I 1111111111111111 11111 111111111111111 111111111111111 IIIII IIIIII IIII IIII IIII
`US008868177B2
`
`c12) United States Patent
`Simon et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 8,868,177 B2
`Oct. 21, 2014
`
`(54) NON-INVASIVE TREATMENT OF
`NEURODEGENERATIVE DISEASES
`
`(75)
`
`Inventors: Bruce Simon, Mountain Lakes, NJ (US);
`Joseph P. Errico, Warren, NJ (US);
`John T. Raffle, Austin, TX (US)
`
`(73) Assignee: Electrocore, LLC, Basking Ridge, NJ
`(US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 634 days.
`
`(21) Appl. No.: 13/005,005
`
`(22) Filed:
`
`Jan.12,2011
`
`(65)
`
`Prior Publication Data
`
`US 2011/0152967 Al
`
`Jun. 23, 2011
`
`Related U.S. Application Data
`
`(63)
`
`Continuation-in-part of application No. 12/964,050,
`filed on Dec. 9, 2010, which is a continuation-in-part
`of application No. 12/859,568, filedonAug. 19, 2010,
`said
`application No.
`12/859,568
`is
`a
`continuation-in-part of application No. 12/408,131,
`filed on Mar. 20, 2009.
`
`(60)
`
`Provisional application No. 61/415,469, filed on Nov.
`19, 2010.
`
`(51)
`
`(52)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61N 1136
`A61N2/08
`A61N 1140
`A61N2/02
`A61N2/00
`U.S. Cl.
`CPC ............... A61N 1140 (2013.01); A61N 1/36114
`(2013.01); A61N 2102 (2013.01); A61N 21006
`(2013.01)
`USPC ...................................... 607/2; 607/45; 600/9
`
`(58) Field of Classification Search
`CPC ........... A61N 2/02; A61N 2/006; A61N 1/40;
`A61N 1/36114
`USPC ................................. 607/2, 45; 600/9, 13-15
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,196,737 A
`4,702,254 A
`4,915,110 A
`5,269,303 A
`
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`10/1987 Zahara
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`(Continued)
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`OTHER PUBLICATIONS
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`
`(Continued)
`
`Primary Examiner - Carl H Layno
`Assistant Examiner -
`Jessica Anthony
`(74) Attorney, Agent, or Firm - Dentons US LLP
`
`ABSTRACT
`(57)
`Methods and devices for the non-invasive treatment of neu(cid:173)
`rodegenerative diseases through delivery of energy to target
`nervous tissue, particularly the vagus nerve. In certain
`embodiments, the devices include a magnetic stimulator hav(cid:173)
`ing coils with toroidal windings, which are in contact with an
`electrically conducting medium that is adapted to conform to
`the contour of a target body surface of a patient. The coils
`induce an electric current and/or an electric field within the
`patient, thereby stimulating nerve fibers within the patient.
`The stimulation brings about reduction of neuroinflammation
`in patients suffering from conditions comprising Alzheimer's
`Disease, Parkinson's Disease, Multiple Sclerosis, postopera(cid:173)
`tive cognitive dysfunction and postoperative delirium.
`
`60 Claims, 7 Drawing Sheets
`
`81
`
`I
`
`I
`
`84
`!
`Retinoic I
`Acid
`!ss
`,___ Cytokine, e.g.,
`82
`
`Anti-Inflammatory
`
`I
`Vagal
`Nerve
`Stimulation
`
`96
`
`971
`
`93
`
`Pro-Inflammatory
`Cytokine. e.g ..
`TNF-a
`
`--
`
`192 II Inflammation 186
`
`94
`
`95
`
`TGF-J}
`
`Neu1otrophic
`Factor, e.g.,
`BDNF
`
`I
`
`83
`
`91
`
`LUMENIS EX1053
`Page 1
`
`

`

`US 8,868,177 B2
`Page 2
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`U.S. Patent
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`Oct. 21, 2014
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`Sheet 1 of 7
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`US 8,868,177 B2
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`350
`
`FIG. 1
`
`NS Device 300
`
`lmpu!se
`Generator
`310
`
`Contra!
`Unit
`330
`
`PC'ViEff
`Source
`320
`
`FIG. 2
`
`400
`
`Activity
`
`Current
`
`420
`
`Current
`
`Time
`
`Time
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`Sheet 2 of 7
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`US 8,868,177 B2
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`FIG. SA
`
`FIG. 3B
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`30
`
`30
`
`FIG.SC
`
`FIG. 3D
`
`31
`
`31
`
`36
`
`35
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`37 37 35
`
`30
`
`34
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`32
`
`30-
`
`34
`
`34
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`33
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`Sheet 3 of 7
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`US 8,868,177 B2
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`FIG.4A
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`FIG.4E
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`Sheet 4 of 7
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`US 8,868,177 B2
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`FIG. 5
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`30
`
`39
`
`--38
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`Sheet 5 of 7
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`US 8,868,177 B2
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`FIG. 6
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`30
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`U.S. Patent
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`Sheet 6 of 7
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`FIG. 7
`
`66 67 68
`
`76
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`Sheet 7 of 7
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`US 8,868,177 B2
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`FIG. 8
`
`Vagal
`Nerve
`Stimulation
`
`81
`
`82
`
`84
`
`!
`
`Retinoic
`A.cid
`
`96
`
`97
`
`93
`
`'"'
`Anti-Inflammatory t - - - -~ -~
`Pro-l~flammatory
`. I
`Cytokl·ne "' g ~I I fl
`Cytokme. e.g ..
`---, n ammatIon 1 - TNF o:
`86 ~=-~=-·---------=-=--
`T G F-13
`- -
`
`• .....
`
`·,
`
`Neurotrophic
`Factor, e.g ..
`BDNF
`
`83 _
`
`91
`
`94
`
`95
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`1
`NON-INVASIVE TREATMENT OF
`NEURODEGENERATIVE DISEASES
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a continuation-in-part application of
`U.S. patent application Ser. No. 12/964,050 filed Dec. 19,
`2010, which claims the benefit of priority ofU.S. Provisional
`Patent Application No. 61/415,469 filed Nov. 19, 2010 and is
`a continuation-in-part application of U.S. patent application
`Ser. No. 12/859,568 filed Aug. 9, 2010, which is a continua(cid:173)
`tion-in-part of co-pending U.S. patent application Ser. No.
`12/408,131 filed Mar. 20, 2009, the entire disclosure of which
`is hereby incorporated by reference.
`
`BACKGROUND OF THE INVENTION
`
`The field of the present invention relates to the delivery of
`energy impulses ( and/or fields) to bodily tissues for therapeu- 20
`tic purposes. It relates more specifically to the use of non(cid:173)
`invasive methods and devices, particularly methods that make
`use of magnetic stimulation devices, to treat neurodegenera(cid:173)
`tive disorders, using energy that is delivered by such devices.
`The medical disorders include Alzheimer's disease, Parkin(cid:173)
`son's disease, multiple sclerosis, postoperative cognitive dys(cid:173)
`function, and postoperative delirium. The treatment relates to
`stimulation of the vagus nerve to reduce neuro-inflammation,
`wherein pathways involving anti-inflammatory cytokines,
`the retinoic acid signaling system, and/or neurotrophic fac(cid:173)
`tors are enhanced, and/or pathways involving pro-inflamma(cid:173)
`tory cytokines are inhibited.
`Treatments for various infirmities sometime require the
`destruction of otherwise healthy tissue in order to produce a
`beneficial effect. Malfunctioning tissue is identified and then
`lesioned or otherwise compromised in order to produce a
`beneficial outcome, rather than attempting to repair the tissue
`to its normal functionality. A variety of techniques and
`mechanisms have been designed to produce focused lesions
`directly in target nerve tissue, but collateral damage is inevi(cid:173)
`table.
`Other treatments for malfunctioning tissue can be medici(cid:173)
`nal in nature, but in many cases the patients become depen(cid:173)
`dent upon artificially synthesized chemicals. In many cases,
`these medicinal approaches have side effects that are either 45
`unknown or quite significant. Unfortunately, the beneficial
`outcomes of surgery and medicines are often realized at the
`cost of function of other tissues, or risks of side effects.
`The use of electrical stimulation for treatment of medical
`conditions has been well kuown in the art for nearly two
`thousand years. It has been recognized that electrical stimu(cid:173)
`lation of the brain and/or the peripheral nervous