Atty Docket: Cyan.IPR.One
`
`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.
`
`____________
`
`
`
`
`
`PETITIONER’S REQUEST FOR REHEARING
`UNDER 37 C.F.R. § 42.71
`____________
`
`Submitted: January 2, 2014
`
`                                                                 
`1  Consolidated with Case IPR2013-00404
` 
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`

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`Petitioner’s Request for Rehearing Page 1
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`On December 19, 2013, the Board issued a Decision under 35 U.S.C. § 311
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`inter alia instituting inter partes review, and consolidating, IPR2013-00401 (“Pet.
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`‘401”) and IPR2013-00404 (“Pet. ‘404”) (collectively, Pet. ‘401 and Pet. ‘404 are
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`the “Petition” unless a specific petition is cited; collectively the Decisions in Pet.
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`‘401 and Pet. ‘404 are “the Decision” unless a specific decision is cited). Pet.
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`‘401 and Pet. ‘404 are both directed to Claims 1-27 of U.S. Patent No. 5,527,533
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`and share a common set of identically enumerated Exhibits.
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`I. Introduction. The foci of Petitioner’s Request for Rehearing (“Request”)
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`are that: (i) all species claims of an instituted genus claim should be instituted; (ii)
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`Massonet (Exh. 1004) is technically and substantively not redundant with
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`Grangaud (Exh. 1002), especially as to Claims 16-20, 23-25, and 27, and (iii) there
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`is an internal consistency in the Decision concerning the grounds and claims
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`instituted that should be clarified.
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`
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`II. Claim 16 is unpatentable as a species in view of genus Claim 26;
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`Claims 23-25 are unpatentable as species in view of genus Claim 21.
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`A single disclosed species can anticipate an entire genus, In re Berg, 140 F.3d
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`1428 (Fed.Cir., 1998), In re Goodman, 11 F.3d 1046 (Fed.Cir., 1993), and a
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`disclosed genus anticipates all species in that genus unless a given species has a
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`critical range of operation different from that of the genus and a later patent
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`application contains data that establish the critical range and its effect for the
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`IPR2013-00401/404
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`Atty Ref: Cyan.IPR.One  
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`

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`Petitioner’s Request for Rehearing Page 2
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`claimed species. ClearValue Inc. v. Pearl River Polymers Inc., 668 F.3d 1340
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`(Fed. Cir., 2012) (“The disclosure of 150 ppm or less is a genus disclosure as in
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`Atofina. But unlike Atofina where there was a broad genus and evidence that
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`different portions of the broad range would work differently, here, there is no
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`allegation [in the patent application] of criticality or any evidence demonstrating
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`any difference across the range.”); Osram Sylvania v. American Induction
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`Technologies, 701 F.3d 698 (Fed. Cir., 2012) (“In ClearValue, we explained that,
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`in contrast to the patentee in Atofina, ClearValue did not argue that the 50 ppm
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`limitation was critical, or that the claimed method worked differently at different
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`points within the prior art range of 150 ppm or less. Id [668 F.3d 1340, 1344-45].
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`And, ClearValue did not allege that one of ordinary skill would not have
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`recognized 50 ppm as an acceptable value for the range provided in the prior art. Id.
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`at 1345.”); Atofina v. Great Lakes Chem. Corp., 441 F.3d 991 (Fed. Cir. 2006).
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`
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`Claim 26 (“A method of treating an individual suffering from a
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`degenerative retinal disease, said method comprising administering a
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`therapeutically effective amount of astaxanthin to the individual to retard the
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`progress of the disease.”, emphasis added) has been instituted. Claim 26 covers
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`the genus of “degenerative retinal disease”. Claim 16 (“A method of treating an
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`individual suffering from age-related macular degeneration . . .”) is a species
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`within the genus of “degenerative retinal disease”. Age-related macular
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`IPR2013-00401/404
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`Atty Ref: Cyan.IPR.One  
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`Petitioner’s Request for Rehearing Page 3
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`degeneration (“ARMD”) is one of the most common types of degenerative retinal
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`disease. Claim 16 (unclear whether instituted, see Section IV below), as a species
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`within the genus of Claim 26 (clearly instituted), should be instituted. The ‘533
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`patent does not disclose any critical range or other feature relevant to the
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`administration of astaxanthin to treat ARMD, and claim 16 contains no additional
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`limitation other than specifying ARMD as a species of degenerative retinal disease.
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`The ‘533 patent “did not argue that [a] limitation was critical, or that the claimed
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`method worked differently at different points within the prior art range … . And,
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`[the ‘533 patent] did not allege that one of ordinary skill would not have
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`recognized [the dosage disclosed in the ‘533 patent] as an acceptable value for the
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`range provided in the prior art.” ClearValue, 668 F.3d 1340, 1344-45. Moreover,
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`rats do not have a macula (Exh. 1033, para. 78), so data that would distinguish
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`species Claim 16 from genus Claim 26 would be impossible to collect using the rat
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`model in the ‘533 patent.
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`
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`Claims 23-25 all depend directly or indirectly from Claims 21 or 21/22.
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`Claim 21 covers the genus of “free radical-induced injury to a central nervous
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`system”. Claims 22 to 25 are directed to species within the genus of “free radical-
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`induced injury to a central nervous system”. Claims 21 and 22 were clearly
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`instituted. Claims 23-25, like claim 22, recite specific types of “free radical-
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`induced injury to a central nervous system”, which types of injury are species
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`IPR2013-00401/404
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`Atty Ref: Cyan.IPR.One  
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`Petitioner’s Request for Rehearing Page 4
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`within the scope of Claim 21. Under the analysis prescribed by the Federal Circuit
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`in ClearValue, Osram, and Atofina, species Claims 23-25 should clearly be
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`instituted just as species Claim 22 has been instituted.
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`III. Massonet is not redundant as to claims 16-25 and 27, and is not
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`redundant as to preventive use of astaxanthin. Massonet searched for
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`astaxanthin in tissues other than the retina, reported the organs and systems in
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`which administered astaxanthin accumulated and did not accumulate, and reported
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`the preventive and the curative effects of astaxanthin in the tissues in which
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`astaxanthin accumulated. Astaxanthin is transported from the bloodstream into
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`cells of a tissue only where there are membrane transport proteins that recognize
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`and bind with xanthophylls such as astaxanthin, zeaxanthin, lutein, and
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`canthaxanthin. Ex. 1033, ¶¶24-25. Astaxanthin is accumulated only in those
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`tissues that have binding proteins that retain astaxanthin in the cells of that tissue
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`(astaxanthin is expelled from cells that lack such proteins). Ex. 1033, ¶¶24-26.
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`Massonet disclosed in Exh.1004 that administered astaxanthin accumulated in
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`specific organs, but did not accumulate in the brain, spinal cord, or central nervous
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`system (other than the retina):
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`Animals treated using the curative method:
`Astaxanthin was regularly found (with no exception) in the retina, pituitary
`glands, thyroids, suprarenals, and ovaries. Both among the males and the
`females, minuscule traces were found in the liver tissue. In the pancreas, kidney,
`spleen, lung, blood, central nervous system, no trace of pigment was detected.
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`IPR2013-00401/404
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`Atty Ref: Cyan.IPR.One  
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`Petitioner’s Request for Rehearing Page 5
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`Animals treated using the preventive method:
`The same results were obtained with regard to the eyes***, pituitary gland,
`thyroids, suprarenals and ovaries. The pigment was not found in the kidney,
`except for a positive result in a female. The identity of the pigment after
`chromatography was confirmed by the spectral features (the absorption
`spectrum with a single broadband feature, max. 490 nm in pyridine). In the
`liver, minuscule traces were found; the searches conducted on the pancreas,
`spleen, lung, central nervous system and blood were negative.
`*** The sacrificed or spontaneously dead animals showed perfectly healthy
`eyes.
`Exh. 1004, 104:29-105:8 (emphasis added).
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`As shown in the preceding excerpt, Massonet conducted experiments to test
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`both the curative (i.e., therapeutic) and the preventive effects of astaxanthin.
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`Massonet reported that astaxanthin administered to vitamin A-deficient rats
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`prevented xerophthalmia, while vitamin A-deficient rats that did not receive
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`astaxanthin contracted xerophthalmia. Prevention of retinal degeneration or other
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`retinal damage, injury, or disease arising from free-radical attack is inherent in the
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`prevention of xerophthalmia by administration of astaxanthin. Exh. 1033, ¶¶ 27,
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`45, 88-89, 105-108, and 122-123. The ‘533 patent used an experimental design
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`that only tested the preventive effects of astaxanthin (i.e., the pharmacological
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`agent was administered before insult or onset of disease), but the ‘533 patent did
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`not test for curative (i.e., therapeutic) effects of astaxanthin, which requires an
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`experimental design in which a pharmacological agent is administered after insult
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`or onset of disease.
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`In the claims construction phase of the concurrent litigation (Exh. 1037)
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`IPR2013-00401/404
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`Petitioner’s Request for Rehearing Page 6
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`between Patent Owner and Petitioner, Patent Owner has construed the claims of
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`the ‘533 patent to encompass the preventive use of astaxanthin as well as its
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`curative effects, and therefore Petitioner expects Patent Owner will almost
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`certainly attempt to construe (particularly given the broader scope of construction
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`in this proceeding) the claims in Pet. ‘401 to assert a claim scope that “treating”
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`includes administering astaxanthin to prevent insult, injury, or disease. If the
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`claim element “treating” is read to include preventive administration of astaxanthin,
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`Claims 1-27 are more obvious under § 103 over Massonet than over Grangaud and
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`should be instituted. Unlike Massonet, Tso and Lam did not search for or detect
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`the presence of astaxanthin in any tissue: in the ‘533 patent, the inventors simply
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`reported changes in rat retinal microstructure and rhodopsin levels after
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`administration of astaxanthin and therefore did not know if any astaxanthin was
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`present in the non-retinal CNS.
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`
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`As to Claims 16-27, Massonet disclosed the therapeutic (curative) and
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`preventive effects of astaxanthin on inflammatory, infective, traumatic,
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`cardiovascular, and other disease processes in the eye and in many organs and
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`systems:
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`When astaxanthin is administered (also for curative purposes) at high doses (of
`at least 50 µg), slowing down of the development of infectious processes can
`be seen in the live animal. Although colpokeratosis is determined in all cases,
`the autopsy seldom reveals genital tract suppuration phenomena; the same
`findings are made in the digestive system where the lesions are less apparent. In
`addition, the cachectic conditions are more unusual.
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`IPR2013-00401/404
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`Atty Ref: Cyan.IPR.One  
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`Petitioner’s Request for Rehearing Page 7
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`In the experiments of preventive nature the results confirm that the
`administration of strong doses delays the occurrence of lesions: in the females
`treated with doses of 50 µg per day, the growth of which went almost normally,
`neck abscesses were found only by the 5th month of treatment; colpokeratosis
`is detected precociously, and vaginal infections and vesical calculus can be
`seen after the 6th month of deficiency (with treatment). In all males treated with
`50 µg astaxanthin for preventive purposes, infectious processes could not be
`found until the 7th month, and the survival of the animals was the same for all
`subjects (longer than the 8th or 9th month). However, the genital system was
`affected and testicular atrophy was found in most of the cases.
` Exh. 1004, 116:34-117:4 (emphasis added; footnote omitted).
`
`
`* * *
`
`With regard to the xerophthalmia signs, they start microscopically by a
`narrowing of the palpebral fissure; while exophthalmia is regularly observed in
`the normal Wistar rat, in the deficient rat the bulbus oculi moves within the
`orbit. Soon, both eyelid edema and cornea drying and opacification occur;
`opposite to this sign, secretions increase and result in hemorrhage**. Then
`considerably large corneal ulcers appear and corneal perforations are not
`unusual.
` We found that hemorrhagic exudates caused by an accidental trauma
`before day 20 of deficiency did not accelerate
`the development of
`xerophthalmia. The observations by Chaix (20) and Courbières (29) have led to
`similar remarks.
`Exh. 1004, 44:29-34 (emphasis added).
`
`There was a well-known association between cachexia and ischemia,
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`cachexia and stroke, and ischemia/stroke/infarction and free-radicals before the
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`Critical Date. Ex. 1001, 3:14-31 (“The damage to the retinal ganglion cells has
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`been attributed to ischemia, and subsequent reperfusion during which free radicals
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`are generated. During reperfusion, the reoxygenation of tissue after an ischemic
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`insult results in a relatively high concentration of oxygen flowing through the
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`IPR2013-00401/404
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`Petitioner’s Request for Rehearing Page 8
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`effected tissue, which contributes to free radical formation. Ischemic insult and
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`reperfusion accompanied by free radical generation also is a major contributor to
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`central nervous system damage, such as damage caused by a stroke.”). Ex. 1020,
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`27:2-6 (“Under pathological conditions they [reactive oxygens] may induce
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`peroxidation of polyunsaturated fatty acids in biological membranes leading to
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`functional impairment. Such oxygen toxicity has been postulated to underlie the
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`pathogenesis of several diseases such as postischemic reflow injury, retinopathy
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`in premature infants, shock[,] and cerebral infarction.” (footnotes omitted,
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`emphasis added)). Pre-Critical Date publications about the well-known association
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`of cachexia and ischemia, and cachexia and stroke, are available upon request.
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`In the ‘533 patent, the only cause of damage, injury, disease, ischemia,
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`degeneration, inflammation, condition of the neurons, or other insult or condition
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`is the action of free-radicals, and the only treatment in the ‘533 patent is
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`administering astaxanthin. Massonet provides, in more detail and scope than
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`Grangaud, grounds that are highly relevant, not redundant, and a reasonable basis
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`for concluding that Claims 1-27 are unpatentable, especially if “treating” is
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`construed by Patent Owner, as fully expected, to include preventive use of
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`astaxanthin.
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`IV. Clarification of the Claims Instituted in the Decision. Petitioner
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`seeks clarification of an internal inconsistency in the Decision about which claims
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`IPR2013-00401/404
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`Atty Ref: Cyan.IPR.One  
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`Petitioner’s Request for Rehearing Page 9
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`were instituted. The Decision on pages 19-20 of Pet. ‘401states, “We decline to
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`institute on the following grounds as they are redundant to the above-mentioned
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`grounds for which the Petition to institute inter partes review has already been
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`granted:
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`Claims 1, 3, 8-15, 22, and 26 as anticipated under § 102 by Massonet;
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`Claims 1-15, 21-22, and 26 as obvious under § 103 over the combination of
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`Massonet and Dowling;
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`Claims 1-27 as obvious under § 103 over Grangaud; and
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`Claims 1-27 as obvious under § 103 over Massonet.”
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`(Dec. at 19-20 in Pet. ‘401; Dec. at 20 in Pet. ‘404; emphasis added). However,
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`the two “claims 1-27” grounds listed above are not reflected in the “Order” section
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`of the Decision.
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`Petitioner therefore seeks modification of the Decision to recite that the
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`Petition is “granted as to Claims 1-27 of the ‘533 patent and an inter partes review
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`is instituted for the following grounds:
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` (i) Claims 1, 3, 8-15, 21, 22, and 26 as anticipated under § 102(b) by
`
`Grangaud;
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`(ii) Claims 1-15, 21, 22, and 26 as obvious under § 103(a) over
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`Grangaud and Dowling;
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`(iii) Claims 1-27 as obvious under § 103 over Grangaud; and
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`IPR2013-00401/404
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`Atty Ref: Cyan.IPR.One  
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`Petitioner’s Request for Rehearing Page 10
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`(iv) Claims 1-27 as obvious under § 103 over Massonet.”
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`Maintaining Massonet as grounds for invalidation of Claims 1-27 is
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`important because of the critical differences between Grangaud and Massonet, as
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`presented in Section III above. Astaxanthin’s free-radical suppression properties
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`were well-known as of the Critical Date. Exs. 1020, 1022, and 1031. The
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`“discovery” on which Claims 1-27 are allegedly based is that astaxanthin is
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`transported into the retina, but Massonet was first (i) to identify the tissues in
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`which administered astaxanthin accumulated, and (ii) to disclose, decades before
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`the ‘533 patent, the preventive and therapeutic administration of astaxanthin to
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`treat free-radical induced damage, injury, and disease.2
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`                                                                 
`2 Once in the retina, astaxanthin has at least two inherent modes of action
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`relevant to the ‘533 patent: 1) action as a strong suppressor of free-radicals, and 2)
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`conversion into vitamin A. Ex. 1033, ¶¶23-26. Exs. 1008, 1010, and 1012.
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`Conversion of astaxanthin into vitamin A provides a rhodopsin precursor;
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`rhodopsin is essential for visual transduction and improving retinal neuronal
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`condition and vision after insult. Ex. 1025. All retinal damage, injury, or disease
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`disclosed in the ‘533 patent arises solely from the action of free-radicals (Ex. 1001,
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`11:52-56 and 12:37-43) and the only treatment in the ‘533 patent is administering
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`astaxanthin in a therapeutically effective amount. Ex. 1001, Claims 1-27.
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` 
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`IPR2013-00401/404
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`Atty Ref: Cyan.IPR.One  
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`

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`Petitioner’s Request for Rehearing Page 11
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`Massonet’s disclosure is not technically or substantively redundant with that
`
`of Grangaud: Massonet is far broader than Grangaud and reports where
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`astaxanthin accumulated in the body, where it did not accumulate, and the
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`administration of astaxanthin to prevent and to treat injury and disease in various
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`body organs (not just the eye). Thus, Massonet is more applicable to claims such
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`as Claims 16-20, 23-25, and 27. More broadly, Claims 1-27 are obvious under §
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`103 over Massonet for the irrefutable reason that if astaxanthin is present in a cell
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`(e.g, a neuron), astaxanthin suppresses free-radicals in that cell and thereby
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`prevents, or therapeutically treats, by suppression of free-radicals, the damage,
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`injury, disease, or condition caused by free-radicals. Ex. 1033, ¶¶23-26 and ¶123.
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`
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`V. Conclusion.
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`For the foregoing reasons, Petitioner respectfully requests clarification of the
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`Decision to state that the Petition is “granted as to Claims 1-27 of the ‘533 patent
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`and an inter partes review is instituted for the following grounds:
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` (i) Claims 1, 3, 8-15, 21, 22, and 26 as anticipated under § 102(b) by
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`Grangaud;
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`(ii) Claims 1-15, 21, 22, and 26 as obvious under § 103(a) over
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`Grangaud and Dowling;
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`(iii) Claims 1-27 as obvious under § 103 over Grangaud; and
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`IPR2013-00401/404
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`Petitioner’s Request for Rehearing Page 12
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`(iv) Claims 1-27 as obvious under § 103 over Massonet.”
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`In the alternative, Petitioner respectfully requests modification of the
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`Decision to state that the Petition is “granted as to Claims 1-27 of the ‘533 patent
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`and an inter partes review is instituted for the following grounds:
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` (i) Claims 1, 3, 8-15, 21, 22, and 26 as anticipated under § 102(b) by
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`Grangaud;
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`(ii) Claims 1-15, 21, 22, and 26 as obvious under § 103(a) over
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`Grangaud and Dowling; and
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`(iii) Claims 1-27 as obvious under § 103 over Massonet.”
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`
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`
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`
`
`By:
`
`
` /Joseph A. Rhoa/
`Reg. No. 37,515
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`IPR2013-00401/404
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`Atty Ref: Cyan.IPR.One  
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`

`
`Ptnr’s Req. for Rehearing. Consolidated Cases IPR2013-00401 & -00404
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`
`
`CERTIFICATE OF SERVICE
`
`I hereby certify service of the foregoing Petitioner’s Request for Rehearing
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`to the following lead and back-up counsel for patent owner on January 2, 2014 via
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`email (pursuant to agreement between the parties):
`
`Mark D. Schuman
`Iain A. McIntyre
`CARLSON CASPERS
`225 South Sixth Street, Suite 4200
`Minneapolis, Minnesota 55402
`(mschuman@carlsoncaspers.com)
`(imcintyre@carlsoncaspers.com)
`
`
`
`By: /Joseph A. Rhoa/
`Bobby Foster, for
`Joseph A. Rhoa
`Reg. No. 37,515