Office Actions and Responses (including Declarations) in App. No. 08/330,194
`
`CYAN EXHIBIT 1006
`
`

`

`! SER1AL HUMIER 1
`
`FIUNG DATE
`
`~ 1 Addrns: CXlo\IIMISSIONER OF PATVIT'S AND TRADEMAAKS
`We9hington, c.e. 2œ31
`l "nORNE'!' DOCKET NO.
`ARST NAMED INVEHTOR
`
`08/330,194
`
`10/27/94
`
`TSO
`
`15M1 /0130
`
`JAMES J NAPOLI
`MARSHALL O'TOOLE GBRSTBIN MURRAY & BORUN
`6300 SEARS TOWER
`233 SOUTH WACKER DRIVE
`CHICAGO IL 60606-6402
`
`this r& a oommunleation lrom the examiner ln ~8 ot ywr appIleation.
`COMMISSIONER OF PATENTS AND TRADEMARKS
`
`H
`
`2761131748
`EXAMINER
`WEBBER,P
`ART UNIT
`
`PAPER HUMBER
`
`15 02
`DATE MAILED:
`
`01/30/95
`
`0 This actlol'1ls maoe 11na!.
`~ this app!lcatlot'l has been examil'llld ~ Responslve \0 communication flled on t?/-()3- F..,) -
`A shortened ! tatutory perlod!or respoose 10 mis action Is sella ,xplre Â
`~Irom!he date 01 tNs lenllr.
`monlh(s),
`Failure ta r8$pOI'ICI wttNl'I the peflod!or response will ÇIl\ISe the appIieallon \0 become abandoned. 35 U,S.C. 133
`
`Plr1 1 niE FOLLOWlNG ATTACHMENT(S) ARE PART OF THIS ACTION:
`
`•• ~ Notice 01 Aefer.noces CIl&d by Examiner. PTQ-.892.
`Notice 01 Art Cllad by AppIIcant. PTO·\449.
`3.
`In1om1atlon on How to EMeeI C/fawing Chal1Q8$, PTQ-1474_
`5.
`
`:L 0 Notk:e of Oraflsman'. Pat&l1t Drawlng Rev\eW, PTO-948.
`4. 0 Notice DI Inlonnal Palenl Application, PTo. 152.
`..0 _ _ _______ .
`
`Part Il SUMMARY OF ACTION
`
`1. J&l ClallTl$' ________ -'/'-_~z.."'_~?'_ _ _ ___________ pendlng ln the appIk:adon.
`
`01 the above. cI.aIms _ ______________________ are wlthelrawn lrom consideration.
`2.0 Claims, _______________________________ haYe been eanœlttd.
`3. 0 C~lms ___________________________ _ area/lowed.
`4 • .Di3 Clalm' ________ ~/'_ _
`_'Z.""_'F'__ ___________ l(ereJeded.
`5. 0 Clalms ________________________ are oI;Jjeç1ed ID.
`6. 0 C~lms' ____________ _ ___ _____ __ l(e subjed ID resbictlon or electlon requlrement.
`
`7.~ ThIs application hu been Wed with Informai c!rawing.s urder37 C.F.R. 1.85 whIcI'l are iICCII$ltabla lor examln.adon purposes.
`8.0 Formal drawlngs are required in responst ID \hIs 0tI1ce action.
`9.0 The correcled or subs~lUt8 drawlngs hav1I bien reœived 00
`• Under37 C.F.R. 1.84 these drawings
`1(1 O aceeptaOte; 0 Il0l aeeeplablt (see ex~an.ation or Notlee o! Oraltsman's Palenl Orawing Revlew, PT().948).
`
`10. 0 The proposed addI1IooaI or &ubslilute $IlIet(s) DI drawlngs.llied on ______ . ha. (have) bien Cl approved by the
`examiner; Cl disapPrOVlId by the uamlr.ar (SIe 8xplanation).
`Il. 0 The proposed dlawing COlTe<:Uo~. filed ______ ~, has betln Cl approved; Cl d1sawovecl (ste e)(pianation).
`12. 0 AeknowI&dgemenl ls made DI the daim lor prIortty under 35 U.S.C. 119. The œrtJl1ecI COP)' has 0 b&an recelved [J IlOt been raœ!ved
`Cl bien liled ln parenl appIlca~on. seriai 110.
`; lIIed on _ _ _____ _
`13. 0 Sloce thls appllca~on apppears to bflin condition lor a1lowance excepllor tonnaJ malt" •• prosacu11on as 10 the menlsl. closed ln
`aocordanr::e wIIh the practlœ undllr Ex parte Ouayle, 1935 C.D. Il; 453 a.G. 213.
`
`,4.DOIher
`
`~"" °y3J'O .. l'Y
`),.UJ
`
`PTOL-3:le (Re\!. 2Ir.I)
`
`EXAMINER'S ACTION
`
`

`

`SeriaI No.
`Art Unit
`
`08 / 330, 194
`1502
`
`- 2-
`
`Claims 1-28 are pending in this application and considered
`belov.
`
`iolloving 1a a quotation oÏ the firet paragraph of 35
`The
`U •. S. C.
`112:
`The specification ahall contain B vr1tten description of the
`invention, and of the manner and process of mak1ng Bnd us1ng
`it, 1n auch
`:full, clear,
`concise, end exact terme as t.e
`enable any persan sk111ed
`in the art ta vhich 1t perta1ns,
`or vith vh1ch it 1e most nearly connected, ta make and use
`the seme and ahall set :forth the best mode contemplated by
`the inventor of cerrying out his invention.
`
`The specification 1e objected
`
`ta under 35 U.S . C.
`
`112,
`
`tiret paregraph,
`
`as
`
`fail1ng
`
`ta prov1de
`
`an adequate vr1tten
`
`description of the invention end failing ta adequatel y
`
`teach hov
`
`ta make and / or
`
`use the
`
`invention, i.e. ~ai~ing to provide an
`
`1
`
`enabling disclosure.
`
`This
`
`objection
`
`ia
`
`based upon
`
`inadequate disclosure,
`
`regarding the use o~ the applicants' active agent, astaxanthin,
`
`~or the treatment a~ in jury to the brain and / or spinal cord (such
`
`BS
`
`stroke,
`
`traumatic spinal
`
`cord
`
`in jur y
`
`and degenerative
`
`d1sease{s) o~ the central nervous
`
`system,
`
`as vell ae
`
`the
`
`ame11orat1on of neuronal damage.
`
`Note that the prior art recited on pages 10-12 1e directed
`
`to eye d1eeases and
`
`injuries, per ~ (note page 10,
`
`lines 10-12
`
`o~ the present specizication, vith regard ta
`
`the disclosed and
`
`claimed method o~ treatment ) .
`
`Further,
`
`the recitation o~
`
`such
`
`terminal ogy
`
`1s nat
`
`necessarily
`
`a basis
`
`for claiming same.
`
`The specification,
`
`there~ore, fails
`
`to enable admin1str~tion of astaxanthin
`
`for
`
`

`

`Serial Na. 08 / 330,194
`Art Unit
`1502
`
`- 3 -
`
`response being e11cited and
`
`shovn to be due ta
`
`the ef~ects a~
`
`astaxanthin,
`
`per se .
`
`The body of art vhich
`
`ia additionally
`
`cited, on pages 10-11 af
`
`the specification, ~aile ta euggest
`
`seme •
`
`Although the applicanta Basert
`
`thet such treatment or
`
`• • • 1ioration iB possible because --- The eye ia an extension o~
`
`the brain, and therefore a part of the central nervous system ---
`
`(page 1 of the present specification), contemporary knovledge in
`
`thia art area cautions against extrapolating
`
`to conclusions
`
`regerding ef~icacy
`
`or eradication
`
`in
`
`the
`
`CNS based upon
`
`ther.peutic ophthalmic succese,
`
`absent
`
`a clear and probative
`
`correlation betveen same.
`
`Claima 14-16,
`
`22-26 and 28 are rejected under 35 U.S.C.
`
`112 ,
`
`firet paragraph,
`
`for
`
`the
`
`reBsons set forth
`
`in
`
`the
`
`abjection ta the specification.
`
`Claims 14-16, 22-26 and 28 are rejected under 35 U.S.C.
`
`112, firet paragraph, BS the disclosure is enabling only for
`
`claims
`
`limited
`
`ta methoda taught by the present speci~icBtion.
`
`See M.P . E. P. 706.03(n) and 706.03(z ).
`
`This
`
`rejection
`
`ia baaed
`
`upon
`
`the
`
`leck o~ diaclosure
`
`regarding the use of astaxanthin ta treat Any and all injuries ta
`
`the brain (e.g. stroke, etc . l, any and all inju r ies to the spinal
`
`cord or Any and all degenerative di s ease(s ) of the CNS, vithout
`
`li. itation and all neuronal damage, vithout limitation.
`
`

`

`Serial ND.
`Art Unit
`
`08/330, 194
`1502
`
`-4-
`
`The applicants must
`
`show
`
`support for
`
`the breadth of the
`
`above-stated methods,
`
`in that
`
`such ia presented in the claimB
`
`vithout any readily appreciable manner of limitation.
`
`Claims 1-28 are rejected under 35 U. S.C .
`
`112,
`
`second
`
`paragraph, as being indefinite for failing to particularly point
`
`out and dist1nctly clBim
`
`the subject matter vhich applicant
`
`regards as the invention .
`
`The
`
`claims
`
`vhich
`
`incorporate
`
`the
`
`terminology,
`
`tnerapeutically-effective
`
`amount
`
`vith
`
`regard
`
`to
`
`the
`
`administration of astaxanthin (in vhich
`
`the active
`
`ingredient
`
`employed
`
`~or
`
`the
`
`pur poses of
`
`treating
`
`ameliorating or
`
`beneficiating damage or in jury to the eye, brain or spinal cord,
`
`including stroke, traumatic in jury and/or degenerative disease(s)
`
`,
`f
`
`are
`
`indefinite since 1) the claims fail
`
`to set
`
`forth aliment
`
`related dosage reference points and 2) the specification fa ils to
`
`set forth any
`
`information as
`
`to hoy dosages may differ
`
`in
`
`ohtaining either of the aforestated effects.
`
`See Ex parte
`
`Balzarini, 21 USPQ 2d 1893.
`
`The terminology,
`
`--- beneficiating
`
`rend ers
`
`the claims
`
`vhich incorporate same indefinite in that such
`
`language fails to
`
`place any clear limitation upon the intended effect Dr result of
`
`the claimed method, based upon astaxanthin administration. For
`
`exsmple, hoy
`
`ia the vision of en
`
`individuel wbeneficiated R
`
`by
`
`,
`
`Bsid administration? Appropriate clarification is advised.
`
`

`

`Serial No.
`Art Unit
`
`08/330, 194
`1502
`
`"
`
`-5-
`
`The
`
`terminology,
`
`reducing
`
`free-radicBl
`
`induced eye
`
`injury
`
`la lndefinite without a vell defined standard "iram
`
`vhich ta meeeure.
`
`One of ord1nary skill in
`
`this art aree could
`
`nct determlne what
`
`the minimum value would be and consequently
`
`which circumstances are vith!n the clalms and wh1ch clearly fall
`
`outside the bounds of the claims.
`
`follow1ng la a quotation of 35
`The
`the basls for aIl obviousness rejections
`action:
`
`U. 5. C.
`103 wh1ch
`set forth in th1s
`
`forme
`O:fiice
`
`invention 1e nct
`A patent may nct be obtained though the
`1dentically disclosed or descr1hed as set forth in section
`102 of this title,
`if the differences betveen the subject
`matter sought ta he patented and the prior art are su ch that
`the subject matter as e vhole vould have been obvious at the
`time
`the invention vas made
`to a persan heving ordinary
`skill
`in
`the art
`to vhich said subject matter pertains.
`Patentability shall not be negatived by the manner
`in vhich
`the invention vas made.
`
`Subject matter developed by another perscn, vhich quali~ies
`as prior art only under subsection (~) or (9) o~ section 102
`o~ this title, shall not preclude patentability under this
`section vhere
`the subject matter and
`the cleimed invention
`vere, at the time the invention was made, ovned by
`the same
`persan or subject to an obligation oÏ assignment to the same
`person.
`
`In
`inventors.
`joint
`This application currently names
`103,
`considering patentebility of the claims under 35 U.S.C.
`the examiner presumes that
`the subject matter of the various
`claims vas
`commonly ovned et the
`time any inventions covered
`therein vere made absent any evidence te the contrary. Applicant
`ia advised of the obligation under 37 C.F.R ,
`1.56 to point out
`the
`inventer and invention dates o~ each claim that vas not
`commonly ovned at the time
`a later invention vas made in order
`for the examiner
`to consider the applicability oÏ potential 35
`U. S. C.
`102 ( f ) or (g) prior art under 35 U. S. C.
`103.
`
`

`

`Serial No.
`Art Unit
`
`08 / 330,194
`1502
`
`-6-
`
`,
`f
`~
`!
`
`Claims 1-24 and 27 are
`
`rejected under 35 U. S . C.
`
`103 as
`
`be1ng unpatentable over Getierrez
`
`(EP 467,795)
`
`and Li et al.
`
`(Curr. Eye Res, Vol 10(2), 1991,
`
`pages 133-144) in viey of K1aui
`
`et a1.
`
`( US pat. #3,920,834) .
`
`Gutierrez teaches that it 1s vell knovn to use beta-cerotene
`
`(i.e. a partiel structural homologue of Vitamin A,
`
`being non-
`
`oxidized or slight1y oxidized) or astexanthin (i.e. a structural
`
`homologue of Vitamin A, being oxid1zed in
`
`the form of a ketone)
`
`to obtain protective anti-free radical activity, beneïicial
`
`inhibition of
`
`the melanin formation mechanism
`
`and / or beneficial
`
`melenoblaatic function
`
`for cella in compositions vhich treat or
`
`Buppreas the adverse effecte of solar radiation.
`
`Li et al. disc10ee that it is knovn in thie art area that
`
`beta-carotene
`
`a knovn oxygen radical scavenger) ia effective in
`
`ameliorating photic retinel
`
`in jury (i.e. lipid peroxidation in
`
`retinel photic in jury rnediated by oxygen free radicale).
`
`See
`
`page 141, colurnn 2, the first full paragraph. Note
`
`that the use
`
`af
`
`intraperitoneal administration
`
`of
`
`such
`
`oxygen
`
`radical
`
`scavengere, for the treatment and suppression of retinel in jury,
`
`is conventional on this art erea. See the abstrect, for exemple.
`
`It ie cleer trom the Li et al. disclosure that cerotenoid
`
`sCBvengerCe) are suitable active-agents
`
`for methods su ch as that
`
`

`

`!
`i
`
`r
`
`SeriaI No. 08/330,194
`Art Unit
`1502
`
`-7-
`
`cle1med, as ev1denced by the use oÏ beta-carotene.
`
`It la Ïurther
`
`evident ÎTom
`
`the Gutierrez disclosure that bath astaxanthin Bnd
`
`bete-carotene ere equally suitable for the present purpose, i.e.
`
`use in the treatment or suppression of light induced anomalies or
`
`injuries. Henee, the singuleT selection and usege of aetaxanth1n
`
`yould naturelly folloy
`
`irem
`
`the Bforesteted
`
`teach1ngs of
`
`the
`
`usage of an oxygen radical sCBvenger selected
`
`irem either beta-
`
`carotene or astexanth1n
`
`in B method of treating Dr
`
`suppressing
`
`retinel 1njury
`
`ta ob tain
`
`the benef1c1al properties
`
`intended by
`
`the app11cants, i.e. protect1ve anti-free radical Bct1v1ty .
`
`Therefore, et
`
`the
`
`time
`
`the
`
`invention
`
`vas made,
`
`the
`
`re~erences as eombined above would have
`
`rendered the elaimed
`
`methods o~ treating retinal
`
`injuries prima facie obvious sinee
`
`one o~ ordinary skill in this art Bree vould have been motivated
`
`to use
`
`the knovn method, disclosed by Li et al.,
`
`and ta select
`
`the Guttierrez active-agent for
`
`its knovn suitability, per the
`
`further discloBure of Klaui et al. shoving the conventionality of
`
`orally or
`
`topically sdministering either astaxanthin or beta-
`
`carotene, in combinat ion vith another carotenoid (canthaxanthin),
`
`in total carotenoid dosages betveen 5-100 mg for the purpose of
`
`reducing or suppressing photosensitivity
`
`(Bee '920- st column l,
`
`lines 21,48,53,55 and 60 and column 2, line 11).
`
`

`

`SeriaI No.
`Art Uni t
`
`08 / 330, 194
`1502
`
`-8-
`
`' Claims 25-26 and 28 are
`
`rejected under 35 U.S.C .
`
`103 as
`
`being unpatentable over Gutierrez and Li et al. in viev 01 Klaui
`
`et al. as applied
`
`to claims 1-24 and 27 above,
`
`and 1urther in
`
`viev 01 Borg (US pat. #5,243,094).
`
`Guttierrez, Li et al.
`
`and Klaui et al. do not speciz1cally
`
`disclose
`
`the use of the applicants' spec1zic carotenoid, nor the
`
`treatment oz stroke, spinal cord
`
`in jury or degeneretive CN5
`
`diaeese ( a), per !!!..
`
`Such disclosure ia limited to
`
`treetment of
`
`the eye.
`
`Hovever, beceuae Borg teeches thet cerotenoids, i.e.
`
`Vitemin A homologs
`
`(
`
`see above),
`
`provide
`
`the
`
`benefit of
`
`neuroprotective
`
`and neurogenerative
`
`ef:fect
`
`in
`
`injuries
`
`including attenuation of ischemia e:ffects, promotion o:f neuronal
`
`survivel and :facilitation oz
`
`the repair of traumBtic lesions
`
`to
`
`the CHS
`
`and PHS), it vould have been further obvious
`
`to one of
`
`ordinary skill in the art, at the time the invention vas made, to
`
`expect success
`
`in treating or suppressing such MS
`
`injuries via
`
`the parenteral or oral administration o:f Vitamin A homologs,
`
`including aataxanthin as claimed (note dosages betveen 0.5-500 mg
`
`at column 14,
`
`lines 55-65). See column 11, lines 16-38; columns
`
`13-14; column 1 5,
`
`lines 1-8; the Table bridging columns 19-20:
`
`column 21, line 56;
`
`column 25, lines 46-69; column 27, lines 48-
`
`69 and column 26, lines 14-19.
`
`

`

`Serial No .
`A.rt Unit
`
`08 /3 30,194
`1502
`
`-9-
`
`Johnson et al.
`
`( ~. En v iron. Micro.,
`
`3S ( 6 ) , 1978,
`
`pp .
`
`1155-1159} la clted of lnterest.
`
`this communication
`concernlng
`inqulry
`Any
`com~unications ~rom the e x aminer should be directed
`Web ber vhose telephone number ia (703) 308-6016.
`
`or earlier
`to Pamela S.
`
`telephone are
`by
`the examiner
`reach
`to
`· I~ at.tempts
`unauccess~ul, the examiner's supervisor, Thurman K. Page, can be
`reached on (703) 308-2927 . The ~ax phone number
`ior this art
`unit ia ( 703 ) 305-5408 .
`
`Any inquiry a~ a genersl nature or relating ta the statue ai
`this application shauld be directed
`ta the Group receptianiat
`vhose telephone number ia (703) 308-2351.
`
`l
`i
`
`p.s.webber~Â~
`Jan~ary 1a~1995
`
`

`

`IN THE UNITED STATES PATENT
`AND TRADEMARI: OPPICE
`
`Applicante:
`
`~ O.M. TSO ST AL .
`
`SeriaI No. 08/330,194
`
`Filed: Oc tober 27, 1994
`
`For: MBTHOD OP R&'l'ARDl:HG AND
`AMBLl:ORA'l'ING CENTRAL NlRVOOS
`SYSTEM. AND Bn: DAMAGE
`
`Attorney Docket No. 27611/31748
`
`Group Art Unit: 1502
`
`Examiner: Pamela S. Webber
`
`l hereby certify that this
`paper is baing depoaited with
`the United States Postal
`Service with sufficient
`postage AS first class mail in
`an envelope addressed to:
`Assistant Commiesioner for
`Patents, Washington, D.C.
`20231 on this dat e:
`May u... 199 5
`
`~
`Q~~~~~JUN 16 1995
`rrrc'l"ûll
`LUL/V)
`
`Jamee J. Napoli
`Regi.'r."on No. 3
`Attorney for Appli
`
`i
`
`• , .
`1
`1 , ,
`
`AMENDMENT • A ·
`
`Assistant Commissioner for Patents
`washington, D. C.
`20231
`
`Sir:
`
`In response to the Office Action of January 30,
`
`1995, please amend
`
`the above-identified application as
`
`follows. Reconsideration and allowanc e of the applica tion are
`
`respectfully requested.
`
`IN THE CLAIMS :
`
`Amend claims
`
`/ f / / /
`l, 4, 8 - 13, and 15 a s follows:
`
`1.
`
`(Amended) A method./of [beneficiatingl arnelio (cid:173)
`
`rating the vision of an
`
`sufferi ng
`
`from
`
`[eye]
`
`retinal damage or [eyel
`
`diaease, said method compris-
`
`ing administering a
`
`effective amount of
`
`astaxanthin to, ·the irld:l vltlu'l.l
`
`

`

`/ ~ ,
`
`4.
`
`(Amended )
`
`The method of claim 1 wherein the
`
`astaxanthin le admin!stered topically directly to the eye.
`
`8.
`
`(Amended )
`
`The method of claim l "'herein the
`
`[eye] retinal damage comprises [a) free radical-induced (eye]
`
`retinal damage .
`
`9.
`
`(Arnended l
`
`The method of claim l ""berein the
`
`[eye1 retinal damage comprises [a) light - induced [eyel retinal
`
`damage .
`
`10 .
`
`(Amended ) The method of claim 1 wherein t he
`
`[eye )
`
`retinal damage comprises pho t o receptor cel i
`
`(eye]
`
`recinal damage or damage to neurons of inner retinal layera.
`
`11.
`
`(Amended ) The metbod or c laim 1 wherein the
`
`[eye] retinal damage comprises ganglio n cell (eye] ret i nal
`
`damage.
`
`12.
`
`(Amendedl The method of claim l ",herein the
`
`(eye] retinal damage comprises age-related macular degenera-
`
`tion.
`
`13.
`
`(Amended l A me
`
`cd o f
`
`(r edu c i ng l pro tect i ng
`
`neurone
`
`from
`
`free
`
`nduced
`
`(eye)
`
`r et i nal
`
`i n j ury
`
`comprising administering
`
`rapeutically effect.ive arnount of
`
`- 2 -
`
`(/ (
`
`

`

`15.
`
`(Amended) The method of claim 14 wherein the
`
`neuronal damage comprises photic
`
`in jury
`
`to
`
`the retina~
`
`ischemic insult to the retina . or intraocular pressure·related
`
`insult to the retina.
`
`/
`Cancel claim 16~i~out/preju~e.
`
`Amend claims
`
`20, 2j, 27, and 28 as follows:
`
`20.
`
`(Amended ) A meth'gli"of treating an inflammatory
`
`disease of
`
`[the eyel
`
`comprising administering a
`
`of astaxanthin to an individ·
`therapeutically effectl.vE~f'1~19
`
`ua!.
`
`1fJ.-.' 13 .
`
`(Amended) The method of claim
`
`wherein the
`
`central nervous system comprises a brain, a spinal cord and
`
`(an eye] a retina.
`
`27. {Amended l A method
`
`retarding a degenerative
`
`[eyel retinal disease, said m"t 'm,' comprising administering a
`
`therapeutically effective anlmlnitof astaxanthin to an individ-
`
`ual .
`
`28 .
`
`(Amended ) ~'~~~hod of retarding a degenerative
`
`central nervous system dl~l,al,eof a brain or spinal cord, said
`
`method comprising
`
`a therapeutically effective
`
`amount of
`
`an individual.
`
`- 3 -
`
`

`

`IN THE UNITED STATES PATENT
`AND TRADEMAltX OPPICE
`
`, ,
`
`~
`.~t. J[' 1995
`',~LE!Vm
`
`Applicanta:
`
`MAJU{ O, M, TSO ET AL ,
`
`Serial No . 08/330,19 4
`
`Filed: Octobe r 27, 1994
`
`For: MaTHOD OP RBTARDING AND
`AME~I ORATING CENTRAL NBRVOOS
`SYSTEM AND BYE DAMAGE
`
`Attorney Docket No. 27611/31748
`
`Group Art Unit:
`
`1502
`
`Examiner : Pamela S. Webber
`
`1 hl!fe by eertily th"t thl$
`correwondenc:e IS be'rc dePOSlted
`lOI .th the UMO)d S tJIU Pos""
`Serv.ce as Il,s' C:IIU nI ... 11 ln
`an "",elo:;e ~~J,"\:wd 10:
`Cor.lm,~ ,. on~r 01 ".l.~\lls and
`Tr3dl!nlar~s. W,',~"r:g:CI1 , D.C,
`20::31
`on May 26
`B;a~~,
`James J . Napoli
`Pr n'e-d Name 01 PerWHl S,&n"'l
`Reg. No. 32,361
`
`l~
`
`DECLARATION OP MARX O.M. TSO
`ONDER 37 C,P,R. 51,132
`
`Assistant Commissioner for Patents
`Wash ington , D.C.
`20231
`
`Sir :
`
`NOW COMES Mark O.M. Tao, Declarant herein, and
`
`states as follows:
`
`1.
`
`l am a co-inventor of the invention disclosed
`
`and claimed in the above-identified patent application,
`
`2 .
`
`l presently hold
`
`the
`
`following positions:
`
`Professor and Chairman, Department of Ophthalmology and Visual
`
`Sciences, Chinese University of Hong Kong, Hong Kong (1994 to
`
`1995 ) ; Professor of Ophthalmology, Lions of Illinois Eye
`
`Reeearch Institute, University of Illinois at Chicago, College
`
`of Medicine, Chicago, Illinois (1976-present); Director of the
`
`Georgiana Theobald Ophthalmic pathology Laboratory, Univ ersity
`
`

`

`of Illinois Hospital Eye & Ear Infirmary, university of
`
`Illinois at Chicago, College of Medicine, Chicago, Illinois
`
`(1976-present ) i and Director of the Macula Clinic, university
`
`of Illinois Hospital Eye & Ear Infirmary, university of
`
`Illinois at Chicago, College of Medicine, Chicago, Illinois
`
`(1976-present ) .
`
`3.
`
`My previous positions were : Staff Ophthalmol(cid:173)
`
`ogist, Department of Ophthalmic Pathology, Armed Forces
`
`Institute of Pathology, washington, D.C. (1969-1971); Assis(cid:173)
`
`tant Clinical Professor of Ophthalmology, The George washing(cid:173)
`
`ton University Medical Center, Washington, D.C.
`
`(1969-1971);
`
`Assistant Research Professor of Ophthalmology, The George
`
`Washington University Medical Center, Washington, D.C. (1971 -
`
`1972); Research Associate, Ophthalmic pathology Branch, Armed
`
`Forces Institute of Pathology, washington, D.C.
`
`(1971-1976 ) ;
`
`Visiting Staff of Retina Clinics of George Washington Univer(cid:173)
`
`sity Hospital, D. C. General Hospital & Freedrnen' s Hospital
`
`(1972-1976 ) ; and Associate Research Professor of Ophthalmolo (cid:173)
`
`gy, The George Washington University Medical School
`
`(1973-
`
`1976) .
`
`4.
`
`l received an M.D. from the university of Hong
`
`Kong in 1961 and earned other degrees.
`
`l am licensed to
`
`practice medicine in four states and the District of Columbia.
`
`A complete summary of my education and training, including
`
`degrees earned and board certifications are listed in my
`
`curriculum vitae submitted concurrently with this declaration.
`
`5.
`
`l have practiced medicine, conducted research,
`
`published over 200 articles, presented lectures at numerous
`
`2 -
`
`

`

`conferences, served as a member on numerous editorial boards
`
`and scientific or medical advisory boards, and have a member-
`
`ship in numerous societies in the fields of ophthalmology,
`
`vision, and pathology.
`
`1 have been a special lecturer or
`
`visiting professor thirty-nine times since 1972.
`
`6.
`
`One of my main fields of research, as reflected
`
`in my publications , is the retina, including , for example , the
`
`retinal pigment epithelium, retinoblastoma, photic injury to
`
`the retina, the blood-brain barrier at the optic nerve head,
`
`ischemic retinopathy, and age-related macular degeneration.
`
`A list of my publications more fully reflecting my fields of
`
`research i5 recited in the attached curriculum vitae.
`
`7.
`
`1 have read and understand the Office Action
`
`dated January 3D, 1995, which was issued in connection with
`
`U.S. Patent Application SeriaI No. 08/330,194.
`
`1 also have
`
`reviewed and understand the following patents and publications
`
`cited by the examiner in U. S . S . N. 08/330,194:
`
`Gutierrez EP 0 467 795 (EP '795);
`
`Z . Li et al ., ~Desferrioxamine ameliorates retinal
`photic
`in jury
`in albino
`rats, ft Current Bye
`Research, 20(2), 1991, pp. 133-144,
`(Li et al .
`publication) ;
`
`Klaui et al. U.S. Patent No. 3,920,834 (834); and
`
`Borg U.S. Patent No. 5,243,094 ( '094 ) .
`
`1 was the primary investigator of the subject matter in the Li
`
`et al. publication.
`
`8.
`
`Claims 1-24 and 27 of U.S . S . N. 08/330,194 were
`
`rejected as being obvious over a combinat ion of EP
`
`'795 and
`
`- 3 -
`
`

`

`the Li et al. publication in view of Klaui et al.
`
`'834
`
`because:
`
`(1) EP '795 discloses that ~·carotene or astaxanthin
`
`can be used to treat the effects of solar radiation on the
`
`skin, and
`
`(2)
`
`the Li et al. publicat.ion teaches
`
`that. ~.
`
`carotene ameliorates retinal photic in jury .
`
`The examiner,
`
`therefore,
`
`reasoned
`
`that it would have been obvious
`
`to
`
`substitute astaxanthin for ,8-carotene in the treatment of
`
`retinal diseases and injuries. The examiner apparently relies
`
`upon Klaui et al. '834 for the teaching that carotenoids are
`
`administered orally or topicall y.
`
`(See Office Action of
`
`January 30, 1995, pages 6 and 7.) Claims 25, 26, and 28 were
`
`similarly rejected as being obvious over
`
`the same cited
`
`references in further view of Borg '094.
`
`9. EP' 795 and Klaui
`
`' 834 each are directed to
`
`applying a carotenoid to protect
`
`the skin against solar
`
`radiation.
`
`The Li et al. publication is directed to a
`
`compound that ameliorates retinal photic in jury .
`
`Pers ons
`
`skilled in the art of treating diseases and injuries of the
`
`central nervous system (CNSl are a ware that the retina, which
`
`is a component of the CNS , is drastically different from the
`
`skin structurally, physiologically, pathologically ,
`
`and
`
`pharmacologically. The structure of the CNS is discussed in
`
`more detail in paragraphe 26-32,
`
`infra.
`
`10 . Persons skilled in the art also are aware that
`
`photosensitivity exhibited by the skin ie different from the
`
`photosensitivity exhibited by
`
`the retina.
`
`In
`
`the skin,
`
`melanocytes respond to light by absorbing the light.
`
`In
`
`effect, the skin acts as a nsinkM for the 1ight .
`
`In the
`
`retina, the response to light is much more complex than mere
`
`- 4
`
`-
`
`

`

`absorption. The photoreceptors in the retina transduce the
`
`light and perforrn the function of an information transfer
`
`system. Therefore, although the skin and the retina are both
`
`sensitive to light, their respective responsea to light are
`
`completely different mechanistically and functionally .
`
`11.
`
`In addition, the skin and the retina respond
`
`differently ta photic in jury.
`
`Photic injury ta the skin
`
`resu!t9 in tissue changes or damage wherein the tissue is
`
`regenerated over time, i.e., the injury is not permanent.
`
`Photic in jury ta the retina results in the 10ss of neurons
`
`that do not regenerate, i.e. , the in jury is permanent.
`
`12. Therefore,
`
`from my experience and training,
`
`persans skilled in the art of the diseases and injuries to the
`
`CNS do not look ta the dermatological art when searching for
`
`compounds to ameliorate photic in jury to the retina and other
`
`CNS components. The skin and retina are sa different struc '
`
`turally and in function that persans skilled in art of the
`
`CNS,
`
`including the retina, do not correlate treatment of the
`
`skin to treatment of the retina or other CNS components.
`
`13. Assuming arguendo, however,
`
`that a pers on
`
`skilled in the art of retinal diseases and in jury remotely
`
`happens to look to the dermatological art, there i9 no support
`
`for the reasoning that a compound useful for treat ing a skin
`
`injury or disease also would be useful to treat a retinal
`
`in jury or disease. First, there is no correlation between
`
`using a compound ta treat the skin and a compound ta treat the
`
`retina because the retina and skin differ so greatly in
`
`structure and function, as set forth in paragraphs 9·11,
`
`5 -
`
`

`

`supra . Second, and of equal importance, no correlation exists
`
`because of the presence of the blood-retinal brain barrier.
`
`There is no corresponding blood-skin barrier .
`
`14. The specification of U.S.S.N. 08/330,194, at
`
`pages 8 and 9 and pages 21 and 22, discusses the wel l- known
`
`blood- retinal brain barrier of
`
`the CNS .
`
`The blood-retinal
`
`brain barrier protects the retina and the brai n from poten-
`
`tially harmful plasma constituents. The blood - retinal brain
`
`barrier permits only specifie compounds to cross the barrier
`
`and reach the retina. AS stated in the specification, at page
`
`8, line 9 through page 9 , line 7:
`
`-Therefore only two of the about ten
`carotenoids present in human serum are
`found in the retina. Beta-carotene and
`l ycopene,
`the
`t wo most abundant car(cid:173)
`otenoids in human serum, either have not
`been detected or have been detected only
`in minor amounts in the retina. Beta(cid:173)
`carotene is relatively inaccessible ta
`the retina because ~-carotene is unable
`to cross the blood - retinal brain barrier
`of the retinal pigment epithelium effec(cid:173)
`tive l y. AS will be explained in detail
`here inafter, small amounts of ~-car o tene
`have been f ound to cross the blood - reti(cid:173)
`nal brain barrier."
`
`and at page 21, line 30 through page 22, line 10:
`
`"As previously stated, the retinal
`pigment epithelium protects the retina by
`providing a blood-re t inal brain barrier.
`The barrier excludes plasma cons tituents
`that are potentially harmful ta the reti(cid:173)
`na.
`As also previously stated,
`the
`blood-retinal brai n barrier only permits
`lutein and zeaxanthin t a enter the reti(cid:173)
`na, and excludes ot her carotenoids pres(cid:173)
`ent in human serum, including ~-carotene
`which is the most abundant carotenoid in
`human serum .
`Therefore, an experiment
`was performed to determine whether asta(cid:173)
`xanthin, wh ich
`i9 not a component of
`human plasma, has the ability to cross
`the blood-retinal brain barrier."
`
`- 6
`
`-
`
`

`

`The skin possesses no similar barriers.
`
`In contrast,
`
`the
`
`blood vessels of the skin are open and porous, and readily
`
`permit the vast majority compounds to penetrate into the skin.
`
`15. Any contention that astaxanthin would obviously
`
`have an ability to cross the blood-retinal brain barrier
`
`because n-carotene has a limi ted ability to cross the blood(cid:173)
`
`retinal brain barrier and because P-carotene and astaxanthin
`
`both are disclosed as skin protectants from solar radiation,
`
`i8 incorrect. The excerpts fr om the specification cited in
`
`paragraph 14 supra teach that even though carotenoids have
`
`similar structures:
`
`(1 ) only two of the ten carotenoids
`
`present in human serum are found in the retina in appreciable
`
`quantities, and
`
`(2)
`
`the two most abundant carotenoids , n·
`
`carotene and lycopene, have not been dete cted or have been
`
`detected in small arnounts in the retina. This illustrates
`
`that no acientific basia presently exists for a pers on skilled
`
`in the art to predict whether or not a compound can cross the
`
`blood- retinal brain barrier. Therefore, a search for com-
`
`pounds that treat retinal and brain injuries and diseases i8
`
`a highly unpred ictabl e art.
`
`In addition, there ie no basis
`
`from whi ch to predict that astaxanthin would effect ively cross
`
`the blood-retinal brain barrier.
`
`In contra8t, based on the
`
`observation that 8 of 10 carotenoids present in human serum do
`
`net cross the blood-retinal brain barrier, a pers on skilled in
`
`the art would have concluded that the probability of asta(cid:173)
`
`xanthin crossing the blood-retinal brain barrier to ameliorate
`
`the retinal in jury or disease is low .
`
`- 7 -
`
`

`

`16 .
`
`In summary,
`
`there is no basis from which to
`
`predict that astaxanthin would effectively cross the blood-
`
`retinal brain barrier because:
`
`( 1 ) a small minority of
`
`carotenoids are known to cross
`
`the barrier, and
`
`(2 )
`
`the
`
`mechanistic basis of crossing
`
`the barrier is unknown
`
`to
`
`persons skilled in the art. Therefore, any contention that it
`
`would have been obvious to substitute astaxanthin for fJ-
`
`carotene because both are use fuI to protect the skin, and
`
`because fJ-carotene iB found in the retina in minimal amountB,
`
`cannot be supported by the current state o f the art or by the
`
`publication and patents cited by the examiner.
`
`17. AB set forth in the present specification,
`
`starting at page 22, line 11, we have found that astaxanthin
`
`has the unpredictable and unexpected ability to cross the
`
`blood-retinal brain barrier readily.
`
`The present specif i-
`
`cation, starting at page 23, line 3 through page 31, line 15,
`
`also demonstrates the unexpected ability of astaxanthin to
`
`protect the retina, to ameliorate retinal damage caused by
`
`photic in jury , and to ameliorate in jury to neurons after
`
`retinal ischemic insult.
`
`18.
`
`In particular , astaxanthin was compared to fJ-
`
`carotene, and as stated at page 29, line 17 through page 30,
`
`line 22 of the specification:
`
`"Therefore, astaxanthin not only
`protected the photoreceptor cells from
`photic injury (i.e., greater level of
`rhodopsin six hours after photic in jury)
`but also ameliorated the effects of the
`photic in jury because rhodopsin levels
`did not fall for a period of six days
`after the photic in jury , but increased.
`
`- B -
`
`

`

`A similar test was performed whe rein
`{J-carotene was injected into rats, and
`rhodopsin levels in the retinae of the
`euthanized rats were determined.
`Rats
`were given four intraperitoneal injec(cid:173)
`tions of
`,B-carotene at a dose of 35
`kg/mg. A control group of rats also was
`used.
`Af ter exposure
`to continuous
`green-filtered fluorescent light with an
`intensity of 220-250 foot -candles for 24
`hours, the rhodopsin level was measured
`as an indication of photic in jury . The
`,B-carotene-treated rats had
`rhodopsin
`levels of 1.18, 0.20, and 0.55 nrnol, six
`h0urs, six days and thirteen d