Trials@uspto.gov
`Tel: 571-272-7822
`
`
`
`
`Paper 65
`Entered: December 12, 2014
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`CYANOTECH CORPORATION,
`Petitioner,
`
`v.
`
`THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS,
`Patent Owner.
`____________
`
`Case IPR2013-004011
`Patent 5,527,533
`____________
`
`Before SCOTT E. KAMHOLZ, SHERIDAN K. SNEDDEN, and
`GEORGIANNA W. BRADEN, Administrative Patent Judges.
`
`
`SNEDDEN, Administrative Patent Judge.
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`1 Consolidated with Case IPR2013-00404
`
`
`
`
`Tel: 571-272-7822
`
`
`
`
`Paper 65
`Entered: December 12, 2014
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`CYANOTECH CORPORATION,
`Petitioner,
`
`v.
`
`THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS,
`Patent Owner.
`____________
`
`Case IPR2013-004011
`Patent 5,527,533
`____________
`
`Before SCOTT E. KAMHOLZ, SHERIDAN K. SNEDDEN, and
`GEORGIANNA W. BRADEN, Administrative Patent Judges.
`
`
`SNEDDEN, Administrative Patent Judge.
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a) and 37 C.F.R. § 42.73
`
`
`1 Consolidated with Case IPR2013-00404
`
`
`
`
`
`IPR2013-00401 and IPR2013-00404
`Patent 5,527,533
`
`
`I. INTRODUCTION
`
`Cyanotech Corporation (“Cyanotech”) filed corrected petitions in
`
`IPR2013-00401 (Paper 9, “Pet. ’401”) and IPR2013-00404 (IPR2013-
`
`00404, Paper 8, “Pet. ’404”) requesting inter partes review of claims 1–27
`
`of U.S. Patent No. 5,527,533 (“the ’533 patent”). The Board consolidated
`
`IPR2013-00401 and IPR2013-00404 and instituted trial for the challenged
`
`claims on the following grounds of unpatentability asserted by Cyanotech:
`
`Reference(s)
`Grangaud2
`Grangaud and Dowling3
`
`Basis Claims challenged
`§ 102
`1, 3, 8–15, 21, 22, and 26
`§ 103
`1–15, 21, 22, and 26
`
`Decision to Institute, 19 (Paper 17 (“Dec.”)).
`
`After institution and consolidation of both trials, the Board of Trustees
`
`of the University of Illinois (“the University”), filed its Patent Owner’s
`
`Response (“Resp.”). Paper 32.4 Cyanotech filed a Reply (Paper 43,
`
`“Reply.”). The University did not file a motion to amend claims.
`
`Cyanotech relies upon declarations of Florian J. Schweigert
`
`(Ex. 1033) and C. Kathleen Dorey, Ph.D. (Ex. 1045) in support of its
`
`
`2 RENÉ GRANGAUD, RESEARCH ON ASTAXANTHIN, A NEW VITAMIN A
`FACTOR (1951) (unpublished doctorate dissertation, University of Lyon)
`(Ex. 1003, the English translation of which is Ex. 1002).
`3 J.E. Dowling & I.R. Gibbons, The Effect of Vitamin A Deficiency on the
`Fine Structure of the Retina, in THE STRUCTURE OF THE EYE 85-99 (1961)
`(Ex. 1026).
`4 This reference to “Paper” and all other references to “Paper” from this
`point forward in this Final Written Decision of consolidated proceedings
`IPR2013-00401 and IPR2013-00404 refer to paper numbers on record in
`IPR2013-00401.
`
`2
`
`
`
`IPR2013-00401 and IPR2013-00404
`Patent 5,527,533
`
`
`Petition. The University relies upon a declaration of Shalesh Kaushal M.D.,
`
`Ph.D. (Ex. 2015) in support of its Response.
`
`Cyanotech filed a Motion to Exclude certain of the University’s
`
`evidence. Paper 47. The University filed an Opposition (Paper 51), and
`
`Cyanotech filed a Reply (Paper 54).
`
`Oral argument was conducted on July 16, 2014. A transcript is
`
`entered as Paper 64 (“Tr.”).
`
`This Final Written Decision addresses challenges to the patentability
`
`of claims 1–15, 21, 22, and 26.
`
`Cyanotech has proved by a preponderance of the evidence that claims
`
`1–14 and 26 of the ’533 patent are unpatentable. Cyanotech has failed to
`
`prove the unpatentability of claims 15, 21, and 22.
`
`A. The ’533 Patent (Ex. 1001)
`
`The retina of the eye, a component of the central nervous system, is
`
`important for sight. Ex. 1001, 1:49–52; see also, Ex. 1045, 6–12. Retinal
`
`structures important to vision include: a ganglion cell layer, which connects
`
`the retina to the brain; an inner nuclear layer containing neurons, such as
`
`bipolar cells; and an outer nuclear or photoreceptor cell layer. Ex. 1045, 6–
`
`12. Photoreceptor cells convert light into signals that are transmitted to the
`
`other neurons. Ex. 1001 at 1:57–60. The loss of a significant number of
`
`photoreceptor cells adversely affects visual function. Id. at 3:6–13.
`
`The ’533 patent discloses that eye diseases or injuries that can cause
`
`damage to the retinal tissue and neurons include age-related macular
`
`degeneration, photic injury, photoreceptor cell damage, ganglion cell
`
`damage, traumatic injury, ischemic insult-related diseases, and inflammatory
`
`3
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`IPR2013-00401 and IPR2013-00404
`Patent 5,527,533
`
`
`diseases. Id. at 1:9–14. Regarding photic injury, the ’533 patent discloses
`
`that excessive light energy reaching the retina can overwhelm the metabolic
`
`systems of photoreceptor cells causing damage to these neurons, either
`
`directly or indirectly. Id. at 1:65–67. The ’533 patent further discloses that
`
`free radical species can be generated by enzymatic processes or from the
`
`combination or continuous or excessive exposure to light and the relatively
`
`high concentration of oxygen in the eye. Id. at 2:1–5. The ’533 patent
`
`discloses that the free radical species lead to functional impairment of cell
`
`membranes and may cause temporary or permanent damage to retinal tissue.
`
`Ex. 1001, 2:13–21. According to the ’533 patent, however, the presence of
`
`antioxidant compounds counteracts the free radical species generated by
`
`light to protect the retina from damage. Id. at 2:29–32.
`
`The ’533 patent relates to methods of treating diseases and injuries to
`
`the central nervous system, especially the eyes, comprising administering a
`
`therapeutically-effective amount of astaxanthin. Ex. 1001, 1:9–19 and 6:54–
`
`62. The ’533 patent discloses that astaxanthin is a highly-effective
`
`antioxidant and ameliorates free radical-induced eye damage. Id. at 15:56–
`
`60. Astaxanthin is disclosed as particularly suited for treatment of the eye
`
`because, unlike other carotenoids such as β-carotene, astaxanthin can cross
`
`the blood-retinal brain barrier readily. Id. at 10:18–22. According to the
`
`’533 patent, comparative studies with β-carotene demonstrate that
`
`astaxanthin is more effective than β-carotene at protecting rats from photic
`
`injury. Id. at 13:60 to 14:50.
`
`4
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`IPR2013-00401 and IPR2013-00404
`Patent 5,527,533
`
`
`B. Exemplary Claims
`
`Independent claims 1, 13, 14, 21, and 26 are illustrative of the claims
`
`at issue in this inter partes review and recite as follows:
`
`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.
`
`13. A method of treating an individual comprising
`administering a therapeutically effective amount of
`astaxanthin to the individual to protect neurons in a retina
`of the individual from free-radical induced retinal injury.
`
`14. A method of treating an individual suffering from
`neuronal damage to a retina comprising administering a
`therapeutically-effective amount of astaxanthin to the
`individual to improve the condition of the retina.
`
`21. A method of treating an individual suffering from a
`free radical-induced injury to a central nervous system,
`said method comprising administering a therapeutically-
`effective amount of astaxanthin to the individual to
`improve the condition of the central nervous system.
`
`26. A method of treating an individual suffering from a
`degenerative retinal disease, said method comprising
`administering a therapeutically effective amount of
`astaxanthin to the individual to retard the progress of the
`disease.
`
`II. DISCUSSION
`
`A. Claim Interpretation
`
`In an inter partes review, claim terms in an unexpired patent are
`
`interpreted according to their broadest reasonable construction in light of the
`
`specification of the patent in which they appear. 37 C.F.R. § 42.100(b);
`
`5
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`IPR2013-00401 and IPR2013-00404
`Patent 5,527,533
`
`
`Office Patent Trial Practice Guide, 77 Fed. Reg. 48,756, 48,766 (Aug. 14,
`
`2012). Claim terms are given their ordinary and customary meaning, as
`
`would be understood by one of ordinary skill in the art in the context of the
`
`entire disclosure. In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed.
`
`Cir. 2007). Any special definition for a claim term must be set forth in the
`
`specification with reasonable clarity, deliberateness, and precision. In re
`
`Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994).
`
`We expressly interpret below only those claim terms that require
`
`analysis to resolve arguments related to the patentability of the challenged
`
`claims.
`
`1. Construction of the phrase “retinal damage or retinal disease”
`
`We construed the phrase “retinal damage or retinal disease” recited in
`
`claims 1–12 in the alternative to refer to two classes of conditions: retinal
`
`damage and retinal disease. Dec. 9. The University argues for the
`
`construction of the terms “retinal damage” and “retinal disease” as a single
`
`concept such that both “retinal damage” and “retinal disease” refer to an
`
`identical class of medical conditions. Resp. 15–16. Specifically, the
`
`University contends that the specification confirms that free radical damage
`
`is associated with both injuries and disease. Id. (citing Ex. 1001, 15:23–27
`
`(“The administration of astaxanthin to an individual suffering from an eye
`
`injury or disease, such as free radical induced injury, beneficiates the vision
`
`of the individual by rescuing further photoreceptor cells from damage
`
`destruction.”); 15:57–60 (“the administration of astaxanthin also provides a
`
`method of treating free radical induced disease or injury to the central
`
`nervous system in general”)).
`
`6
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`IPR2013-00401 and IPR2013-00404
`Patent 5,527,533
`
`
`As stated by the University, the specification discloses methods of
`
`treating damage caused by injury or disease (Resp. 14–15), however, the
`
`specification does not contain any indication that the patentee intended to act
`
`as his own lexicographer clearly defining “disease” and “damage” in the
`
`same manner. For example, the specification does not clearly convey the
`
`patentee’s intent to appoint a special meaning to the phrase “retinal damage
`
`or retinal disease.”
`
`We must determine, therefore, the ordinary meaning of “disease” and
`
`“damage” as used in these claims to one of skill in the art in light of the
`
`specification and prosecution history. In re Paulsen, 30 F.3d at 1480. In
`
`this regard, the term “damage,” as used in the specification, refers to damage
`
`resulting from injury or disease. Ex. 1001, 1:14–19. The specification does
`
`not equate damage and disease, but provides that damage may be caused by
`
`disease. Id. The meaning of the term disease, however, refers to conditions
`
`that may cause damage (such as degenerative eye disease), and are treatable
`
`themselves. Id. at 15:36–40. That is, the underlying cause of the damage is
`
`treatable, not just the damage alone. The University does not direct our
`
`attention to anything in the specification or prosecution that would clearly
`
`alter the ordinary meaning of “disease” and “damage.” Resp. 14–16.
`
`In view of the above, we do not construe “retinal damage” and
`
`“retinal disease” as a single concept. The evidence of record does not
`
`support a finding that the patentee acted as his own lexicographer by clearly
`
`defining the claim terms “damage” and “disease” in the same manner. In
`
`our Decision to Institute, we adopted the dictionary definition of “disease”
`
`and construed the term as “[a] morbid entity ordinarily characterized by two
`
`or more of the following criteria: recognized etiologic agent(s), identifiable
`
`7
`
`
`
`IPR2013-00401 and IPR2013-00404
`Patent 5,527,533
`
`
`group of signs and symptoms, or consistent anatomic alterations.” Dec. 8–9;
`
`see, Pet. ’401 (citing Ex. 1040). We adopted the dictionary definition of
`
`“damage” and construed the term as “[h]arm, diminution, or destruction of
`
`an organ, body part, system, or function.” Id. We maintain these
`
`constructions for “disease” and “damage” as they are consistent with the use
`
`of these terms in the Specification. “Retinal damage” refers to damage to
`
`the retina and “retinal disease” refers to disease of the retina. The phrase
`
`“retinal damage or retinal disease” refers to either retinal damage or retinal
`
`disease.
`
`We also maintain our constructions of “disease” and “damage” with
`
`respect to claims 8–12, which recite particular types of retinal damage, and
`
`thus, further limit “retinal damage” recited in claim 1. Claims 8–12,
`
`however, do not limit further “retinal disease,” as recited in claim 1. Thus,
`
`for example, claim 12 encompasses a method of treating an individual
`
`suffering from damage caused by age-related macular degeneration or
`
`suffering from any retinal disease.
`
`B. The Prior Art
`
`1. Summary of Grangaud
`
`Grangaud discloses the results of experiments conducted on rats fed a
`
`vitamin A-deficient diet. Ex. 1002, 43. The animals developed
`
`complications of vitamin A deficiency that included xerophthalmia (“dry
`
`eye”) and death. Visible signs of xerophthalmia were described as ocular
`
`lesions. See e.g., id. at 44, 49. The restoration of vitamin A or astaxanthin
`
`to the vitamin A-deficient diet was sufficient to heal the ocular lesions. Id.
`
`Grangaud concluded that astaxanthin has vitamin A activity. Id. at 56.
`
`8
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`
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`IPR2013-00401 and IPR2013-00404
`Patent 5,527,533
`
`
`Grangaud further noted that the antioxidant strength of astaxanthin is
`
`comparable to that of vitamin A, and that astaxanthin shares the
`
`antixerophthalmic activity of vitamin A. Id.
`
`Grangaud is silent as to the mechanism of the disease pathogenesis for
`
`vitamin A deficiency. Grangaud provides no evidence tending to establish
`
`that the vitamin A-deficient rats exhibited retinal damage.
`
`2. Summary of Dowling
`
`Dowling discloses the results of a study showing the effect of vitamin
`
`A deficiency on the fine structure of the retina. Ex 1026. Dowling used an
`
`albino rat model kept on a vitamin A-free diet, supplemented with vitamin A
`
`acid. Id. at 85. The vitamin A acid kept the rats healthy and growing, but
`
`did not support the visual cycle and thus the rats gradually become night-
`
`blind. Id. Dowling discloses that the visual cells (photoreceptor cells) of
`
`animals fed such a diet degenerated after 2 months on the diet. Id. at 87–88.
`
`Other retinal cells, such as bipolar and ganglion cells, however, appeared
`
`normal, even after 6 months on the diet. Id. Dowling also discloses that the
`
`damage to the retinal cells is reversible by giving vitamin A to the deficient
`
`animals. Id. at 94.
`
`C. Patentability of Original Claims
`
`To prevail in its challenges to the patentability of claims, the
`
`petitioner must establish facts supporting its challenges by a preponderance
`
`of the evidence. 35 U.S.C. § 316(e); 37 C.F.R. § 42.1(d).
`
`9
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`IPR2013-00401 and IPR2013-00404
`Patent 5,527,533
`
`
`1. Anticipation of Claims 1, 3, 8–15, 21, 22, and 26 by Grangaud
`
`The Court of Appeals for the Federal Circuit summarized the
`
`analytical framework for determining whether prior art anticipates a claim as
`
`follows:
`
`in a printed
`invention was “described
`the claimed
`If
`publication” either before the date of invention, 35 U.S.C.
`§ 102(a), or more than one year before the U.S. patent
`application was filed, 35 U.S.C. § 102(b), then that prior art
`anticipates the patent. Although § 102 refers to “the invention”
`generally, the anticipation inquiry proceeds on a claim-by-claim
`basis. See Hakim v. Cannon Avent Group, PLC, 479 F.3d 1313,
`1319 (Fed. Cir. 2007). To anticipate a claim, a single prior art
`reference must expressly or inherently disclose each claim
`limitation. Celeritas Techs., Ltd. v. Rockwell Int’l Corp., 150
`F.3d 1354, 1361 (Fed. Cir. 1998). But disclosure of each
`element is not quite enough—this court has long held that
`“[a]nticipation requires the presence in a single prior art
`disclosure of all elements of a claimed invention arranged as in
`the claim.” Connell v. Sears, Roebuck & Co., 722 F.2d 1542,
`1548 (Fed. Cir. 1983) (citing Soundscriber Corp. v. United
`States, [] 360 F.2d 954, 960 (1966) (emphasis added)).
`
`Finisar Corp. v. DirecTV Grp., Inc., 523 F.3d 1323, 1334–35 (Fed. Cir.
`
`2008). We must analyze prior art references as a skilled artisan would. See
`
`Scripps Clinic & Res. Found. v. Genentech, Inc., 927 F.2d 1565, 1576 (Fed.
`
`Cir. 1991) (to anticipate, “[t]here must be no difference between the claimed
`
`invention and the reference disclosure, as viewed by a person of ordinary
`
`skill in the field of the invention”).
`
`To establish inherent disclosure, the evidence must show that a feature
`
`necessarily is described in the reference, and that it would be recognized by
`
`persons of ordinary skill. In re Robertson, 169 F.3d 743, 745 (Fed. Cir.
`
`1999); cf. EMI Grp. N. Am., Inc. v. Cypress Semiconductor Corp., 268 F.3d
`
`10
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`IPR2013-00401 and IPR2013-00404
`Patent 5,527,533
`
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`1342, 1351 (Fed. Cir. 2001) (“Theoretical mechanisms or rules of natural
`
`law that are recited in a claim, that themselves are not patentable, however,
`
`do not need to be recognized by one of ordinary skill in the art for a finding
`
`of inherency.”). The mere fact that a certain thing may result from a given
`
`set of circumstances is not sufficient to establish inherency. In re Rijckaert,
`
`9 F.3d 1531, 1534 (Fed. Cir. 1993). Inherency may not be established by
`
`probabilities or possibilities. In re Oelrich, 666 F.2d 578, 581 (CCPA
`
`1981).
`
`Cyanotech contends that Grangaud’s disclosure of the administration
`
`of dietary astaxanthin to cure xerophthalmia (“dry eye”) in vitamin A-
`
`deficient rats anticipates claims 1, 3, 8–15, 21, 22, and 26, which are
`
`directed to a method of administering a therapeutically effective amount of
`
`astaxanthin to improve the vision of an individual suffering from retinal
`
`damage or retinal disease. Pet. 15–17. For the reasons expressed below, we
`
`conclude that Cyanotech has demonstrated by a preponderance of evidence
`
`that Grangaud anticipates claims 1, 3, 8–14 and 26. Cyanotech has failed to
`
`establish by a preponderance of evidence that Grangaud anticipates claims
`
`15, 21, and 22.
`
`a. Claims 1, 3, and 10
`
`Claim 1 encompasses a method of treating an individual suffering
`
`from retinal damage with the administration of astaxanthin in an amount
`
`sufficient to improve the vision of the individual. Claims 3 and 10 depend
`
`directly from claim 1. Claim 3 requires astaxanthin to be administered
`
`orally. Claim 10 specifies that the retinal damage may be photoreceptor cell
`
`retinal damage.
`
`11
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`IPR2013-00401 and IPR2013-00404
`Patent 5,527,533
`
`
`Although Grangaud discloses the administration of astaxanthin to cure
`
`ocular lesions (Ex. 1002, 43, 44, 49), Cyanotech concedes that Grangaud
`
`does not discuss whether or not vitamin A-deficient rats exhibit retinal
`
`damage. Pet. 18–19. Cyanotech contends, however, that animals
`
`developing xerophthalmia due to vitamin A-deficiency inherently suffer
`
`retinal damage. Id. For support of this assertion, Cyanotech relies on the
`
`Declaration of Florian J. Schweigert (“Schweigert declaration”) (Ex. 1033)
`
`to establish that vitamin A-deficient rats exhibiting dry eye necessarily have
`
`retinal damage and, more specifically, photoreceptor cell retinal damage.
`
`With reference to Dowling (Ex. 1026), Dr. Schweigert testifies that
`
`severe vitamin A deficiency causes degeneration in the retina that precedes
`
`dry eye. Ex. 1033 ¶¶ 27, 36, and 39–43. Dowling reported that albino rats
`
`experienced degeneration of visual cells (photoreceptor cells) after about 2
`
`months of vitamin A deficiency. Ex. 1026, 87-88. Such retinal damage
`
`could be reversed upon restoring vitamin A to rats’ diets. Id. at 94. The
`
`other retinal cells (bipolar and ganglion cells), however, appeared normal
`
`with vitamin A deficiency. Id. at 87-88. According to Schweigert, the
`
`astaxanthin administration by Grangaud necessarily treats retinal damage,
`
`because astaxanthin is converted in rat retina into vitamin A, which is then
`
`used to reconstruct the retina. Ex. 1033 ¶¶ 23 and 43; see Ex. 1045, 59, 60,
`
`and 160.
`
`The University argues that at the time of invention it was accepted
`
`scientific fact that astaxanthin did not have any Vitamin A activity. Resp.
`
`30–31 and 35–36 (citing Ex. 2015 ¶¶ 97–102; Ex. 2010, 2483). The
`
`University adds that the work of Grangaud was rejected as unreliable to
`
`establish that astaxanthin exhibited Vitamin A activity. Id. at 30–31. These
`
`12
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`IPR2013-00401 and IPR2013-00404
`Patent 5,527,533
`
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`arguments are unpersuasive to controvert the evidence presented by
`
`Cyanotech that, during Vitamin A deficiency, astaxanthin is converted to
`
`Vitamin A by the rat. Ex. 1002, 44; Ex. 1033 ¶¶ 42–43 and 51; Ex. 1045,
`
`59–60, 73, 160, 163–164. That is, while astaxanthin itself is without
`
`Vitamin A-like activity, a biological pathway exist in rats that is capable of
`
`metabolically converting astaxanthin to Vitamin A, whereby Vitamin A may
`
`present its own activity.
`
`In view of the above, we conclude that the preponderance of the
`
`evidence presented by Cyanotech demonstrates that retinal damage is
`
`inherent to the condition of vitamin A deficiency-induced xerophthalmia.
`
`Grangaud’s animals were kept on a vitamin A-deficient diet for about 2
`
`months (Ex. 1002, 43), and Dowling supports a conclusion that animals kept
`
`on such a diet would have suffered retinal damage. Ex. 1026, 88–89.
`
`Dowling also supports a finding that restoration of vitamin A to the diet
`
`could reverse the damage caused by a vitamin A deficiency. Id. at 94–96.
`
`Grangaud did not administer vitamin A itself, but rather administered
`
`astaxanthin. Astaxanthin, however, is capable of being converted to vitamin
`
`A in rats, which then would be available to correct the retinal damage caused
`
`by a vitamin A-deficient diet, as well as treat ocular lesions resulting from
`
`xerophthalmia, thereby improving the vision of the rats. Pet., 14-16; Ex.
`
`1002, 44; Ex. 1033 ¶¶ 42–43 and 51; Ex. 1045, 60 and 160. As such, the
`
`inherent action of astaxanthin would have resulted in improved vision in
`
`Grangaud’s animal model.
`
`The University argues that it is unclear whether Grangaud isolated
`
`astaxanthin. Id. at 27–31. The University contends that Grangaud’s
`
`spectrographic analysis of the Aristoeomorpha foliacea (krill) oil
`
`13
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`administered to the xeropthalmic rats was insufficient to identify the active
`
`compound in the oil as astaxanthin because the peaks observed by Grangaud
`
`were “broad” and different from the peak for free astaxanthin referenced in
`
`the literature (492 nm). Resp. 28 (citing Ex. 2015 at ¶¶ 86–90). That is, the
`
`University argues that it is unclear whether Grangaud isolated astaxanthin or
`
`whether Grangaud correctly identified astaxanthin as the compound that
`
`gave rise to the observed vitamin A activity. Id. at 27–31.
`
`We are not persuaded by the University’s argument. Even if we were
`
`to agree with the University that Grangaud’s krill oil contained other
`
`carotenoids, the University does not dispute that Grangaud’s krill oil
`
`contained astaxanthin, which, upon administration to vitamin A-deficient
`
`rats, is converted to vitamin A for use in the retina. Ex. 1002, 50:31–51:20;
`
`Ex. 1033 ¶¶ 23, 42, 43, 51.
`
`The University’s also argues that neither Grangaud nor Dowling
`
`suggests that vitamin A deficiency (to which each is directed) is related, in
`
`any way, to either free radical damage to a retina or central nervous system,
`
`or to any of the disorders or diseases to which the claims are directed. This
`
`argument is unpersuasive as the evidence shows that astaxanthin is
`
`converted in vivo to vitamin A, which is then available to treat vitamin A
`
`deficiency-induced xerophthalmia. Ex. 1002, 50:31–51:20; Ex. 1033 ¶¶ 23,
`
`42, 43, 51
`
`In view of the above, we find that Grangaud’s disclosure of a method
`
`of feeding astaxanthin to rats suffering vitamin A deficiency-induced
`
`xerophthalmia meets all elements of the methods recited in claims 1, 3, and
`
`10. Accordingly, we conclude that Grangaud anticipates claims 1, 3, and 10.
`
`14
`
`
`
`IPR2013-00401 and IPR2013-00404
`Patent 5,527,533
`
`
`b. Claims 8–9 and 11–12
`
`Claims 8–9 and 11–12 depend directly from claim 1 and further limit
`
`the retinal damage element of claim 1. Claim 8 requires the retinal damage
`
`to include free radical-induced retinal damage. Claim 9 requires the retinal
`
`damage to include light-induced retinal damage. Claim 10 requires the
`
`retinal damage to include ganglion cell retinal damage. Claim 11 requires
`
`the retinal damage to include age-related macular degeneration.
`
`The evidence of record shows that vitamin A functions as a precursor
`
`to the structural protein rhodopsin, found in the retina. Ex. 2105 ¶ 84.
`
`Dowling discloses that the loss of this structural protein in vitamin-A
`
`deficiency causes photoreceptor cell loss and night-blindness, which may be
`
`corrected by adding vitamin A back to the diet. Ex. 1026; see Ex. 1045, 29–
`
`30 and Ex. 2015 ¶ 46. In view of the above, we find that the preponderance
`
`of the evidence presented by Cyanotech supports a finding that Grangaud’s
`
`animals were suffering from vitamin A deficiency that necessarily resulted
`
`in retinal damage.
`
`The preponderance of the evidence presented by Cyanotech, however,
`
`fails to demonstrate that Grangaud’s animals were suffering necessarily from
`
`free radical-induced retinal damage (claim 8) or light-induced retinal
`
`damage5 (claim 9). Certain forms of vitamin A may have antioxidant
`
`properties, and thus, be capable of protecting the retina from free radical-
`
`induced retinal damage (Ex. 1033 ¶ 37), however, vitamin A is not the only
`
`antioxidant that plays a role in the retina—at least both vitamin C and E also
`
`
`5 Light generates free radicals in the retina, and thus, light-induced retinal
`damage is a specific form of free radical-induced retinal damage. Ex. 2015,
`¶ 60; see Ex. 1001, 2:1-4.
`
`15
`
`
`
`IPR2013-00401 and IPR2013-00404
`Patent 5,527,533
`
`
`play an antioxidant role in the retina. Ex. 1029 and Ex. 1045, 18–19.
`
`Grangaud’s animals were suffering from vitamin A deficiency, but the
`
`retinal damage seen with this condition may be explained by the lack of
`
`rhodopsin. Ex. 2015 ¶ 50 and Ex. 1045, 86–88. There is insufficient
`
`evidence on this record to conclude that the absence of vitamin A alone
`
`would create conditions that resulted necessarily in free radical-induced
`
`retinal damage. Accordingly, we are not able to conclude that Grangaud’s
`
`animals were suffering necessarily from free radical-induced retinal damage,
`
`as required by claims 8 and 9.
`
`Regarding claim 11, Dowling teaches that animals suffering from
`
`vitamin A deficiency have normal ganglion cells. Ex. 1026, 88. Thus, the
`
`evidence does not support a finding that Grangaud’s animals were
`
`experiencing ganglion cell retinal damage. Ex. 1026. Regarding claim 12,
`
`Grangaud does not disclose the treatment of an animal suffering from age-
`
`related macular degeneration. Accordingly, we are not able to conclude that
`
`Grangaud’s animals were necessarily suffering from the conditions required
`
`by claims 11 and 12.
`
`However, as discussed previously, we do not construe the phrase
`
`“retinal damage or retinal disease” as a single concept. As such, claims 8–9
`
`and 11–12 do not limit further the concept of disease in the preamble of
`
`claim 1, from which claims 8–9 and 11–12 depend. We also construed the
`
`term “disease” to refer to conditions in which the underlying cause of
`
`damage is treatable. In this regard, Grangaud discloses a method of treating
`
`an individual suffering from retinal disease—that is, xerophthalmia.
`
`Xerophthalmia is a nutritional disorder that may be treated by replacement
`
`of vitamin A, and thus, meets the element of retinal disease recited in the
`
`16
`
`
`
`IPR2013-00401 and IPR2013-00404
`Patent 5,527,533
`
`
`claims. Ex. 2015 ¶ 56. Accordingly, we conclude that Grangaud anticipates
`
`claims 8–9 and 11–12.
`
`c. Claim 13
`
`Claim 13 recites a method comprising administering a therapeutically-
`
`effective amount of astaxanthin to protect neurons in a retina from free-
`
`radical induced retinal injury. Cyanotech presents evidence that astaxanthin
`
`is an antioxidant that is capable of being transported into the retina, and
`
`argues that the biological role of astaxanthin obtained from the diet
`
`inherently involves protecting neurons in a retina from free-radical induced
`
`retinal injury. Pet. 14–15, 22 and 59 (citing Ex. 1002 and Ex. 1033 ¶¶ 24–25
`
`and 43–45).
`
`As discussed above, Grangaud discloses the results of experiments
`
`conducted on albino rats fed a vitamin A-deficient diet. Ex. 1002, 43. The
`
`University does not dispute that astaxanthin obtained from the diet is capable
`
`of crossing the blood-retinal barrier to protect neurons in a retina from free-
`
`radical induced damage. Resp. 4–8. Rather, the University argues that
`
`evidence of record does not demonstrate that vitamin A protects the retina
`
`from free-radical attack and that the vitamin A-deficient rats in Grangaud do
`
`not suffer retinal damage from free radicals necessarily. Id. at 12 and 19–24.
`
`The language of claim 13, however, does not require the
`
`administration of vitamin A nor does it require an individual to suffer from
`
`free-radical damage. Claim 13 requires the administration of astaxanthin to
`
`an individual and, as summarized above, both parties agree that
`
`astaxanthin’s biological role involves antioxidant activities in the retina.
`
`Paper 64, 18:10–13; Resp. 5. Thus, the necessary result of such
`
`17
`
`
`
`IPR2013-00401 and IPR2013-00404
`Patent 5,527,533
`
`
`administration would be protection of neurons in a retina from free-radical
`
`induced retinal injury. Accordingly, we conclude that Grangaud anticipates
`
`claim 13.
`
`d. Claim 14
`
`Claim 14 recites a method of treating an individual suffering from
`
`neuronal damage to a retina comprising administering a therapeutically-
`
`effective amount of astaxanthin to the individual to improve the condition of
`
`the retina. As discussed above with regard to claims 1 and 10, the
`
`preponderance of evidence of record demonstrates that neuronal damage to a
`
`retina is inherent to the condition of vitamin A deficiency-induced
`
`xerophthalmia. Furthermore, as discussed above, the inherent action of
`
`astaxanthin involves conversion to vitamin A, which is then available to
`
`repair the retina, thereby improving vision in Grangaud’s animal model.
`
`Accordingly, Grangaud’s method of feeding astaxanthin to rats suffering
`
`vitamin A deficiency-induced xerophthalmia meets all elements of claim 14.
`
`e. Claim 15
`
`Claim 15 depends from claim 14 and specifies that the neuronal
`
`damage may be caused by photic injury to the retina. Cyanotech contends
`
`that damage resulting from photo injury is caused by free radicals created by
`
`photic energy. Pet. 23.
`
`As discussed above with regard to claim 8, the preponderance of
`
`evidence of record does not support a conclusion that Grangaud’s animals
`
`were suffering necessarily from free radical-induced retinal damage caused
`
`by photic injury. Certain forms of vitamin A may have antioxidant
`
`properties, and thus, be capable of protecting the retina from free radical-
`
`18
`
`
`
`IPR2013-00401 and IPR2013-00404
`Patent 5,527,533
`
`
`induced retinal damage (Ex. 1033 ¶ 37), however, vitamin A is not the only
`
`antioxidant that plays a role in the retina—at least both vitamin C and E also
`
`play an antioxidant role in the retina. Ex. 1029 and Ex. 1045, 18–19.
`
`Grangaud’s animals were suffering from vitamin A deficiency, but the
`
`retinal damage seen with this condition may be explained by the lack of
`
`rhodopsin. Ex. 2015 ¶ 50 and Ex. 1045, 86–88. There is insufficient
`
`evidence to conclude that the absence of vitamin A alone would create
`
`conditions that resulted necessarily in free radical-induced retinal damage.
`
`Accordingly, we are not persuaded that the preponderance of evidence
`
`shows that Grangaud’s animals were necessarily suffering from photic
`
`injury, as required by claim 15.
`
`f. Claims 21 and 22
`
`Claim 21 recites a method of treating an individual suffering from a
`
`free radical-induced injury to a central nervous system. Claim 22 depends
`
`from claim 22 and specifies that the central nervous system may be the
`
`retina. As discussed above with regard to claim 15, the preponderance of
`
`evidence
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