IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`Cyan.IPR.One
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`Atty Ref: Cyan. IPR.One
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`Petitioner: Cyanotech Corporation
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`Trial Number: IPR2013-00401
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`In re U.S. Patent No. 5,527,533
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`Filed: 27 October 1994
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`Issued: 18 June 1996
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`Inventors: Mark O. M. TSO and Tim-Tak LAM
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`Patent Owner: The Board of Trustees of the University of Illinois
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`Title: Method of retarding and ameliorating central nervous system and eye
`damage
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`Mail Stop Patent Board
`Patent Trial and Appeal Board
`United State Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 5,527,533
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`

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`INTER PARTES REVIEW OF U.S. PATENT 5,527,533
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`Page ii
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`TABLE OF CONTENTS
`TABLE OF CONTENTS ....................................................................................ii
`I. MANDATORY NOTICES ..............................................................................1
` A. Real Party-In-Interest ...................................................................................1
` B. Related Matters.............................................................................................1
` C. Petitioner’s Lead and Back-Up Counsel ......................................................2
` D. Petitioner’s Counsels’ Service Information..................................................2
` E. Certificate of Service.....................................................................................2
` F. Grounds for Standing.....................................................................................2
`II. OVERVIEW OF CHALLENGE AND RELIEF REQUESTED................ 5
` A. Prior Art Patents and Printed Publications....................................................5
` B. Public Accessibility of the Foreign Language References........................... 6
` C. Reasonable Likelihood that Claims 1-27 are Unpatentable..........................9
` D. Relief Requested...........................................................................................9
` E. Statement of Material Fact ……...................................................................9
`III. IDENTIFICATION OF CHALLENGE ……............................................11
`A. Overview…….............................................................................................11
`B. Definition of certain claim terms……........................................................12
`C. Claim elements as found in the Prior Art……...........................................14
`IV. GROUNDS FOR CHALLENGE AND CLAIMS CHART .....................17
`V. FURTHER DISCUSSION........................................................................... 45
`VI. CONCLUSION........................................................................................... 59
`EXHIBIT LIST …...............................................................................................A
`CERTIFICATE OF SERVICE
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`Atty Ref: Cyan.IPR.One 
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`INTER PARTES REVIEW OF U.S. PATENT 5,527,533
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`Page 1
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`I. MANDATORY NOTICES
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`A. Real Party in Interest. The real parties-in-interest on the side of
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`Petitioner are Petitioner, Cyanotech Corporation, and its subsidiary, Nutrex Hawaii,
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`Inc. (“Nutrex”).
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`B. Related Matters. U.S. Patent No. 5,527,533 (‘533 patent) issued from
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`Application No. 08/330,194, filed 27 October 1994 (“Critical Date”). Pursuant to
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`37 C.F.R. § 42.8(b)(2), Petitioner identifies the following judicial or administrative
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`matter that would affect, or be affected by, a decision in this proceeding: U.S.
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`Nutraceuticals LLC d/b/a Valensa International; and The Board of Trustees of the
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`University of Illinois vs. Cyanotech Corporation, and Nutrex Hawaii, Inc. Civ.
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`5:12-cv-366-oc-10PRL (M.D.Fla), filed 29 June 2012 (“M.D.Fla. case”) (Ex.
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`1037), alleging infringement of unspecified claims of the ‘533 patent by Petitioner
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`and Nutrex (see Ex. 1037). This Petition is timely filed, no more than one year
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`after service of that complaint, under 35 U.S.C. § 315(b).
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`Petitioner filed Cyanotech Corporation v. U.S. Nutraceuticals, LLC d/b/a
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`Valensa International and The University of Illinois (Civ. No. 1:12-cv-00352-JMS-
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`RLP), on 20 June 2012 to invalidate the ‘533 patent, but that action was dismissed
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`(Ex. 1038) under Rules 12(b)(7) and 19, Fed. R. Civ. Proc., on 07 Feb. 2013,
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`leaving the parties as if the declaratory judgment action had never been brought.
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`Atty Ref: Cyan. IPR.One 
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`INTER PARTES REVIEW OF U.S. PATENT 5,527,533
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`Page 2
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`This dismissed law suit has no legal significance and thus does not affect this
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`proceeding.
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`C. Petitioner’s Counsel
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`Lead Counsel: Joseph A. Rhoa (Reg. No. 37,515)
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`Backup Counsel: George E. Darby (Reg. No. 44,053)
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`Pursuant to 37 C.F.R. §§ 42.10(b) and 42.15(a), Powers of Attorney and
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`filing fees are submitted with this Petition.
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`D. Petitioner’s Counsels’ Service Information
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`Lead Counsel: Email: jar@nixonvan.com . Tel: 703.816.4000. Fax:
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`703.816.4100. Postal and hand-delivery: Joseph A. Rhoa, Nixon & Vanderhye,
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`P.C., 901 North Glebe Road, 11th Fl., Arlington, VA 22203.
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`Backup Counsel: Email: cyan@teleport-asia.com . Tel: 808.626.1300; Fax:
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`808.626.1350. Postal and hand-delivery: George E. Darby, Paradise Patent
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`Services, Inc., 95-1045 Alakaina St., Mililani, HI 96789.
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`E. Certificate of Service. Petitioner has served by FedEx the Petition and
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`supporting evidence on (i) the correspondent attorney of record of the patent owner
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`as listed on USPTO PAIR and (ii) the patent owner as listed in the USPTO Patent
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`Assignment database.
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`F. Grounds for Standing. Petitioner certifies pursuant to Rule 42.104(a)
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`that the patent for which review is sought is available for Inter Partes Review
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`Atty Ref: Cyan. IPR.One 
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`INTER PARTES REVIEW OF U.S. PATENT 5,527,533
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`Page 3
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`(“IPR”) and that Petitioner is not barred or estopped from requesting an IPR
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`challenging the patent claims on the grounds identified in this Petition.
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`On June 20, 2012, Petitioner filed a declaratory judgment suit in U.S.
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`District Court for the District of Hawaii seeking to invalidate the ‘533 patent. That
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`court dismissed the suit (Ex. 1038) without prejudice under Fed. R. Civ. P. 12(b)
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`and 19(b) because the patent owner, the University of Illinois, was an
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`indispensable party but could not be joined because it was immune from suit in
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`Hawaii under the Eleventh Amendment. There was no adjudication on the merits.
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`Such a dismissal cannot bar Petitioner from requesting Inter Partes Review.
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`Dismissal for failure to join an indispensable party under Fed. R. Civ. P.
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`12(b)(7) and 19 is without prejudice and has no subsequent preclusive effect. See,
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`Fed. R. Civ. P., 41(b). See also, Univ. of Pittsburgh v. Varian Medical Systems,
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`Inc., 569 F. 3d 1328, 1332 (Fed. Cir. 2009) (“a dismissal for failure to join a party
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`is not an adjudication on the merits…”); Hughes v. United States, 71 U.S. (4 Wall.)
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`232, 237; 18 L.Ed. 303 (1866 )(“If the first suit was dismissed for a defect of
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`pleadings, or parties,… the judgment rendered will prove no bar to another suit,”).
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`Graves v. Principi, 294 F.3d 1350, 1356 (Fed. Cir. 2002) (The dismissal of an
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`action without prejudice “leaves the parties as though the action had never been
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`brought.”) (emphasis added). This is true regardless of whether the dismissal is
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`voluntary or involuntary.
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`Atty Ref: Cyan. IPR.One 
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`INTER PARTES REVIEW OF U.S. PATENT 5,527,533
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`Page 4
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`The voluntariness or involuntariness of a dismissal is not controlling in this
`context because, regardless whether the patent claims were dismissed
`without prejudice or extinguished by amendment, the effect is the same. The
`parties were left in the same legal position with respect to the patent claims
`as if they had never been filed. See 8 Moore's ¶¶41.40[9][b], 41.50[7][b];
`9 Charles Alan Wright & Arthur R. Miller, Federal Practice and Procedure
`§§ 2367, 2373 (2d ed. 1994); Hilbun v. Goldberg, 823 F.2d 881, 883 (5th
`Cir. 1987), cert. denied 485 U.S. 962 (1988).
`Nilssen v. Motorola, 203 F.3d 782, at 784-85 (Fed.Cir. 2000) (emphasis added).
`The Federal Circuit reaffirmed this point in Biomedical Patent Management
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`Corporation v. California Department of Health Services, 505 F.3d 1328, 1334
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`(Fed. Cir. 2007): waiver of 11th Amendment immunity in a prior patent
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`infringement case had no effect on subsequent litigation between the same parties
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`because the prior case was dismissed without prejudice, leaving the situation “as if
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`the action had never been filed.” Id. The district court’s reasoning, explicitly
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`affirmed by the Federal Circuit, was that:
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`A federal court that dismisses without prejudice a suit arising out of a federal
`cause of action has not adjudicated the suit on the merits, and leaves the
`parties in the same legal position as if no suit had ever been filed.
`Biomedical Patent Management Corp. v. California Department of Health Services,
`2006 WL 1530177 (N.D. Cal.) (emphasis added).
`The Patent Trial and Appeals Board (“Board”) addressed a similar issue in
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`Box GmbH v. Macauto, IPR2012-00004 (Jan. 24, 2013), where the Board held that
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`a prior infringement suit that had been voluntarily dismissed without prejudice
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`Atty Ref: Cyan. IPR.One 
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`INTER PARTES REVIEW OF U.S. PATENT 5,527,533
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`Page 5
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`under Fed. R. Civ. P. 41(a) did not bar a subsequent IPR because the “Federal
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`Circuit has consistently interpreted the effect of such dismissals as leaving the
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`parties as though the action had never been brought” (emphasis added) citing
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`Graves v. Principi, supra, (“[D]ismissal of an action without prejudice leaves the
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`parties as if the action had never been brought.”); Bonneville Associates, Ltd.
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`Partnership v. Baram, 165 F.3d 1360, 1364 (Fed. Cir. 1999) (“The rule in the
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`federal courts is that ‘[t]he effect of a voluntary dismissal without prejudice
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`pursuant to Rule 41(a) is to render the proceedings a nullity and leave the parties as
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`if the action had never been brought.’”); and Wright, Miller, Kane, and Marcus, 9
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`Federal Prac. & Proc. Civ. § 2367 (3d. ed.) (“[A]s numerous federal courts have
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`made clear, a voluntary dismissal without prejudice under Rule 41(a) leaves the
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`situation as if they never had been filed”) (emphasis added).
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`This consistent Supreme Court, Federal Circuit, and Board authority dictates
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`that the institution of this IPR is not barred by 35 U.S.C. Section 315(a) because
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`the dismissal of the prior declaratory judgment action was without prejudice under
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`Rules 12(b)(7) and 19 and therefore left the parties “as if the action had never been
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`filed.” Biomedical Patent Management Corp., 505 F.3d at 1334.
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`II. OVERVIEW OF CHALLENGE AND RELIEF REQUESTED
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` A. Prior Art Patents and Printed Publications. Pursuant to Rules 42.22(a)
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`and 42.104 (b), Petitioner challenges claims 1 to 27 of U.S. Patent No. 5,527,533
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`Atty Ref: Cyan. IPR.One 
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`INTER PARTES REVIEW OF U.S. PATENT 5,527,533
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`Page 6
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`(“the ‘533 patent”, Ex. 1001) as anticipated by, or obvious over, at least the
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`following printed publications (each a “reference” and collectively, “references”):
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`1. Grangaud, René, “Recherches sur l’Astaxanthine, Nouveau Facteur,
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`Vitaminique A”, 69 pp. (Éditions Desoer, Liège, 1951), (Ex. 1003, the
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`English translation of which is Ex. 1002).
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`2. U.S. Patent No. 5,310,764 (“Treatment of age related macular degeneration
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`with beta-carotene”), to Baranowitz, et al., issued 10 May 1994. (Ex. 1021)
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`3. Dowling, J.E. and Gibbons, I.R., “The effect of vitamin A deficiency on the
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`fine structure of the retina”, in The Structure of the Eye, Smelser C.K.,
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`editor. New York, Academic Press, Inc., p. 85-99 (1961) (Ex. 1026).
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`B. Public Accessibility of the Foreign Language References. Publications
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`1 and 3 above were publicly accessible and cataloged/indexed in a meaningful way
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`such that prior to the Critical Date a diligent search by one skilled in the art would
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`have retrieved the references. Bibliographic citations and abstracts of Grangaud’s
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`“Recherches sur l’Astaxanthine, Nouveau Facteur, Vitaminique A” (Ex. 1003,
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`English translation at Ex. 1002), and Grangaud’s numerous journal articles about
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`astaxanthin and the retina, were easily retrieved prior to the Critical Date under the
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`author’s name or under subject headings of “astaxanthin” or “vitamin A” in
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`Chemical Abstracts (Am. Chem. Soc., Columbus OH, which was available in
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`university libraries, and online internationally since 1983), well prior to the Critical
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`Atty Ref: Cyan. IPR.One 
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`INTER PARTES REVIEW OF U.S. PATENT 5,527,533
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`Page 7
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`Date. Ex. 1003 was indexed in Chemical Abstracts Fifth Decennial Index
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`(“Chem.Ab.5th ”), published in 1956, under "astaxanthin" (Ex. 1007, p.4) and
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`was actually the first entry under the subject. Other entries in Chem.Ab.5th
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`indexed under “astaxanthin” include Grangaud’s publications about astaxanthin
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`“esters, xerophthalmia treatment with”, and “vitamin activity of” astaxanthin. (Ex.
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`1007, p.2). A diligent searcher would have easily located and retrieved these
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`Grangaud publications prior to the Critical Date under the subject entry, determine
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`the author’s name, and search on the author’s name. (Ex. 1033, ¶¶18-19,
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`Schweigert Decl.) Further searching on the author’s name in Chem.Ab.5th would
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`retrieve bibcites to 24 other publications, most of which are about astaxanthin, its
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`relationship to vitamin A, and its role in the eye. (Ex. 1007, p. 2, 5-16) The same
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`process in the Sixth Collective Index (1957-1961) (Ex. 1006, p. 17-22), and
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`Seventh Collective Index (1962-1966) (Ex. 1006, p. 23-32), of Chemical Abstracts
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`would have produced more bibcites to Grangaud and Massonet publications about
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`astaxanthin, its relationship to vitamin A, and its role in the eye. Grangaud’s thesis
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`(Ex. 1003) and Massonet’s thesis (Ex. 1005) were cataloged by author name and
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`title, and have been publicly available in (i) the Yale University library system
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`since no later than 1970 (Ex. 1034, p.2), (ii) the State Library of Berlin since no
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`later than January, 1970 (Exs. 1041, 1042), and (iii) the National Library of France
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`Atty Ref: Cyan. IPR.One 
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`INTER PARTES REVIEW OF U.S. PATENT 5,527,533
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`Page 8
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`since 21 Dec. 1951 for Grangaud’s thesis and since 28 April 1961 for Massonet’s
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`thesis (Exs. 1043, 1044).
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`After 1960, each of Grangaud et al.’s and Massonet et al.’s journal articles
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`about astaxanthin and vitamin A refer to Reneé Massonet’s 1960 doctoral thesis
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`(Ex. 1005, English translation at Ex. 1004). Massonet and Grangaud also co-
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`authored a series of publications about astaxanthin abstracted under “astaxanthin”
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`in Chemical Abstracts through 1965. Ex. 1007, pp. 2-32. Three such
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`publications (Exs. 1009, 1011, and 1013, English translations at Exs. 1008, 1010,
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`and 1012, respectively) cite Exhibit 1005 (and thus, Ex. 1004).
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`As established in Ex. 1034 (Declaration of Scott Bennett, Yale Univ.
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`Librarian Emeritus), because Exs. 1003-1019 were publicly accessible,
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`meaningfully indexed, and readily retrievable by a diligent search by one skilled in
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`the art prior to the Critical Date, they must be regarded as prior art printed
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`publications. (Ex. 1033, ¶18). In re Hall, 781 F 2d 897 (Fed. Cir. 1986) (a single
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`cataloged thesis in one university library constitutes sufficient accessibility to those
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`interested in the art exercising reasonable diligence); Lucent Technologies, Inc. v.
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`Gateway, Inc., 2007 WL 1877983 (S.D. Calif. 2007) (thesis in library qualified as
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`a printed publication because it was indexed and catalogued by title, and cited in
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`another article). Exs. 1009, 1011, and 1013, all indexed in Chemical Abstracts,
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`also cite Exs. 1003 and 1005, indicating that those skilled in the art could easily
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`Atty Ref: Cyan. IPR.One 
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`INTER PARTES REVIEW OF U.S. PATENT 5,527,533
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`Page 9
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`identify and locate Exs. 1003 and 1005 prior to the Critical Date. All English
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`language references were also cataloged and publicly available before the Critical
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`Date, as shown by their publication dates. The Declaration of Barbara Schneider-
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`Kempf (Staatsbibliothek zu Berlin, Berlin, Germany), Ex. 1041 (translation at Ex.
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`1042), and the Declaration of Stéphane Alcandre (Bibliothèque Nationale de
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`France, Paris, France), Ex. 1043 (translation at Ex. 1044), also confirm full
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`cataloging and public availability of Exs. 1003, 1005, 1009, 1011, 1013, 1015,
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`1017, and 1019 before the Critical Date.
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`C. Reasonable Likelihood that Claims 1-27 are Unpatentable. In view
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`of the Exhibits attached hereto, the citations in the Claims Chart and the remarks
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`below, there is a reasonable likelihood that at least one of Claims 1-27 of the ‘533
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`patent are unpatentable under 35 USC §§102 and/or 103. (The claims are
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`construed herein as if supported by the specification–without conceding that point.)
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`D. Relief Requested. Petitioner requests under 35 U.S.C. §§ 311-319 and
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`37 C.F.R. § 42.100, et seq., institution of a trial under 37 C.F.R. Part 42, and
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`cancellation/invalidation of claims 1-27 as unpatentable under 35 U.S.C. §§ 102
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`and/or 103. Petitioner’s evidence is explained below.
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`E. Statements of Material Fact. Under Rule 44.22(c), Petitioner presents
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`the following statements of material fact.
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`Atty Ref: Cyan. IPR.One 
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`INTER PARTES REVIEW OF U.S. PATENT 5,527,533
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`Page 10
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`1. Astaxanthin is a xanthophyll carotenoid (obtained only from dietary or other
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`external sources) that is transported into the retina. Ex. 1001, 8:59-67; 11:6-
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`16.
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`2. Lutein and zeaxanthin are xanthophylls that concentrate in the human retina
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`and are obtained only from dietary sources (and are not carotene carotenoids
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`like β-carotene); their role in vision and in preventing free radical-induced (i.e.,
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`oxidative) retinal damage has been studied since the 1980s. Ex. 1001, 4:30-37;
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`4:59-65; 4:66-6:24; 8:59-67;10:1-12. See Ex. 1032 (molecular structures)
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`3. Canthaxanthin is a xanthophyll carotenoid (obtained only from dietary or other
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`external sources) that is transported into the retina. Ex. 1001, 4:30-38; 6:13-
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`24; 8:59-67; 10:11-22. Astaxanthin differs from zeaxanthin by an additional
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`keto group on each of astaxanthin’s two terminal rings. Ex. 1001, 9:10-44. Ex.
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`1008, pp 4-5. Astaxanthin differs from canthaxanthin by an additional
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`hydroxyl unit on each of astaxanthin’s two terminal rings. Ex. 1001, 9:10-44.
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`Ex. 1008, pp 4-5. Molecular structures of zeaxanthin, canthaxanthin, and
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`astaxanthin are shown and discussed in the specification of the ‘533 patent and
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`in the prior art. Ex. 1001, 8:59-67; 9:1-59.
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`4. The original claims in the ‘533 patent were directed to “beneficiating,” and
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`“protecting,” vision and the central nervous system (“CNS”). Ex. 1006, pdf
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`Atty Ref: Cyan. IPR.One 
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`INTER PARTES REVIEW OF U.S. PATENT 5,527,533
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`Page 11
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`pp. 11-13. (cites to Ex. 1006 use “pdf” page numbering rather than Office
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`Actions (“OA”) and Responses to OA original page numbers)
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`5. In response to indefiniteness (first OA dated 1/30/95, Ex. 1006, pdf pp. 3-6)
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`and obviousness (Ex. 1006, pdf pp. 7-9) rejections, all independent claims
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`were amended to: “A method of ameliorating the vision of an individual
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`suffering from retinal damage” (claim 1); “A method of protecting neurons
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`from free radical-induced retinal injury” (claim 13); and as otherwise shown in
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`the Response to 1OA. Ex. 1006, pdf pp. 11-13.
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`6. After final rejection, “treating” claims were allowed via a telephone interview.
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`Ex. 1006, pdf p. 59. The Interview Summary does not explain the basis for
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`allowance of the claims. Ex. 1006, pdf pp. 60-61.
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`7. The experimental design of the patent only yields data about the preventive
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`use of astaxanthin, administered before retinal injury or disease, not treatment
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`of retinal injury or disease or of any disease of the central nervous system
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`(“CNS”). Ex. 1001, 11:19-40; 13:15-30. See also Ex. 1033, ¶70.
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`III. IDENTIFICATION OF CHALLENGE
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`A. Overview. The ‘533 patent discloses “methods of treating individuals
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`suffering from central nervous system injury or disease … [or] eye injury or
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`disease, and … methods of retarding a degenerative disease of the eye” by
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`administration of astaxanthin. Ex. 1001, 6:48-53. The only cause of retinal
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`Atty Ref: Cyan. IPR.One 
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`INTER PARTES REVIEW OF U.S. PATENT 5,527,533
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`Page 12
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`damage, injury, or disease disclosed in the ‘533 patent is the action of free radicals,
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`e.g., peroxyl, and singlet oxygen, radicals. The only method of alleged treating
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`“damage, injury, or disease” in the ‘533 patent is by administration of astaxanthin
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`before injury. The only damage, injury, or disease exemplified in the ‘533 patent
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`is reduction, in a rat retina, (i) of the “thickness of the outer nuclear layer”
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`(“ONL”), (ii) of the “distance between the internal limiting membrane to the
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`interface of the outer plexiform layer and the outer nuclear layer” (“IRT”), and (iii)
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`of rhodopsin levels. Ex. 1001, 11:52-56, 12:37-43, and Figs. 1-4. Therefore, pre-
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`Critical Date printed publications that disclose the administration of
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`astaxanthin and the accumulation (presence) of astaxanthin in the tissue (e.g.,
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`retinal tissue) to be “treated” by the inherent free radical scavenging action of
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`astaxanthin render unpatentable all claims of the ‘533 patent. There are many
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`such printed publications.
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`B. Definition of certain claim terms. In this proceeding, the claims of the
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`‘533 patent are to be given their “broadest reasonable construction in light of the
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`specification.” 37 C.F.R. § 42.100(b). Petitioner has applied that standard. The
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`words “treating”, “damage”, “injury”, and “disease” have commonly accepted
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`meanings in the field of ‘533 patent (i.e., the pharmaceutical/medical arts).
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`Stedman’s Medical Dictionary, 28th Edition (2006) (Philadelphia, Wolters Kluwer
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`Atty Ref: Cyan. IPR.One 
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`INTER PARTES REVIEW OF U.S. PATENT 5,527,533
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`Page 13
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`Health ), attached as Ex. 1040, provides ordinary meanings appropriate for a
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`number of the following terms (Ex. 1040; see Ex. 1033, ¶¶20, 69-70, and 72-79):
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`“treating”. “Treating”, as used in claims 1-27, means “To manage a disease
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`by medicinal, surgical, or other measures; to care for a patient medically or
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`surgically.”. Ex. 1040, pdf p.2.
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`
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`“damage”. “Damage”, as used in claims 1-27, means “Harm, diminution,
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`or destruction of an organ, body part, system, or function.”. Ex. 1040, pdf p.3.
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`“injury”. “Injury”, as used in claims 1-27, means “The damage or wound
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`of trauma.”. Ex. 1040, pdf p.4.
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`“disease”. “Disease”, as used in claims 1-27, means “A morbid entity
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`ordinarily characterized by two or more of the following criteria: recognized
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`etiologic agent(s), identifiable group of signs and symptoms, or consistent
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`anatomic alterations.”. Ex. 1040, pdf p.5.
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`“individual”. As of the filing date of the ‘533 patent, the rat retina model
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`was accepted by some researchers as a surrogate for human retina; whereas after
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`the filing date of the ‘533 patent the rat retina became no longer accepted by some
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`as a surrogate for human retina. Ex. 1033, ¶78. At the time of the invention, based
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`on the specification of the ‘533 patent, which repeatedly discusses both rats and
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`humans, the term “individual” as used in the claims covers both animals (e.g., rats)
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`and humans.
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`Atty Ref: Cyan. IPR.One 
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`INTER PARTES REVIEW OF U.S. PATENT 5,527,533
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`Page 14
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`Petitioner notes that the claims of the ‘533 patent are directed to
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`administration of astaxanthin as an antioxidant to “treat” free radical-induced
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`damage, injury, and disease, yet the ‘533 patent contains only preventive data.
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`C. Claim elements as Found in the Prior Art.
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`
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`French scientists, René Grangaud and Reneé Massonet, published
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`extensively in the 1948 – 1965 timeframe about the (i) preventive, and therapeutic,
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`use of astaxanthin to treat ocular disease and injury, (ii) the accumulation of
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`administered astaxanthin in rat retina and in other rat organs, and (iii) the
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`preventive and therapeutic efficacy of astaxanthin. Grangaud’s published thesis
`
`(Exs. 1002, 1003) explicated items (i) to (iii) in fine detail, as shown below.
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`Irradiating the retina with bright light (aka photic insult), or other oxidative
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`stress, such as reperfusion, creates peroxyl, singlet oxygen, and other free radicals
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`(Exs. 1035 and 1036); if free radicals are not quickly neutralized (“scavenged”),
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`they attack membranes, especially lipid membranes, and cause serious damage,
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`injury, and disease in the retina and other tissues. Grangaud (Ex. 1003, with
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`English translation at Ex. 1002) disclosed that dietary astaxanthin was transported
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`into the retina and cured xerophthalmia when administered to vitamin A-deficient
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`rats. As explained below, such administration also necessarily prevented, and (in
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`different experimental groups) cured, the same free radical-induced retinal damage,
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`injury, and disease as described in the ‘533 patent. Ex. 1033, ¶¶43-45.
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`Any administration of astaxanthin (other than topical) necessarily results in
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`blood-based transport of astaxanthin to the retina and accumulation of
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`astaxanthin in the retina. Ex. 1033, ¶¶24-25. Retinal tissue contains binding
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`proteins that preferentially transport xanthophyll carotenoids, like lutein,
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`zeaxanthin, canthaxanthin, and astaxanthin, from the retinal capillary network into
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`retinal tissue, but disfavor transport into retinal tissue of carotene carotenoids like
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`β-carotene. Ex. 1033, ¶¶24-25. Astaxanthin is transported in the bloodstream, and
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`from the bloodstream into the retina, by specialized “binding proteins”.
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`Astaxanthin is a strong free radical scavenger (aka antioxidant). Ex. 1033, ¶¶24-
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`25. Suppression of free radicals necessarily occurs if astaxanthin is present in
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`animal tissue that contains free radicals, such as retinal tissue exposed to bright
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`light or other oxidative stress. Ex. 1033, ¶¶24-25. Astaxanthin’s inherent mode
`
`of action in vertebrate tissue, including retinal tissue, is as a strong
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`antioxidant and free radical scavenger. Ex. 1033, ¶¶24-25.
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`Xerophthalmia (“dry eye disease”) results from severe vitamin A deficiency
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`and is “secondary” to retinal damage, injury, and disease (Ex. 1002, 60:22-27. Ex.
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`1033, ¶27. See also, Ex. 1024, Dowling (1958). In other words, if a subject
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`manifests xerophthalmia, photoreceptor cell membrane attack by a barrage of free
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`radicals, photoreceptor cell degeneration, and reduction of the ONL, IRT, and
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`rhodopsin levels have already occurred. Ex. 1033, ¶¶30-36. (See also, Dowling et
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`al. (1958), Ex. 1024; Dowling et al. (1960), Ex. 1025; and Dowling et al. (1961),
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`Ex. 1026). Rats and other vertebrates become diseased, go blind, and die from
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`continued vitamin A deficiency. Id. Infliction of vitamin A deficiency is an
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`injury and causes retinal, corneal, and other injury and diseases. Id. The free
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`radical-induced damage from photic insult or reperfusion following retinal
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`ischemia or high intraocular pressure in the ‘533 patent causes the same free
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`radical-induced damage as caused by severe vitamin A deficiency in Ex. 1002 and
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`Ex. 1026. Ex. 1033, ¶90.
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`If astaxanthin is in the retina (preferentially transported into the retina from
`
`the bloodstream), necessary and inherent results include (i) suppression by
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`astaxanthin of free radicals, such as peroxyl and singlet oxygen radicals, (ii)
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`prevention of initial or further free radical damage and injury (including reduction
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`of ONL, IRT, and rhodopsin levels), and (iii) prevention of resultant free radical-
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`induced disease. Ex. 1033, ¶89.
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`Grangaud, in Ex. 1002, administered astaxanthin (i) to treat ocular damage,
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`injury, and disease, (ii) to slow the progress of ocular damage, injury, and disease
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`in low doses, and (iii) to cure ocular damage, injury, and disease in higher doses.
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`Blood-based transport of astaxanthin into the rat retina in Ex. 1002 is a necessary
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`and inherent result just as it is in the ‘533 patent. Ex. 1033, ¶122. The suppression
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`of free radicals and free radical-induced damage and injury by astaxanthin in the
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`rat retina in Ex. 1002 is a necessary and inherent result just as it is in rat retina in
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`the ‘533 patent (disease is not exemplified in the ‘533 patent). Ex. 1033, ¶123.
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`The method disclosed in Ex. 1002 necessarily results in the accumulation of
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`astaxanthin in the rat retina, and treats free radical retinal damage, injury, or
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`disease of whatever origin (photic, ischemic, inflammatory, degeneration from
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`stroke or trauma, ocular pressure-related, etc.) and in all tissues into which
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`astaxanthin is transported. Ex. 1033, ¶123.
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`The rats in the ‘533 patent and Ex. 1002 (Grangaud’s thesis) and Ex. 1026
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`(Dowling (1961)) suffered from the same free radical-induced retinal damage and
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`injury. Ex. 1033, ¶¶90 and 124. The rats in the ‘533 patent and Ex. 1002
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`(Grangaud’s thesis) responded to the same treatment, administration of astaxanthin.
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`Ex. 1033, ¶¶90 and 124.
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`Therefore, Ex. 1002 (see also, published French version at Ex. 1003)
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`anticipates all claims and/or renders them obvious when combined with Ex. 1021
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`and/or Ex. 1026. Ex. 1033, ¶125-26.
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`IV. GROUNDS FOR CHALLENGE AND CLAIMS CHARTS
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`
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` Ground 1: claims 1, 3, and 8-24, and 26 are anticipated by Grangaud (Exs.
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`1002, 1003).
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`Ground 2A: claims 1-27 are obvious under §103 over Grangaud (Exs. 1002,
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`1003) in view of Ex. 1021 (U.S. Patent No. 5,310,764).
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`Ground 2B: claims 1-27 are obvious over Grangaud (Exs. 1002, 1003) in
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`view of Ex. 1026 (Dowling (1961)).
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`Ground 3: claims 1, 3, and 8-27 are obvious under §103 over Grangaud
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`(Exs. 1002, 1003).
`
`GROUND 1
`
`Claim 1. A
`method of
`treating an
`individual
`suffering from
`retinal damage
`or retinal
`disease, said
`method
`comprising
`administering a
`therapeutically
`effective
`amount of
`astaxanthin to
`the individual
`to improve the
`vision of the
`individual.
`
`GROUND 1. ‘533 PATENT CLAIMS ANTICIPATED BY
`CYAN EXS. 1002, 1003 (Grangaud 1951). ‘533 claim language in left column
`and prior art citations and comments in right column.
`Any administration of astaxanthin (other than topical)
`necessarily results in blood-based transport of astaxanthin to the
`retina. Astaxanthin’s inherent mode of action in vertebrate
`tissue, including retinal tissue, is as a strong antioxidant.
`Suppression of free radicals, such as peroxyl and singlet oxygen
`radicals, and free radical-induced damage necessarily occurs if
`astaxanthin is present in animal tissue that contains free radicals,
`such as retinal tissue exposed to bright light. Ex.1033, ¶26.
`A therapeutically effective amount of a bioactive agent is
`essentially an amount that achieves the intended therapeutic
`effect when administered. A therapeutically effective amount is
`determined by dose/response experiments. Ex. 1002 shows that
`the therapeutically effective amount of astaxanthin require to
`treat ocular disease is a fraction of the amount administered in
`the ‘533 patent. Ex.1033, p.25.
`Grangaud, in Ex. 1002, administered astaxanthin. Blood-
`based transport of astaxanthin into the rat retina in Ex. 1002 is a
`necessary and inherent result just as it is in the ‘533 patent.
`The suppression of free radicals and free radical-induced
`damage, injury, and disease by astaxanthin in the rat retina in Ex.
`1002 is a necessary and inherent result just as it is in rat retina
`in the ‘533 patent. Therefore, Ex. 1002 anticipates claim 1.
`CYAN EX.1002, 43:25-26 (“albino rats … which were
`fed a vitamin A deficient diet since being weaned”); 44:21
`(“[vitamin A] deficiency related lesions”); 44:27-29 (“Among all
`the animals that received shrimp oil [containing astaxanthin]…,
`there was an indisputable reduction in xeroph