UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________
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`Cyanotech Corporation
`Petitioner
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`v.
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`The Board of Trustees of the University of Illinois
`Patent Owner
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`_______________________
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`IPR2013-00401
`Case:
`Patent No.: 5,527,533
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`RESPONSE OF PATENT OWNER
`THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS
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`Table of Contents
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`BACKGROUND ........................................................................................ 1
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`SUMMARY OF THE ARGUMENT ....................................................... 1
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`The Tso Patent ................................................................................... 4
`A.
`B. Grangaud (Ex. 1002) ......................................................................... 8
`C. Dowling (Ex. 1026) ......................................................................... 11
`D.
`Reading (Exhibit 1029) ................................................................... 12
`E.
`Carter-Dawson (Exhibit 1030) ........................................................ 12
`F.
`Xeropthalmia and other damage caused to the eye by Vitamin A
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`defficiency is pathologically and biologically unrelated to free
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`radical-induced injury ..................................................................... 13
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`I.
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`II.
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`III. RESPONSE TO STATEMENT OF MATERIAL FACT ..................... 3
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`IV. THE TSO PATENT AND THE ALLEGED PRIOR ART ................... 4
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`V.
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`INTERPRETATION OF THE INSTITUTED CLAIMS .................... 14
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`A.
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`B.
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`The types of retinal damage required by dependent claims 8-12
`limit the entire “retinal disease or retinal damage” element of
`Claim 1 ............................................................................................ 14
`The University disputes Cyanotech’s proposed construction of
`other terms, but resolution of that dispute is not necessary for this
`inter partes review ........................................................................... 16
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`A.
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`Petitioner has failed to demonstrate that Grangaud anticipates
`Claims 1, 3, 8-15, 21, 22, and 26 .................................................... 17
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`1.
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`2.
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`3.
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`4.
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`5.
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`6.
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`Claims 8, 13, 21, and 22 are not anticipated because
`“free radical-induced injury” is not associated with
`(or necessarily resulting from) Vitamin A deficiency .......... 19
`Claim 9 is not anticipated because Grangaud does not
`involve “light-induced retinal damage” ............................... 24
`Claim 11 is not anticipated because Grangaud does not
`involve “ganglion cell retinal damage” ............................... 25
`Claim 12 is not anticipated because Grangaud did not
`involve “age-related macular degeneration” ...................... 26
`Claim 15 is not anticipated because Grangaud does not
`involve “photic injury to the retina, ischemic insult to the
`retina, or intraocular pressure-related insult to the retina”. 27
`Grangaud does not anticipate any of the instituted claims
`because Cyanotech has not shown that Grangaud
`necessarily used astaxanthin to treat retinal damage
`or retinal disease .................................................................... 27
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`VI. ARGUMENT ............................................................................................ 17
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`B.
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`The instituted claims are not obvious in view of Grangaud
`and Dowling ................................................................................... 32
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`1.
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`2.
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`3.
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`4.
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`Claims 8, 13, 21, and 22 are not obvious because neither
`Grangaud nor Dowling teach or suggest using astaxanthin
`to combat free-radical induced injury to a retina or
`central nervous system .......................................................... 33
`Claim 9 is not obvious because neither Grangaud nor
`Dowling teach or suggest using astaxanthin to treat
`“light-induced retinal damage” ........................................... 38
`Claim 11 is not obvious because neither Grangaud nor
`Dowling reach or suggest using astaxanthin to treat
`“ganglion cell retinal damage” ............................................ 39
`Claim 12 is not anticipated because Grangaud did not
`involve “age-related macular degeneration” ...................... 40
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`5.
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`6.
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`7.
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`Claim 15 is not anticipated because Grangaud does not involve
`“photic injury to the retina, ischemic insult to the retina, or
`intraocular pressure-related insult to the retina” ................ 41
`Grangaud does not anticipate any of the instituted claims
`because Cyanotech has not shown that Grangaud
`necessarily used astaxanthin to treat retinal damage
`or retinal disease ..................................................................... 41
`The objective indica of nonobviousness conclusively
`Show that claims 1-15, 21, 22, and 26 of the Tso patent
`were not obvious ................................................................... 45
`(i) Acclaim/praise ............................................................ 46
`(ii) Commercial success ................................................... 49
`(iii) Commercial acquiescence .......................................... 49
`(iv) Copying ....................................................................... 50
`(v) Unexpected results ...................................................... 50
`(vi) Long-felt need ............................................................. 51
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`VI. CONCLUSION ....................................................................................... 51
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`CERTIFICATE OF SERVICE ........................................................................ 53
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`I.
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`BACKGROUND
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`Cyanotech Corp.’s (“Cyanotech”) Petition requesting inter partes review of
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`U.S. Pat. No. 5,527,533 (“Tso patent”) raised four grounds of invalidity. On
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`October 2, 2013, Patent Owner, the Board of Trustees of the University of Illinois
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`(“University”), filed a Preliminary Response opposing the Petition on procedural—
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`but not substantive—grounds. On December 19, 2013, the Patent Trial and
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`Appeals Board (“Board”) issued a Decision denying the Petition as to claims 16–
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`20, 23–25, and 27, but instituting review as to claims 1–15, 21, 22 and 26.
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`As to the instituted claims, the Board agreed to consider only two of the four
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`grounds identified in Cyanotech’s petition: (i) anticipation under 35 U.S.C. § 102
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`in view of Rene Grangaud, “Recherches sur l’Astaxanthine, Noveau Facteur,
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`Vitaminique A” (1951) (“Grangaud”) (English translation submitted as Ex. 1002)
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`(claims 1, 3, 8–24, and 26); and (ii) obviousness 35 U.S.C. § 103 in view of
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`Grangaud in combination with Dowling et al., “The effect of vitamin A deficiency
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`on the fine structure of the Retina,” in The Structure of the Eye (New York 1961)
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`(“Dowling”) (submitted as Ex. 1026) (claims 1–15, 21, 22, and 26).
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`II.
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`SUMMARY OF THE ARGUMENT
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`Cyanotech has failed to meet its burden of demonstrating that the methods of
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`claims 1–15, 21, 22, and 26 of the Tso patent are anticipated or would have been
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`obvious as of the date of invention. Grangaud and Dowling are directed to
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`xeropthalmia and vitamin A deficiency. Neither Grangaud nor Dowling mentions
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`or suggests that vitamin A deficiency (to which each is directed) is at all related to
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`free radical damage to a retina or central nervous system, or to any of the disorders
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`or diseases to which the claims are directed. Cyanotech tries to fill in the gap with
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`expert testimony that complications from vitamin A deficiency inherently involve
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`free radical damage, but Cyanotech’s expert lacks any support for his conclusion.
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`In fact, one of the references Cyanotech cites in its Petition indicates that vitamin
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`A deficiency does not involve oxidative attack, showing that vitamin A does not
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`serve to protect the retina from free radicals. Given the complete dearth of
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`evidence supporting Cyanotech’s assertion that vitamin A deficiency and
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`xeropthalmia necessarily involve free radical damage, there is no basis for finding
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`methods that claim treatment of such damage either anticipated or obvious.
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`Further, the Grangaud reference that is the lynchpin of Cyanotech’s
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`arguments is inherently unreliable. It used inadequate experimental methods, and
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`it remains unclear whether Grangaud isolated astaxanthin and whether astaxanthin
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`was the compound that gave rise to the observed vitamin A activity. Even more
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`fundamentally, Grangaud’s analysis led to a conclusion that a person of ordinary
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`skill in the art would have (and did) reject: that astaxanthin functions as a
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`provitamin A in rats. The established scientific consensus, both at the time of
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`Grangaud’s thesis and at the time of the invention, was that astaxanthin cannot
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`have vitamin A activity. Accordingly, as Cyanotech itself has noted, Grangaud’s
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`work was subject to “peer rejection.” The unresolved ambiguities of Grangaud’s
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`work are problematic, particularly in the unpredictable arts at issue. Cyanotech has
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`failed to show that Grangaud necessarily performed, or would have motivated a
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`person of ordinary skill in the art to perform, the claimed methods—treating the
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`claimed retinal damages and diseases with astaxanthin.
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`This outcome is further confirmed by a wealth of objective indica of non-
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`obviousness—not the least of which is Cyanotech (and others in the nutritional
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`supplement field) repeatedly characterizing the Tso patent as a “groundbreaking”
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`invention and crediting Dr. Tso as the first to prove that the claimed methods
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`worked. In addition, the claimed invention was unexpected, enjoyed tremendous
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`commercial success, and satisfied the long-felt need for effective methods of
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`combating retinal and central nervous system damage and disease.
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`III. RESPONSE TO STATEMENT OF MATERIAL FACT
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`The University disputes paragraph seven of the “Statements of Material
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`Fact” in Cyanotech’s Petition to the extent it assumes or implies that “treating”
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`does not include prophylactic or preventative treatment.1
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`1 As set forth in this brief, there are many material facts in dispute; however
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`this section only responds to “Statement of Material Fact” set forth by Petitioner
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`(see Petition at pp. 9-11), as required 37 C.F.R. § 42.23(a).
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`IV. THE TSO PATENT AND THE ALLEGED PRIOR ART
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`A.
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`The Tso Patent
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`The Tso patent is directed to methods of administering astaxanthin with
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`respect to retinal or central nervous system diseases or injuries, such as age-related
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`macular degeneration, photic injury, ischemic diseases, and inflammatory diseases.
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`(Ex. 1001 at Abstract.) As the Tso patent explains, a major cause of these diseases
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`or injuries is “the generation and presence of singlet oxygen and other free radical
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`species.” (Id. at 1:39–40.) Such diseases or injuries cannot be repaired, because
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`once injured, the retina and central nervous system have limited regeneration
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`capability. (Id. at 1:23–26.)
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`Age-related macular degeneration (“ARMD”) is one such disease. ARMD
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`is the leading cause of blindness in people over the age of 50. (Ex. 2016, 2017.)
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`This condition affects between 30 and 50 million people worldwide. (Id.) ARMD
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`results from damage to the macula, a small spot near the center of the retina that is
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`necessary for sharp vision. (Ex. 2015 at ¶ 72.) ARMD is impossible to cure; the
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`only treatment is prevention of damage in the first place. (Tso patent at 2:59–:5
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`(“[P]revention is the only way to confront age-related macular degeneration.”).)
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`In the 1990s, Dr. Mark Tso was a Professor of Ophthalmology at the
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`University of Illinois. Dr. Tso, along with his graduate assistant, Dr. Tim-Tak
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`Lam, made the surprising discovery that astaxanthin provides remarkably positive
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`effects in protecting the eye from free radical attack and oxidative damage. Dr.
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`Tso was awarded the patent at issue for his discoveries. The Tso patent was a
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`significant development over previous attempts to treat retinal and CNS diseases
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`with antioxidants. At the time of the invention, certain diseases and injuries of the
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`eye and CNS were untreatable. (Id. at 7:50–51.) Researches had investigated
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`treatments involving naturally-occurring antioxidants, but only a few antioxidant
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`compounds were known to be able to reach the eyes and central nervous system
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`(which are protected by the blood-brain barrier) to treat such injuries and diseases.
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`(Id. at 5:5–9.) Additionally, compounds similar in structure to astaxanthin caused
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`adverse side effects such as the formation of crystalline deposits. (Id. at 4:58–5:12;
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`8:38–40.) Since these similar compounds could not be used to perform the
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`claimed methods, it was surprising to discover that astaxanthin could not only
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`cross the blood-brain barrier and reach the eyes and CNS, but that it did so with
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`unexpected ease and did not cause side effects exhibited by extremely xanthophyll
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`compounds. (Id. at 10:15–22.)
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`Dr. Tso conducted several studies using “classic” eye tests to evaluate his
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`inventions. (Id. at 10:62–14:50.) For example, Dr. Tso “treated” a group of
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`laboratory rats by administering astaxanthin (24 hours before light exposure), and
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`then subjected the test rats (along with an equal number of control rats that
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`received no astaxanthin) to twelve hour cycles of light and darkness for 14 days.
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`(Id. at 11:19–40.) Dr. Tso then measured the thickness of a layer within the retina
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`of the rats. (Id. at 11:52–12:7.) Dr. Tso found that this layer was thicker for the
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`rats treated with astaxanthin, indicating that the compound had protected their
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`retinas from injury. (Id. at 11:61–12:7.) He conducted further tests and evaluated
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`the results according to other commonly accepted procedures, such as measuring
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`distances between certain layers of the retina, and levels of rhodopsin (a compound
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`associated with injury to the eye) in the retina. (Id. at 12:8–14:5.) Dr. Tso’s
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`experiments demonstrated that astaxanthin effectively treats damage, disease, or
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`injury to the retina and CNS caused by oxidative attack (whether due to light
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`damage, ARMD, ischemia, reperfusion following ischemia, or inflammation).
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`(E.g., id. at 14:63–67.)
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`Dr. Tso also conducted a quantitative test to determine whether astaxanthin
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`actually crossed the blood-retinal barrier and accumulated in the retina. To do so,
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`he administered astaxanthin to rats, which were then euthanized. (Ex. 1001 at
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`10:62–11:11.) Dr. Tso then tested the retinas of the euthanized rats for
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`astaxanthin, finding a notable concentration of astaxanthin in retinal wet tissue six
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`hours after the last astaxanthin injection. (Id. at 11:6–11.)
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`The work of Dr. Tso and Dr. Lam did not go unnoticed. Cyanotech itself has
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`identified Dr. Tso as the “first to prove” that astaxanthin crosses the blood-retinal
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`barrier and effectively protects the retina against light-induced damage: “We spoke
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`very briefly about groundbreaking work done by Dr. Mark Tso of the University of
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`Illinois in Chapter 2. Dr. Tso was the first person to prove that Astaxanthin can
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`cross the blood-brain and blood-retinal barriers. Through an extensive series of
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`tests, Dr. Tso went on to prove that Astaxanthin has many protective properties
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`once it reaches the eyes. Among the many benefits that Dr. Tso found include
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`Astaxanthin’s ability to protect the eye from: light-induced damage, photoreceptor
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`cell damage, ganglion cell damage, neuronal damage and inflammatory damage.”
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`(Ex. 2026 (King of Carotenoids book, 2011 ed.), at RA108231.) Cyanotech has
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`also repeatedly lauded the discoveries of Drs. Tso and Lam as “groundbreaking” in
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`its marketing material and scientific literature:
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` “Groundbreaking research conducted by Dr, Mark Tso, University of Illinois,
`Urbana-Champaign found that astaxanthin helps protect the eye from light-
`induced damage, photoreceptor cell damage, ganglion cell damage, neuronal
`damage and inflammatory damage.” (Ex. 2018 at VALENSA000416.)
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` “Astaxanthin has been shown… I think the first work was done by Dr. Tso at
`University of Illinois, showing that astaxanthin could accumulate in the retina
`and provide this protection against oxidation in the retina. It can be very, very
`therapeutic.” (Ex. 2019 at VALENSA000357.)
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` “[Dr.] Tso determined astaxanthin could ameliorate or prevent light induced
`damage, photoreceptor cell damage, ganglion cell damage, and damage to the
`neurons of the inner retinal layers. Other researchers (Shimidzu et al,
`Bagchi, Martin et al, and Beutner) have since confirmed Dr. Tso's finding
`that astaxanthin is the most powerful antioxidant ever discovered for eye
`health, giving your eyes an additional layer of long-term protection.” (Ex.
`2020 at VALENSA000102.)
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` “Dr. Mark Tso first of all proved that astaxanthin could cross the blood-brain
`and blood-retinal barriers by feeding astaxanthin to rats and finding it in their
`eyes. He then proved [astaxanthin] protected the eye from light-induced
`damage, photoreceptor cell damage, ganglion cell damage, neuronal damage,
`and inflammatory damage.” (Ex. 2021 at VALENSA000056.)
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` “Mark Tso, PhD, has shown that astaxanthin can cross the blood-brain
`barrier. When he fed it to rats, he found it in their eyes. He then
`demonstrated that it protects the eyes from light-induced damage,
`photoreceptor cell damage, damage to nerve bundles (called ganglions),
`nerve damage, and inflammatory damage. (Tso, et al., US Patent No.
`5,527533, 1996) Tso showed that astaxanthin is also effective in
`ameliorating retinal damage. (Tso & Lam, 1996)” (Ex. 2022 at
`VALENSA000347.)
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`B. Grangaud (Ex. 1002)
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`Grangaud’s thesis focused on the administration oil extracted from the
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`shrimp species Aristoeomorpha foliacea to test its efficacy against xeropthalmia
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`and growth deficiencies in Vitamin A deficient rats. (Ex. 1002 at 29; 43, 56–58.)
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`Grangaud explained that Vitamin A deficiency in rats results in xeropthalmia, (id.
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`at 43:25–28), noting that mammals require “provitamins A, i.e. substances which
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`organisms are capable of converting into Vitamin A” for normal functioning. (Id.
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`at 42:23–27.) Grangaud does not mention or observe retinal damage or disease in
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`his paper.
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`Grangaud first kept a group of test rats on a Vitamin A-deficient diet. (Ex.
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`1002 at 43–48.) Grangaud observed that the rats showed “serious xeropthalmia.”
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`(Id. at 47.) Specifically, he notes the presence of characteristic “ocular lesions,”
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`“corneal lesions,” and “corneal ulceration.” (E.g. id. at 44:12–45:16; 45 n.1;
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`47:19–25).
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`Grangaud then administered the Aristoeomorpha foliacea oil to some of the
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`Vitamin A-deficient rats, but not others. (Id. at 43–48.) Grangaud observed
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`administration of the oil “cured” xeropthalmic corneal abscesses. (Id. at 44, 47.)
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`The control rats, in contrast, suffered a continued deterioration in health and all
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`subsequently died. (Id.)
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`Grangaud also reported that he examined the eyes of the test rats. Grangaud
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`enucleated the entire eyes, and then ground them into a solution. (Id. at 50.) He
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`then treated the solution via several steps that resulted in its acidification. (Id. at
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`51.) Grangaud observed that the solution from the eyes of the rats given the
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`Aristoeomorpha foliacea oil turned “cyclamen pink” during acidification, while the
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`solution from the untreated rats remained colorless. (Id.) Grangaud also observed
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`that in the enuculeated eyes of the treated rats, only the retinal area was
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`“pigmented.” (Id. at 51, n.1.)
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`From these experiments, Grangaud hypothesized that (1) astaxanthin is an
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`effective substitute for Vitamin A as a treatment for xeropthalmia, and (2) that the
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`“Aristaeormorpha oil, or a transformation product of the latter” was transported
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`into the rat retina. (Id. at 51, 62–63.) Grangaud further hypothesized that
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`astaxanthin was converted into Vitamin A in the rat eye—i.e., the astaxanthin
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`“replac[ed] vitamin A in the visual processes.” (Id. at 63.)
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`Grangaud’s work involved some questionable results that render his
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`conclusions unreliable. (See Ex. 2015 at ¶ 83 (Expert Declaration of Shaleesh
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`Kaushal, M.D., Ph.D).) First, his identification of astaxanthin in the pigment oil
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`was unclear—his spectroscopy data showed peaks different than those reported in
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`the reference literature upon which he relied. (Ex. 1002 at 24:28–33, 32:19–20,
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`33:3–5 (observing peaks at 500 nm for one oil and a broad flat peak at 480–490 nm
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`in another oil, while relying on a peak in the literature of 492 nm).) Grangaud
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`acknowledged that his oil may have included “several constituents.” (Id. at 33:3–
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`8; 35:13–15 (acknowledging “the possibility of the existence of several
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`pigments”); Ex. 2015 at ¶ 90.) Grangaud was also uncertain regarding whether
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`astaxanthin reached the retina intact. (E.g. id. at 51:19–20 (referring to “[o]il of the
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`[crustacean], or transformation product thereof, was found in the retina”); 53:25–
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`26 (referring to “the oil pigment or a related transformation”); 53:13 (referring to
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`“the presence of astaxanthin, or one of its byproducts, in the retina of the treated
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`rats”); Ex. 2015 at ¶¶ 112–113.) Further, Grangaud recognized that his
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`conclusions contradicted established scientific thought: those of skill in the art
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`clearly regarded astaxanthin as having no vitamin A activity. (Id. at 42:27–43:2).
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`(Ex. 2015 at ¶¶ 97–98.)
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`In the 40 years between the day Grangaud published his thesis and Dr. Tso
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`developed his invention, the thesis was cited only two times. (Ex. 1034 at 4.)
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`Cyanotech has noted that “many French scientists found [Grangaud’s reported
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`results] so incredible that they branded Grangaud and Massonet as mavericks and
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`asserted that the reported experiments must be flawed.” (Ex. 2014 (King of
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`Carotenoids book, 2013 ed.), at RA113041.) Cyanotech has further noted that
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`Grangaud’s work suffered “peer rejection.” (Id.)
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`C. Dowling (Ex. 1026)
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`Like Grangaud, Dowling is directed to Vitamin A deficiency. (Ex. 1026 at
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`85.) Dowling administered vitamin A to some rats, and to others he administered
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`only vitamin A acid. Rats receiving the vitamin A acid (but not Vitamin A), lost
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`most of their rhodopsin and the visual cells showed signs of damage. (Id. at 87–
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`94.) Then, when vitamin A was administered, there was significant recovery to the
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`structure of the retina cells. (Id. at 94–97.) Dowling concluded that vitamin A is
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`necessary to the maintenance and formation of the outer retinal cells: “The
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`disappearance of the myeloid bodies during vitamin A deficiency and their
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`reappearance in recovery demonstrates that these structures, like the outer
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`segments, are dependent on vitamin A for their maintenance and formation.” (Id. at
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`98.) Dowling does not disclose any evidence or hypothesis that the retinal
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`degeneration observed following Vitamin A deficiency was at all related to
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`oxidative damage. (Ex. 2003 (Schweigert Dep.) at 62:9–12, 18–20.)
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`D. Reading (Exhibit 1029)
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`Cyanotech also submitted an article by Reading entitled “The Effect of
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`Deficiency of Vitamins E and A on the Retina,” published in 1980 in the journal
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`entitled “Nutrition Reviews.” (Ex. 1029 (hereinafter “Reading”).) Reading
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`summarized multiple studies performed by Robison et al. regarding the impact of
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`vitamin A deficiency and vitamin E deficiency on oxidative stress to the eyes.
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`Specifically, Robison et al. analyzed the amount of free radical attack or oxidation
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`in the eye resulting from vitamin A and/or vitamin E deficiency. They did so by
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`measuring the amount of lipofuscin, a compound formed when retinal tissue is
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`damaged by oxidation, formed in the eye. (Ex. 1029 at 386.) The levels of this
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`compound were five times higher in rats that were vitamin E deficient (whether or
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`not they were also vitamin A deficient). (Id. at 387.) Conversely, rats that were
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`only vitamin A deficient, but that were not vitamin E deficient, did not have any
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`increase in lipofuscin levels (suggesting that no oxidation was taking place). (Id. at
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`387.) This reference showed that vitamin A does not protect the eye from
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`oxidative attack. (Ex. 2015 at ¶¶ 52–54.)
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`E. Carter-Dawson (Exhibit 1030)
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`Cyanotech also submitted an article by Carter-Dawson entitled “Structural
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`and biochemical changes in vitamin A-deficient rat retinas,” published in 1979 in
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`the journal entitled “Investigative Opthalmology & Visual Science.” (Ex. 1030
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`(hereinafter “Carter-Dawson”).) Carter-Dawson studied the effects of vitamin A
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`deficiency on the retinas of rats exposed to very low levels of light. (Id. at 438.)
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`Carter-Dawson observed significant damage to the rod and cone cells in the rat
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`retinas, despite the fact that they were exposed to only minimal levels of light. (Id.
`
`at 442–43.)
`
`F.
`
`Xeropthalmia and other damage caused to the eye by Vitamin A
`deficiency is pathologically and biologically unrelated to free
`radical-induced injury
`
`Vitamin A is essential to healthy, normal functioning of mammalian eyes.
`
`
`
`Vitamin A is necessary because it is one of the two essential building blocks for
`
`rhodopsin. (Ex. 2015 at ¶ 46; Ex. 2003 (Schweigert Dep.) at 21:8–24; see also Ex.
`
`2009 at p.1555; Ex. 1025 at p. 587.) Rhodopsin is the compound in the rod cells of
`
`the eye that converts light into a nerve impulse that can be sent to the brain. (Id.)
`
`Without adequate vitamin A (the source of retinal), the body cannot synthesize
`
`rhodopsin and the visual cells in the retina deteriorate. (Ex. 2015 at ¶ 46; Ex. 2003
`
`(Schweigert Dep.) at 22:6–8.) One of the diseases resulting from such vitamin A
`
`deficiency is xeropthalmia, which manifests as dryness of the eye and resulting
`
`corneal ulcers. (Id.)
`
` 13
`
`

`

`Vitamin A deficiency, and the problems in the eye that result from it, are not
`
`related to oxidative attack or free radical damage.2 (Ex. 2015 at ¶ 50.) The ocular
`
`pathology of vitamin A deficiency results from the body’s inability to synthesize
`
`adequate rhodopsin, not from a deficiency of free radical scavangers in the eye.
`
`(Id. at ¶¶ 50–58.) Rhodopsin is vital to rod structure—the inability to synthesize
`
`rhodopsin causes collapse of the rods in the photoreceptor cell later. (Ex. 2015 at ¶
`
`46; Ex. 1033 at ¶ 38.)
`
`V.
`
`INTERPRETATION OF THE INSTITUTED CLAIMS
`
`A.
`
`The types of retinal damage required by dependent claims 8–12
`limit the entire “retinal disease or retinal damage” element of
`Claim 1
`
`
`Claims 8–12 must be interpreted in a manner that is consistent with the way
`
`the terms are used in both the patent and the prosecution history. See In re Suitco
`
`Surface, Inc., 603 F.3d 1255, 1259 (Fed. Cir. 2010) (stating that the broadest
`
`reasonable interpretation must be consistent with the specification); see also In re
`
`Abbott Diabetes Care, Inc. 696 F.3d 1142, 1149 (Fed. Cir. 2012); (relying in part
`                                                            
`2 The health problems caused by the nutritional disease of vitamin deficiency
`
`are by no means limited to the eye, but cause problems throughout the body. (Ex.
`
`2003 (Schweigert Dep.) at 23:25-25:23; Ex. 1025 at 587.) Among many other
`
`problems, vitamin A deficiency causes significant weight loss, disintegration of
`
`tissues in the body, and balance problems.
`
` 14
`
`

`

`on the purpose of the invention in rejecting PTO claim interpretation as
`
`overbroad); In re Morris, 127 F.3d 1048, 1054 (Fed. Cir. 1997) (“[I]t would be
`
`unreasonable for the PTO to ignore any interpretive guidance afforded by
`
`applicant’s written description.”).
`
`The claim language and specification confirm that the applicants used the
`
`terms “retinal damage or retinal disease” as a single concept. (Ex. 1001 at 1:8–18
`
`(referring to “disease or injury” and the providing a single, unified list for both
`
`terms), 1:30–36 (referring to “eye injuries and diseases” and providing a single,
`
`unified list corresponding to both terms), 3:28–31 (same); 6:58–61; 14:63–67.)
`
`Indeed, the specification confirms that free radical damage is associated with both
`
`injuries and disease. (Id. at 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”).) As both a natural reading of the claims, and these
`
`passages in the specification show, the phrase “retinal damage or retinal disease”
`
`as used in the claims does not refer to two separate options but, rather, represent a
`
`single claim element. Thus, the additional limitations set forth in dependant claims
`
` 15
`
`

`

`8–12 limit this entire element to the specified form of retinal damage or disease set
`
`forth in the respective dependant claim.
`
`This understanding is confirmed by the prosecution history, wherein the
`
`applicants consistently specified their intent to recite the function to be performed
`
`in the body of the claim. (Ex. 2023 at 4–5 (Prosecution File History).) Any
`
`reading otherwise would render claims 8–12 redundant with claim 1.
`
`B.
`
`The University disputes Cyanotech’s proposed constructions of
`other terms, but resolution of that dispute is not necessary for this
`inter partes review
`
`
`The University disagrees with Cyanotech’s construction of the term
`
`“treating” or “treating an individual suffering from,” to the extent that Cyanotech’s
`
`definition would exclude prophylactic or preventative treatment. The Tso patent
`
`uses the term “treating” to refer simply to the administration of astaxanthin. For
`
`example, the Tso patent consistently refers to rats to which astaxanthin had been
`
`prophylactically administered as “treated.” (E.g., Ex. 1001 at 14:32–34 (“The
`
`treated rats demonstrated better preservation of [the retina]”); 7:29–33; see also
`
`7:36–38; 7:40–42; 7:43–45; 12:18–19.) The Tso patent also explains that
`
`prevention is the only way to treat many of the diseases or damage to which the
`
`claims are directed. (E.g. id. at 2:64–67 (“Therefore, because no treatment for this
`
`disease exists once the photoreceptor cells are destroyed, prevention is the only
`
`way to confront age-related macular degeneration.” (emphasis added).)
`
` 16
`
`

`

`Cyanotech itself has admitted that “the experimental design of the [Tso] patent
`
`only yields data about the preventive use of astaxanthin, administered before
`
`retinal injury or disease.” (Petition at 11, ¶ 7.) Much of the damage or disease to
`
`which the Tso patent claims are directed is degenerative in nature, meaning that
`
`there is no clear beginning point for them. Rather, they occur on a continuum,
`
`from undetectable and pre-symptomatic, to symptomatic, and then finally to
`
`complete cellular destruction or death. Thus, treating such damage or disease
`
`necessarily includes prophylactic or preventative treatment. Notwithstanding,
`
`resolution of this claim construction dispute is not necessary to resolve the validity
`
`issues presented here.
`
`The University also disputes Cyanotech’s construction of the term
`
`“individual,” as well as Cyanotech’s definitions for “damage,” “injury,” and
`
`“disease” to the extent they depart from the plain and ordinary meaning at the time
`
`of invention. However, once again resolution of these claim construction disputes
`
`is not necessary for the purposes of addressing Cyanotech’s invalidity arguments.
`
`VI. ARGUMENT
`
`A.
`
`Petitioner Has Failed to Demonstrate that Grangoud Anticipates
`Claims 1, 3, 8–15, 21, 22, and 26
`
`
`“Inherent anticipation requires that the missing descriptive material is
`
`‘necessarily present,’ not merely probably or possibly present, in the prior art.”