstitution. Id. at 3. To reconstitute the
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`sincalide for injection, 5 mL of sterile water is added to the vial containing the lyophilized
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`sincalide formulation. Id. Sincalide for Injection is described as a parenteral drug. Id.
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`U.S. Pharmacopeia & National Formulary 24, The National Formulary 19, “Sincalide for
`Injection” 1522-1523 (2000) (“USP 24”)
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`
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`USP 24 published in 2000, more than one year prior to the earliest priority date of the
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`’046 patent, and therefore qualifies as prior art under 35 U.S.C. § 102(b). USP 24 discloses that
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`“Sincalide for Injection is a sterile, synthetically prepared C-terminal octapeptide of
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`cholecystokinin and sodium chloride.” USP 24 at 1522. USP 24 states that it is preserved in
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`single-dose containers. Id. Sincalide for Injection has a pH between 5.0 and 7.5. Id. USP 24
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`discloses preparing a sincalide solution by dissolving USP Sincalide RS in aqueous sodium
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`chloride solution. Id. USP 24 recites that Sincalide for Injection is preserved in single-dose
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`containers, preferably in Type I glass. Id. Additionally, USP 24 discloses that Sincalide for
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`Injection is a “constituted solution.” Id. Sincalide for Injection contains about 1 mcg/mL of
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`sincalide. Id.
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`WO 00/51629 to Yasushi Sato, entitled “Preparations Stabilized Over Long Time” (“Sato”)
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`Sato published on September 8, 2000, more than one year prior to the earliest priority
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`date of the ’046 patent, and therefore qualifies as prior art under 35 U.S.C. § 102(b). Sato also
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`published as EP119722A1, on April 17, 2002, qualifying as prior art under 35 U.S.C. § 102(e).
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`Sato originally published in Japanese; a certified English translation of Sato is provided
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`herewith. All citations to Sato are to the English translation provided, corresponding to the
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`Japanese language PCT. Sato discloses a stable G-CSF (granulocyte colony-stimulating factor),
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`a glycoprotein. Sato at 4. In addition to G-CSF, Sato also discloses that other physiologically
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`active proteins within the scope of the disclosure include, inter alia, cholecystokinin (CCK). Id.
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`at 11. Sincalide (CCK-8) is the C-terminal octapeptide of CCK. Sato discloses that the G-CSF
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`formulations contain one or more amino acids, selected from the group consisting of lysine,
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`histidine, arginine, aspartic acid, glutamic acid, threonine and asparagine; one or more amino
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`acids selected from hydrophobic amino acids, and methionine. Id. at 5. Several formulations in
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`both Table 1 and Table 2 disclose arginine and methionine as suitable amino acids to be used in
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`conjunction. Sato discloses that the formulations can be in the form of a lyophilized formulation.
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`Id. at 6. Sato discloses that the formulation can contain mannitol, see id. at 5, and a surfactant,
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`most preferably selected from polysorbates 20 and/or 80. See id. at 5. The pH of the
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`formulations disclosed in Sato can range from a pH of about 5 to 7. Id. at 5–6. Sato also
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`discloses a method for inhibiting a physiologically active protein containing a methionine residue
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`from producing a variant oxidized at the methionine residue. The method involves adding
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`methionine. Id. at Abstract, 6. The formulations can also contain isotonizing agents, where
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`mannitol is especially preferred in an amount of 5–60 mg/mL. Id. at 8. The formulations
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`disclosed in Sato can also have a buffer, and a chelating agent. Id. at 9.
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`Nema et al., “Excipients and Their Use in Injectable Products,” 51 PDA J. OF PHARMA. SCI.
`AND TECH. 166 (1997) (“Nema”)
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`Nema published in 1997, more than one year prior to the earliest priority date of the
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`’046 patent, and therefore qualifies as prior art under 35 U.S.C. § 102(b). Nema provides a
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`roadmap for a skilled artisan to produce stabilized parenteral drug formulations, including
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`peptide products. Nema at 169, Table VI and col. 2. Nema teaches that injectable products can
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`include excipients such as solvents, solubilizers, wetting agents, chelating agents, antioxidants,
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`preservatives, buffers, bulking agents, and tonicity adjustors. Id. at Tables I–VII. Specifically,
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`Nema describes using polysorbate 20 and polysorbate 80, among other excipients, as solubilizing
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`or wetting agents in parenteral formulations. Id. at 167, Table II. Nema further discloses that
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`polysorbate 20 and polysorbate 80 are the most commonly used solubilizing agents in parenteral
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`formulations. Id. Nema discloses that there are only a limited number of chelating agents used
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`in parenteral products, including DTPA, also known as pentetic acid. Id. at 167, col. 2–168, col.
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`1, and Table III. Nema discloses the use of bulking agent/tonicity adjustors, such as mannitol,
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`for parenteral formulations. See id. at 169, col. 1 and Table VII. Nema describes using buffers.
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`Id. at 168–169. Nema teaches various suitable phosphate buffers, including phosphoric acid,
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`monobasic potassium, monobasic sodium, dibasic sodium, and tribasic sodium phosphate, and
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`teaches that phosphate is one of the most common buffers in parenteral formulations. Id. at 169,
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`Table VI. Nema also discloses antioxidants suitable for use in parenteral formulations, including
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`metabisulfite sodium, which is disclosed as one of the most commonly used antioxidants. Id. at
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`Table VI. Nema discloses that “[s]ulfite, bisulfite, and metabisulfite constitute the majority of
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`antioxidants used in parenteral products.” Id. at 168, col. 1.
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`Yu-Chang John Wang and Musetta A. Hanson, “Parenteral Formulations of Proteins and
`Peptides: Stabilities and Stabilizers,” 42 J. PARENTERAL SCI. AND TECH. S4 (1988)
`(“Wang”)
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`Wang published in 1988, more than one year prior to the earliest priority date of the
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`’046 patent, and therefore qualifies as prior art under 35 U.S.C. § 102(b). Wang provides
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`“comprehensive information to the scientists setting out to design a stable and elegant injectable
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`formulation containing a protein, peptide, or both.” Id. at S4, col. 2. Wang discloses that
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`methionine is susceptible to oxidization. Id. at S6, col. 2, at g. Wang discloses that this
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`oxidation can lead to the degradation of proteins and peptides. Id. at S4, col. 2. Wang teaches
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`“use of excipients to stabilize parenteral formulations of proteins and peptides,” and provides
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`many examples of stabilizers. Id. at S4, col. 2, S9 at IV, Table I and Table Ia. Wang describes
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`that amino acids, including lysine, arginine, and methionine, were known to work as stabilizers
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`in protein or peptide formulations. Id. at Table II. Wang further discloses use of chelating
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`agents. Id. at S12, S18–20. Wang discloses that judicious use of surfactants can be
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`advantageous to stabilize the proteins or peptides against denaturants. Id. at S13–S15, Table III.
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`Wang further discloses that pH can play an important role in stabilizing a protein or peptide
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`product and that a proper selection of pH is key to having a stable product. Id. at S22. Wang
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`also discloses use of mannitol, and discloses that polyols stabilize proteins. Id. at S16.
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`U.S. Patent No. 5,763,409 to Bayol et al., entitled “Stable Freeze-Dried Formulation
`Comprising a Protein Assay Kit” (“Bayol”)
`
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`Bayol issued on June 9, 1998, more than one year prior to the earliest priority date of the
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`’046 patent, and therefore qualifies as prior art under 35 U.S.C. § 102(b). Bayol discloses
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`preparing stable freeze-dried products containing a peptide, such as cholecystokinin (CCK);
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`sincalide (CCK-8) is the C-terminal octapeptide of CCK. Bayol at 3:60–67, 4:17–22. Bayol
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`teaches lyophilized peptide and protein formulations that comprise surfactants. Id. at 4:64–67.
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`Bayol discloses inclusion of chelating agents. Id. at 3:38–41. The freeze-dried peptide
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`formulation forms disclosed in Bayol contain a buffer. Id. at 3:26–33. Bayol also teaches the
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`inclusion of mannitol. Id. at 3:60–67.
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`U.S. Patent No. 5,565,423 to Sandow et al., entitled “Cyclopeptides and Their Use as
`Absorption Promoters when Applied to the Mucosa” (“Sandow”)
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`Sandow issued on October 15, 1996, more than one year prior to the earliest priority date
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`of the ’046 patent, and therefore qualifies as prior art under 35 U.S.C. § 102(b). Sandow
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`discloses the use of sincalide for diagnosis of pancreatic function. Sandow at 5:1–25. Sandow
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`discloses sodium EDTA as a chelating agent. Id. at 6:24–25. Sandow further discloses,
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`isotonicizing additive such as mannitol, and buffers, such as potassium sodium phosphate, citric
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`acid and its salts or mixtures of the two in sincalide formulations, to establish a pH range
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`between 3 and 8. Id. at 6:17–21.
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`WIPO Publication No. WO 90/12029 to Tapan Audhya and Gideon Goldstein, entitled
`“Lyophilized Peptide Formulations” (“Audhya”)
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`
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`Audhya published on October 18, 1990, more than one year prior to the earliest priority
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`date of ’046 patent, and therefore qualifies as prior art under 35 U.S.C. § 102(b). Audhya
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`discloses that many peptides are unstable during lyophilization, which can negatively affect the
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`peptide’s biological activity. Audhya at 1, 4. Audhya teaches that formulations of peptides
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`having between 5 and 20 amino acids should be desirably in the pH range of from about 6.5 to
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`about 7.2. Id. at 6:10–12.
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`EP Application No. 1136068 to Hanyu et al., entitled “Powder Containing Physiologically
`Active Peptide” (Hanyu)
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`Hanyu published on September 26, 2001, and therefore qualifies as prior art to the ’046
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`patent under 35 U.S.C. § 102(a). Hanyu describes stabilizing physiologically active peptides
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`through addition of stabilizing excipients and then drying the composition. Hanyu at [0008].
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`Hanyu teaches these formulations can include a nonionic surfactant. Id. Hanyu teaches these
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`formulations can also include mannitol. Id. at [0019].
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`Bacarese-Hamilton et al., “Oxidation/Reduction of Methionine Residues in CCK: A Study
`by Radioimmunoassay and
`Isocratic Reverse Phase High Pressure Liquid
`Chromatography,” 6 Peptides 17 (1985) (“Bacarese-Hamilton”)
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`
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`Bacarese-Hamilton published in 1984, more than one year prior to the earliest priority
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`date of ’046 patent, and therefore qualifies as prior art under 35 U.S.C. § 102(b). Bacarese-
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`Hamilton discloses that the amino acid methionine, found in CCK, is among the amino acids
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`most susceptible to oxidization, and is likely to be the primary oxidative concern for the stability
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`of CCK. Bacarese-Hamilton at 17. Bacarese-Hamilton also discloses the use of sulfur-reducing
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`agent (dithiothreitol) to prevent oxidation of CCK. Bacarese-Hamilton at 21.
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`U.S. Patent No. 6,057,428 to Keyt et al., entitled “Variants of Vascular Endothelial Cell
`Growth Factor” (“Keyt”)
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`Keyt issued in May 2000, more than one year prior to the earliest priority date of the
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`’046 patent, and therefore qualifies as prior art under 35 U.S.C. § 102(b). Keyt discloses the
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`preparation of vascular endothelial growth (VEGF) variants, which provide materials that are
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`selective in respect to binding characteristics to the kinase domain region and the FMS-like
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`tyrosine-kinase region. Keyt at Abstract. Keyt discloses the VEGF formulations may also have:
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`Ingredients . . . such as antioxidants, e.g., ascorbic acid; low molecular weight
`(less than about ten residues) polypeptides, e.g., polyarginine or tripeptides,
`proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic
`polymers such as polyvinylpyrrolidone; amino acids, such as glycine, glutamic
`acid, aspartic acid, or arginine; monosaccharides, disaccharides, and other
`carbohydrates including cellulose or its derivatives, glucose, mannose or dextrins.
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`Id. at 20:52–60.
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`Keyt further discloses that if the VEGF variant is only partially soluble in water, it can be
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`formulated as a microemulsion by formulating it with Tween (such as Tween 80), Pluronics, or
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`PEG, in an amount of 0.04–0.05% (w/v), to increase solubility. Id. at 20:46–51. Keyt discloses
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`that suitable optional ingredients include chelating agents such as EDTA, and sugar alcohols
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`such as mannitol or sorbitol. Id. at 20:60–63. Keyt also discloses that if the VEGF is water
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`soluble, it can be formulated with a buffer “such as phosphate or other organic acid salt
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`preferably at a pH of about 7 to 8.” Keyt at 20:43–46.
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`U.S. Patent No. 6,120,761 to Yamazaki et al., entitled “Erythropoietin Solution
`Preparation” (“Yamazaki”)
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`
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`Yamazaki issued on September 19, 2000, more than one year prior to the earliest priority
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`date of the ’046 patent, and therefore qualifies as prior art under 35 U.S.C. § 102(b). Yamazaki
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`discloses “an erythropoietin solution preparation containing an amino acid as a stabilizer, and
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`having excellent long-term storage stability.” Yamazaki at Abstract. Yamazaki discloses that
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`suitable amino acid stabilizers are free amino acids and their salts, such as sodium salts,
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`potassium salts, and hydrochlorides. Id. at 2:47–49. The amino acids can be added in
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`combination. Yamazaki at 2:49–51. Preferred amino acid stabilizers include D-, L- and DL-
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`forms of arginine, lysine, and their salts, among others. Id. at 2:51–58. Preferably, the L-forms
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`of arginine and lysine, or their salts are used. Id. Yamazaki discloses that sulfur-containing
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`reducing agents may be used, if desirable. Id. at 2:37–40. Yamazaki also discloses use of a
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`polyoxyethylene sorbitan alkyl ester, including “most preferably” polysorbate 20 and/or
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`polysorbate 80, as an adsorption preventing agent. Id. at 3:33–39. Yamazaki further discloses
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`that ingredients usually added to a preparation include sugars, such as mannitol and sorbitol, and
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`inorganic salts, including sodium chloride, potassium phosphate, and sodium phosphate. Id. at
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`3:20–30. Yamazaki discloses that the solution can contain an aqueous buffer, such as a
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`phosphate or citrate buffer, resulting in a pH ranging between 5.0 and 8.0. Yamazaki at 3:48–50.
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`WO 98/46250 to Pietras, entitled “Peptide Antiestrogen Compositions and Methods for
`Treating Breast Cancer” (“Pietras”)
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`
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`Pietras published on October 22, 1998, more than one year prior to the earliest priority
`
`date of the ’046 patent, and therefore qualifies as prior art under 35 U.S.C. § 102(b). Pietras
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`discloses methods and compositions comprising native, site-specific mutagenized, and synthetic
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`peptides comprising portions of the human estrogen receptor. Pietras further discloses that the
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`invention can be provided as a kit, and is preferably formulated in an injectable form, such as
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`parenteral injection. Pietras at 10:17–23. Pietras further discloses buffers, to maintain the pH
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`range between 6 and 8. Id. at 50:24–28. Pietras also discloses tonicity agents, antioxidants and
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`stabilizers, including sodium metabisulfite, and wetting agents including polysorbates 80 and 20.
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`Id. at 50:24–51:7.
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`U.S. Patent No. 5,747,447 to Swift et al., entitled “Stable Polypeptide Composition”
`(“Swift”)
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`
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`Swift issued on May 5, 1998, more than one year prior to the earliest priority date of the
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`’046 patent, and therefore qualifies as prior art under 35 U.S.C. § 102(b). Swift discloses an
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`injectable polypeptide stabilized by dissolving the peptide, forming a liquid solution in citrate
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`buffer of about pH 5.0–5.5. Swift at Abstract. Swift discloses that polypeptides possess
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`“chemical and physical properties that present special problems which can cause instability in
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`storage and delivery.” Id. at 1:17–20. The disclosed liquid composition can be stored in a sterile
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`delivery vial, bag or bottle. Id. at 2:19–22. Swift further discloses that the polypeptide can be
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`any biologically active, substantially pure polypeptide that can be injected into a patient for
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`treatment. Id. at 4:20–25.
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`U.S. Patent Application No. US 2003/0104996 to Li et al., entitled “L-Methionine as a
`Stabilizer for NESP/EPO in HSA-Free Formulations” (“Li”)
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`
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`Li was filed on August 30, 2001, and therefore qualifies as prior art to the ’046 patent
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`under 35 U.S.C. § 102(e). Li discloses single use and multi-dose pharmaceutical formulations
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`comprising a biologically active agent and methionine, “wherein said formulations demonstrate
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`improved stability.” Li at Abstract. Li discloses that protein formulations can be unstable, and
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`undergo degradations. Id. at [0009]. Li further discloses that individuals of skill in the art knew
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`that it was beneficial to inhibit the oxidation of methionine-containing polypeptides, and that it
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`was known that methionine oxidation could be prevented by adding free L-methionine in an
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`amount sufficient to inhibit oxidation. Li at [0010]. Li discloses formulations which contain a
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`buffering agent, such as sodium or potassium phosphates or their hydrogen or dihydrogen salts,
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`or any other pharmaceutically acceptable buffering agent. Id. at [0031]. Phosphate buffers can
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`be used in an amount of 0.01 mM to 5 mM. Id. at [0038]. The preferred compositions of Li
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`have a pH in the range of 5.0 to 7.0. Id. at [0031]. Li further discloses that free L-methionine in
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`an amount of 0.05 to 50 mM assists in creating formulations having superior stability. Id. at
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`[0038]. The formulations disclosed in Li may further have a tonicity agent, such as sodium
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`chloride, mannitol, glycerine, and sorbitol. Id. at [0035]. Li further discloses that anti-oxidants,
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`including amino acids such as lysine, and chelating agents, such as DTPA, may be used in the
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`formulations. Id. at [0036].
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`Waterman et al., “Stabilization of Pharmaceuticals to Oxidative Degradation,” 7 PHARM.
`DEVELOPMENT AND TECH. 1 (2002) (“Waterman”)
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`
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`Waterman published in April 2002, and therefore qualifies as prior art to the ’046 patent
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`under 35 U.S.C. §§ 102(a) and 102(e). Waterman discloses “[a] guide for stabilization of
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`pharmaceuticals to oxidation.” Waterman at Abstract. Waterman discloses that chelating
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`agents, such as EDTA, can be added to mitigate metal contamination. Id. at 20, col. 2.
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`Waterman further discloses that pH can play a significant role in the stabilization of drugs to
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`oxidation. Id. at 21, col. 1.
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`Arakawa et al., “Factors Affecting Short-Term and Long-Term Stabilities of Proteins,” 46
`ADVANCED DRUG DELIVERY REVIEWS 307 (2001) (“Arakawa”)
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`
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`Arakawa published in 2001, and qualifies as prior art to the ’046 patent under 35 U.S.C.
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`§§ 102(a) and 102(e). Arakawa discloses that most proteins are only marginally stable at neutral
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`pH, and are readily denatured by pH changes. Id. at 308. “The pH [of a protein solution] should
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`be in an appropriate range. The choice and amount of buffer must take into account the desired
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`pH.” Id. at 322. Arakawa further discloses that “[f]reeze-thawing and freeze-drying are the most
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`commonly used methods for the long-term storage of proteins, although many proteins are not
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`stable against these stresses.” Id. at 308. Amino acids are a suitable cryoprotectant for proteins.
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`Id. at 314. Amino acids are also known to be stabilizers. Id. at 310. Arakawa further discloses
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`that protein solutions must be isotonic, and discloses mannitol as a suitable tonicity modifier. Id.
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`at 322.
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`Li et al., “Chemical Instability of Protein Pharmaceuticals: Mechanisms of Oxidation and
`Strategies for Stabilization,” 48 BIOTECH. AND BIOENGINEERING 490 (1995) (“Li 1995”)
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`Li 1995 published in 1995, more than one year prior to the earliest priority date of the
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`’046 patent, and therefore qualifies as prior art under 35 U.S.C. § 102(b). Li 1995 discloses that
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`“[o]xidation is one of the major chemical degradation pathways for protein pharmaceuticals” and
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`further discloses that Methionine is one of the amino acid residues most susceptible to oxidation,
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`due to its high reactivity with various reactive oxygen species. Li 1995 at 490. Li 1995 further
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`discloses that pH affects oxidation, and that a small selection of generally acceptable and safe
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`buffers can be used in protein formulations. Id. at 495–96. Li 1995 discloses that “[a]dditives
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`employed to prevent oxidation in formulations invariably include antioxidants, chelating agents,
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`and some other excipients.” Id. at 497. The “other excipients” include, for example, mannitol.
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`Id. at 497–98.
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`Wei Wang, “Instability, Stabilization, and Formulation of Liquid Protein
`Pharmaceuticals,” 185 INT’L J. PHARM. 129 (1999) (“Wang 1999”)
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`
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`Wang 1999 published in 1999, more than one year prior to the earliest priority date of the
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`’046 patent, and therefore qualifies as prior art under 35 U.S.C. § 102(b). Wang 1999 focuses on
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`the stabilization of protein pharmaceuticals, and discloses that protein instability is one of the
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`major reasons protein pharmaceuticals are administered through injection. Wang 1999 at
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`Abstract. The most common method for stabilizing liquid protein pharmaceuticals is the use of a
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`formulation excipient(s), such as sugars and polyols, amino acids, amines, salts, polymers, and
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`surfactants. Id. at 163–64. Wang 1999 further discloses that proteins are often stable at a narrow
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`pH range. Id. at 146, 164.
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`X.H. Zhou and A. Li Wan Po, “Peptide and Protein Drugs: I. Therapeutic Applications,
`Absorption and Parenteral Administration,” 75 INT.’L J. PHARM. 97 (1991) (“Zhou”)
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`
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`Zhou published in 1991, more than one year prior to the earliest priority date of the ’046
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`patent, and therefore qualifies as prior art under 35 U.S.C. § 102(b). Zhou provides a review of
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`protein and peptide drugs. Zhou at Summary. Zhou discloses that parenteral administration is
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`almost universally required for systemic delivery of peptide and protein drugs, and that most
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`peptide/protein drugs can be efficiently delivered by pa