PATENT
`Attorney
`Docket
`No.:
`AEGIS
`1210-14
`IN
`THE
`UNITED
`STATES
`PATENT
`AND
`TRADEMARK
`OFFICE
`Applicant(s):
`Edward
`T.
`Maggio
`Art
`Unit:
`1649
`Application
`No.:
`13/371,274
`Examiner:
`Borgeest,
`Christina
`M.
`Filed:
`February
`10,
`2012
`Conf.
`No.:
`3112
`Title:
`ABSORPTION
`ENHANCERS
`FOR
`DRUG
`ADMINISTRATION
`MAIL
`STOP
`RCE
`Commissioner
`for
`Patents
`P.O.
`Box
`1450
`Alexandria,
`VA
`22313-1450
`DECLARATION
`UNDER
`37
`C.F.R.
`41.132
`
`Sir:
`I,
`Dr.
`Edward
`T.
`Maggio,
`do
`hereby
`declare
`and
`state
`that:
`1.
`1am
`named
`as
`an
`inventor
`on
`U.S.
`Patent
`Application
`Serial
`No.
`13/371,274
`and
`am
`currently
`Chief
`Executive
`Officer
`and
`Director
`of
`Aegis
`Therapeutics,
`LLC.
`2.
`I
`hold
`a
`B.S.
`in
`Chemistry
`from
`Polytechnic
`University,
`a
`Ph.D.
`degree
`in
`Biochemistry
`from
`the
`University
`of
`Michigan,
`and
`was
`a
`National
`Institute
`of
`Health
`postdoctoral
`fellow
`at
`the
`University
`of
`California,
`San
`Francisco
`in
`the
`Department
`of
`Pharmaceutical
`Chemistry.
`I
`consider
`myself
`to
`be
`an
`expert
`in
`the
`field
`of
`pharmaceutical
`chemistry
`and
`in
`particular
`in
`the
`area
`of
`pharmaceutical
`formulations.
`3.
`I
`am
`familiar
`with
`the
`contents
`of
`the
`above-identified
`application,
`and
`have
`reviewed
`the
`Office
`Action
`dated
`April
`10,
`2013.
`I
`understand
`that
`the
`Examiner
`has
`rejected
`claims
`7,
`9-15,
`17
`and
`18
`under
`35
`U.S.C.
`§103,
`as
`allegedly
`obvious
`over
`Meezan
`et
`al.
`(U.S.
`Patent
`No.
`5,661,130;
`hereinafter
`'Meezan')
`in
`view
`of
`Lahat
`et
`al.
`(The
`Lancet,
`1998;
`352:620;
`hereinafter
`'Lahat');
`and
`claim
`16
`under
`35 U.S.C.
`§103,
`as
`allegedly
`obvious
`over
`Meezan
`in
`view
`of
`Lahat
`and
`further
`in
`view
`of Frey
`(U.S.
`Pat.
`App.
`Pub.
`No.
`2002/0141971;
`hereinafter
`'Frey').
`WEST\242306846.
`I
`356894-000097
`Exhibit
`1076
`03/17/2026
`Padagis US LLC, EX1076
`1
`
`
`
`
`
`
`
`In
`re
`Application
`of:
`Edward
`T.
`Maggio
`Application
`No.:
`13/371,274
`Filed:
`February
`10,
`2012
`Page
`2
`PATENT
`Attorney
`Docket
`No.:
`AEGIS
`
`1210-14
`4.
`I
`am
`familiar
`with
`and
`have
`generally
`reviewed
`the
`references
`cited in
`the
`Office
`Action,
`in
`particular,
`Meezan,
`Lahat
`and
`Frey.
`5.
`The
`present
`invention
`is
`based
`on
`the
`discovery
`that
`the
`alkyl
`glycoside,
`dodecyl-
`-D-maltoside
`(also
`referred
`to
`as
`n-dodecyl-f3-D-maltoside),
`increases
`absorption
`of
`therapeutic
`agents
`to
`the
`cerebral
`spinal
`fluid
`(CSF)
`of
`the
`central
`nervous
`system
`(CNS)
`of
`a
`subject
`upon
`nasal administration.
`6.
`In
`Appendix
`A,
`the
`absorption
`increasing
`activity
`of
`certain
`alkyiglycosides
`as
`well
`as
`other
`agents
`were
`analyzed.
`The
`experiment
`described
`was
`performed
`under
`my
`general
`direction
`and
`guidance.
`As
`described
`in
`Appendix
`A,
`formulations
`including
`a
`therapeutic
`agent
`(Homo
`sapien
`derived
`antibody
`Fe
`fragment
`(hFc))
`and
`various
`compounds
`including
`dodecyl-f3-
`D-maltoside
`were
`compared.
`As
`shown
`in
`Table
`1,
`nasal
`administration
`of
`formulations
`comprising
`therapeutic
`agent
`(hFc)
`and
`0.5%
`(w/v)
`-n-dodecyl--D-maltoside
`to
`isoflurane
`anesthetized
`animals
`resulted
`in
`therapeutic
`agent
`concentrations
`in
`CNS
`tissues
`that
`were
`increased
`relative
`to
`other
`alkyl
`glycosides
`as
`well
`as
`other
`agents
`that
`were
`tested,
`particularly
`n-decyl--D-ma1toside.
`Surprisingly,
`a
`near
`200%
`increase
`in
`CNS
`absorption,
`e.g.,
`absorption
`through
`the
`CSF,
`was
`determined
`for
`dodecyl--D-ma1toside
`as
`compared
`to
`decyl-3-D-
`maltoside.
`7.
`One
`of
`ordinary
`skill
`in
`the
`art
`would
`appreciate
`the
`significance
`of
`the
`experimental
`results
`presented
`in
`Appendix
`A.
`The
`determination
`that
`dodecyl-3-D-maltoside
`exhibits
`nearly
`a
`two
`fold
`increase
`in
`CNS
`absorption
`as
`compared
`to
`decyl-f3-D-maltoside,
`an
`alkyl
`glycoside
`which
`differs
`in
`alkyl
`length
`by
`only
`2
`carbons
`from
`dodecyl-3-D-maltoside,
`is
`indeed
`surprising
`and
`unexpected.
`Further,
`one
`would
`expect
`to
`observe
`a
`similar
`increase
`in
`absorption
`by
`dodecyl--D-maltoside
`for
`other
`therapeutic
`agents,
`such
`as
`anti-seizure
`agents.
`WEST\2423
`06846.1
`356894-000097
`2
`
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`
`
`Sep
`
`19 13
`
`09:45p
`ET
`&
`GN
`Maggio
`858
`485-1463
`p.3
`In
`re
`Application
`of:
`Edward
`T.
`Maggio
`Application
`No.:
`131371,274
`Filed:
`February
`1.0,
`2012
`Page
`3
`PATENT
`Attorney
`Docket
`No.:
`AEGIS
`
`1210-14
`Even more
`significant
`is
`that
`such
`unexpected
`results
`are
`achieved
`at
`concentrations
`of
`dodecyl-
`J3-Dma1toside
`at
`which
`acceptable
`levels
`of
`cytotoxicity
`are
`preserved.
`8.
`I
`further
`declare
`that
`the
`statements
`made
`herein
`of
`my
`own
`knowledge
`and
`that
`all
`statements
`made
`on
`information
`and
`belief
`are
`believed
`to
`be
`true,
`and
`further
`that
`these
`statements
`were
`made
`with
`the
`knowledge
`that
`willful
`false
`statements
`and
`the
`like
`so
`made
`are
`punishable
`by
`fine,
`or
`imprisonment,
`or
`both
`under
`Section
`1001
`of
`Title
`18
`of
`the
`United
`States
`Code,
`and
`that
`such
`willful
`false
`statements
`may
`jeopardize
`the
`validity
`of
`the
`application
`or
`any
`patent
`issued
`thereon.
`Date:
`
`l9Sept2OI3
`
`WEST\24230684&1
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`
`Appendix
`A
`to
`Declaration
`AEGIS121O-14
`Experiment:
`
`Nasal
`Administration
`of
`Dodecyl--D-maltoside
`and
`Therapeutic
`Agent
`In
`this
`experiment,
`the
`ability
`of
`various
`agents
`to
`deliver
`a
`therapeutic
`agent
`to
`the
`central
`nervous
`system
`(CNS)
`including
`the
`cerebral
`spinal
`fluid
`(CSF)
`via
`nasal
`administration
`was
`tested.
`Nasal
`administration
`of
`a
`Homo
`sapien
`derived
`antibody
`Fe
`fragment
`(hFc)
`to
`CNS
`tissues
`was
`increased,
`relative
`to
`control
`hFc
`formulations,
`by
`inclusion
`of
`the
`compounds
`listed
`in
`Table
`1.
`Table
`1:
`Antibody
`hFc
`formulations
`that
`increase
`antibody
`fragment
`delivery
`to
`central
`nervous
`system
`tissues,
`relative
`to
`control
`hFc
`formulations,
`in
`isoflurane
`anesthetized
`animals.
`Compound
`Identity
`and
`Quantity
`in
`PBS
`(pH
`7.4)
`Diluent
`Based
`Formulations
`Containing
`36
`mg/ml
`hFc
`Mean
`Fold
`Increase*
`
`in
`Brain
`Delivery
`Efficiency
`of
`hFc
`after
`Nasal
`Administration
`of
`Formulation
`Compound
`Identity
`Quantity
`n-dodecyl-f
`-D-maltoside
`0.5%
`(w/v)
`7.6
`
`(n
`--
`21)
`n-decy1-3-D-maltoside
`0.5%
`(w/v)
`43
`(n=7)
`propylene
`glycol
`10-20%
`(v/v)
`4.5
`(n=13)
`heptakis(2,6-di-O-methyl)-
`beta-cyclodextrin
`5%
`(w/v)
`3.1
`(n=8)
`Sodium
`tauroursodeoxycholate
`1%
`(w/v)
`4.0
`(n6)
`Page
`1
`of
`3
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`Appendix
`A
`to
`Declaration
`AEG1S1210-14
`*
`represents
`mean
`fold
`increase
`in
`brain
`delivery
`efficiency
`(DE)
`of
`nasally
`administered
`hFc
`relative
`to
`control
`formulation
`(PBS;
`pH
`7.4
`and
`36
`mg/mi
`hFc)
`A
`rat
`model
`was
`used
`for
`evaluating
`intranasal
`drug
`delivery
`to
`the
`brain.
`Male
`Sprague-
`Dawley
`rats
`were
`anesthetized
`with
`3.0%
`isoflurane
`inhalant
`to
`facilitate
`nasal
`administration
`of
`the
`liquid
`formulations
`comprising
`hFc.
`Anesthetized
`rats
`were
`placed
`on
`their
`backs
`and
`their
`necks
`and
`head
`were
`supported
`with
`a
`platform
`to
`elevate
`their
`heads
`at
`a
`45°
`angle.
`A
`micro-
`cannula
`was
`then
`inserted
`1
`cm
`into
`the
`right
`nostril
`of
`the
`animals
`and
`a
`50 iL
`bolus
`of
`the
`liquid
`formulations
`was
`administered
`over
`the
`span
`of
`1
`minute.
`A
`heating
`pad
`was
`used
`to
`maintain
`body
`temperature
`of
`anesthesized
`animals.
`20
`minutes
`after
`nasal
`administration
`of
`the
`hFc
`formulations,
`animals
`were
`perfused
`via
`cardiac
`puncture
`with
`phosphate
`buffered
`saline
`(PBS)
`containing
`protease
`inhibitors
`(1
`Roche
`protease
`inhibitor
`cocktail
`tablet
`per
`10
`ml
`of
`PBS)
`and
`5
`nM
`EDTA
`tetrasodium
`salt.
`Brains,
`blood
`and
`other
`tissues
`were
`then
`dissected, collected,
`and
`analyzed
`for
`hFc
`content.
`Control
`hFc
`formulations
`comprised
`36
`mg/ml
`hFc
`in
`PBS
`at
`pH
`7.4.
`The
`formulations
`described
`in
`Table
`1
`above
`each
`contained
`an
`absorption
`compound
`in
`the
`quantity
`indicated
`in
`the
`Table.
`Formulations
`were
`made
`using
`PBS
`at
`pH
`7.4
`as
`the
`diluent
`and
`contained
`a
`final
`hFc
`concentration
`of
`36
`mg/ml.
`As
`seen
`in
`Table
`1,
`nasal
`administration
`of
`hFc
`formulations
`comprising
`0.5%
`(w/v)
`-n-
`dodecyl-3-D-maltoside
`to
`isoflurane
`anesthetized
`animals
`resulted
`in
`hFc
`concentrations
`in
`CNS
`tissues
`that
`were
`increased
`relative
`to
`other
`alkyl
`glycosides
`tested
`(e.g.,
`n-decyl-f3-D-maltoside)
`and
`isoflurane
`anesthetized
`animals
`receiving
`the
`control
`hFc
`formulation
`in
`PBS
`only.
`A
`near
`Page
`2
`of
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`
`Appendix
`A
`to
`Declaration
`AEGIS
`
`1210-14
`200%
`increase
`in
`absorption
`is
`shown
`for
`n-dodecyl-f3-D-maltoside
`as
`compared
`to
`n-decyl-f3-D-
`maltoside.
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