111111
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`1111111111111111111111111111111111111111111111111111111111111
`US006965791B 1
`
`(12) United States Patent
`Hitchcock et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,965, 791 Bl
`Nov. 15, 2005
`
`(54)
`
`IMPLANTABLE BIOSENSOR SYSTEM,
`APPARATUS AND METHOD
`
`(75)
`
`Inventors: Robert W. Hitchcock, Sandy, UT (US);
`James L. Sorenson, Salt Lake City, UT
`(US)
`
`(73) Assignee: Sorenson Medical, Inc., Salt Lake City,
`UT (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 148 days.
`
`(21) Appl. No.: 10/401,224
`
`(22) Filed:
`
`Mar. 26, 2003
`
`Int. Cl? ................................................. A61B 5/05
`(51)
`(52) U.S. Cl. ...................... 600/345; 600/309; 600/347;
`600/365; 204/403.01
`(58) Field of Search ................................ 600/300, 309,
`600/345-365, 372-381; 204/403.01-403.15,
`204/406, 407, 433, 279, 280, 297.01
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`4,561,963 A *
`12/1985 Owen et a!. ................ 204/433
`4,567,963 A *
`2/1986 Sugimoto ................... 182/236
`4,703,756 A *
`11/1987 Gough et a!. ............... 600/347
`4,861,454 A *
`8/1989 Ushizawa et a!.
`.......... 204/414
`5,165,407 A *
`11/1992 Wilson et a!.
`.............. 600/345
`2/1995 Lord et a!.
`5,390,671 A
`5,527,444 A *
`6/1996 Sweeney, Jr. ............... 204/415
`10/1996 Cheney, II et a!.
`5,568,806 A
`12/1996 Halili et a!.
`5,586,553 A
`9/1999 Mastrototaro et a!.
`5,951,521 A
`12/2001 Heller et a!.
`6,329,161 B1
`6,360,888 B1 *
`3/2002 Mcivor et a!. .............. 206/305
`6,613,379 B2 *
`9/2003 Ward eta!. ................ 427/2.11
`2004/0254433 A1 * 12/2004 Ban dis et a!. ............... 600/347
`
`OTHER PUBLICATIONS
`
`Teflon. Academic Press Dicitionary of Science and Tech(cid:173)
`nology (1992). http://www.xreferplus.com/entry /3166958. *
`Brindra et al., Design and in Vitro Studies of a Needle-Type
`Ghucose Sensor for Subcutaneous Monitoring, Anal. Chern.,
`1991, pp. 1692-1696, vol. 63.
`Churchouse et al., Needle Enzyme Electrodes for Biological
`Studies, Biosensors, 1986, pp. 325-342, vol. 2.
`Matthews et al., An Amperometric Needle-type Glucose
`Sensor Tested in Rats and Man, Diabetic Medicine, 1988,
`pp. 248-252, vol. 5.
`Moussy et al., Performance of Subcutaneously Implanted
`Needle-Type Glucose Sensors Employing a Novel Trilayer
`Coating, Anal. Chern, 1993, pp. 2072-2077, vol. 65.
`Moussy et al., A miniaturized Nafion-based glucose sensor:
`in vitro and in vivo evaluation in dogs, The International
`Journal of Artificial Organs, 1994, pp. 88-94, vol. 17. No.2.
`* cited by examiner
`
`Primary Examiner-Max F. Hindenburg
`Assistant Examiner-Patricia Mallari
`(74) Attorney, Agent, or Firm-TraskBritt
`
`ABSTRACT
`(57)
`An implantable biosensor assembly and system includes an
`enzymatic sensor probe from which subcutaneous and inter(cid:173)
`stitial glucose levels may be inferred. The assembly may be
`associated by direct percutaneous connection with electron(cid:173)
`ics, such as for signal amplification, sensor polarization, and
`data download, manipulation, display, and storage. The
`biosensor comprises a miniature probe characterized by
`lateral flexibility and tensile strength and has large electrode
`surface area for increased sensitivity. Irritation of tissues
`surrounding the probe is minimized due to ease of flexibility
`and small cross section of the sensor. Foreign body reaction
`is diminished due to a microscopically rough porous probe
`surface.
`
`52 Claims, 12 Drawing Sheets
`
`Dexcom Inc. v. WaveForm Technologies, Inc.
`IPR2017-01051
`Exhibit 1028
`
`

`

`U.S. Patent
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`Nov. 15, 2005
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`Sheet 1 of 12
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`Dexcom Inc. v. WaveForm Technologies, Inc.
`IPR2017-01051
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`Dexcom Inc. v. WaveForm Technologies, Inc.
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`Exhibit 1028
`
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`Nov. 15, 2005
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`Dexcom Inc. v. WaveForm Technologies, Inc.
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`Nov. 15, 2005
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`Dexcom Inc. v. WaveForm Technologies, Inc.
`IPR2017-01051
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`Nov. 15, 2005
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`Dexcom Inc. v. WaveForm Technologies, Inc.
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`Nov. 15,2005
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`Dexcom Inc. v. WaveForm Technologies, Inc.
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`Nov. 15,2005
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`Dexcom Inc. v. WaveForm Technologies, Inc.
`IPR2017-01051
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`Nov. 15,2005
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`Dexcom Inc. v. WaveForm Technologies, Inc.
`IPR2017-01051
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`

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`Dexcom Inc. v. WaveForm Technologies, Inc.
`IPR2017-01051
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`Nov. 15, 2005
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`Dexcom Inc. v. WaveForm Technologies, Inc.
`IPR2017-01051
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`

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`Nov. 15, 2005
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`Dexcom Inc. v. WaveForm Technologies, Inc.
`IPR2017-01051
`Exhibit 1028
`
`

`

`US 6,965,791 Bl
`
`1
`IMPLANTABLE BIOSENSOR SYSTEM,
`APPARATUS AND METHOD
`
`TECHNICAL FIELD
`
`This invention relates generally to medical devices and
`associated methods such as measuring glucose for ongoing
`diabetes management. The inventions described herein also
`be used for enzymatic determination of other analytes. This
`invention provides a particularly useful application for an
`implantable biosensor.
`
`BACKGROUND
`
`Heretofore, treatment and management of diabetes has
`been undertaken through many and varied techniques. For(cid:173)
`merly, glucose in urine was measured, though recognized as
`less than adequate due to the time delay inherent in the
`metabolism and voiding process. Currently, the approach
`predominantly used for self- monitoring of blood glucose
`requires periodic pricks of the skin with a needle, whereby
`a blood sample is obtained and tested directly to provide
`information about blood glucose levels. This information is
`then utilized as a basis from which to schedule the admin(cid:173)
`istration of insulin to maintain glucose equilibrium within
`the patient. Direct measurement of glucose levels in periodic
`blood samples from diabetes patients provides reasonably
`useful information about insulin levels at certain selected
`points in time. However, the dynamic nature of blood
`glucose chemistry and the complexity of factors influencing
`blood sugar levels renders such periodic information less
`than optimal.
`The glucose level in the subcutaneous interstitial fluid
`very closely approximates the glucose level in the blood,
`with a negligible time lag. The variables of patient food
`selection, physical activity and insulin dosage, regime and
`protocol for a person with diabetes each have a dynamic
`impact on physiologic balance within the patient's body that
`can change dramatically over a short period of time. If the
`net result of changes in these variables and dynamics results
`in disequilibrium expressed as too much glucose ("hyperg(cid:173)
`lycemia"), then more insulin is required, whereas too little
`glucose ("hypoglycemia") requires immediate intervention
`to raise the glucose levels. A deleterious impact on physi(cid:173)
`ology follows either such disequilibrium.
`Hyperglycemia is the source of most of the long-term
`consequences of diabetes, such as blindness, nerve degen(cid:173)
`eration, and kidney failure. Hypoglycemia, on the other
`hand, poses the more serious short-term danger. Hypogly(cid:173)
`cemia can occur at any time of the day or night and can cause
`the patient to lose consciousness. Guarding against hypogly(cid:173)
`cemia may require frequent monitoring of blood glucose
`levels and render the skin-prick approach tedious, painful
`and in some cases impractical. Even diligent patients who
`perform finger-sticking procedures many times each day
`achieve only a poor approximation of continuous monitor(cid:173)
`ing. Accordingly, extensive attention has been given to
`development of improved means of monitoring patient glu(cid:173)
`cose levels for treatment of diabetes.
`Many efforts to continuously monitor glucose levels have
`involved implantable electrochemical biosensors. These
`amperometric sensors utilize an immobilized form of the
`enzyme glucose oxidase to catalyze the conversion of oxy(cid:173)
`gen and glucose to gluconic acid and hydrogen peroxide.
`Such sensors may be used to measure hydrogen peroxide
`resulting from the enzymatic reaction. Alternatively, these
`
`5
`
`2
`glucose oxidase based biosensors measure oxygen con(cid:173)
`sumption to infer glucose concentrations.
`Typical implantable, subcutaneous needle-type biosen(cid:173)
`sors are disclosed in various publications, such as the
`following examples. An Amperometric Needle-type Glu(cid:173)
`cose Sensor Tested in Rats and Man, by D. R. Matthews, E.
`Bown, T. W. Beck, E. Plotkin, L. Lock, E. Gosden, and M.
`Wickham discloses an amperometric glucose-measuring 25
`gauge (0.5 mm diameter) needle-type sensor using a glucose
`10 oxidase and dimethyl ferrocene paste behind a semi-perme(cid:173)
`able membrane situated over a window in the needle.
`Performance of Subcutaneously Implanted Needle-Type
`Glucose Sensors Employing a Novel Trilayer Coating, by
`Francis Moussy, D. Jed Harrison, Darryl W. O'Brien, and
`15 Ray V. Rajotte teaches a miniature, needle-type glucose
`sensor utilizing a perfluorinated ionomer, N afion, as a pro(cid:173)
`tective, biocompatible, outer coating, and poly ( a-phe(cid:173)
`nylenediamine) as an inner coating to reduce interference by
`small, electroactive compounds. Glucose oxidase immobi-
`20 lized in a bovine serum albumin matrix was sandwiched
`between these coatings. The entire assembly of Pt working
`electrode and Ag/AgCl reference electrode was 0.5 mm in
`diameter and could be inserted subcutaneously through an
`18-gauge needle. Needle Enzyme Electrodes for Biological
`25 Studies by S. 1. Churchouse, C. M. Battersby, W. H. Mullen
`and P. M. Vadgama presents yet another needle enzyme
`electrode characterized as the most promising approach to
`miniaturization for invasive use. A Miniaturized Nation(cid:173)
`based Glucose Sensor by F. Moussy, D. 1. Harrison, and R.
`30 V. Rajotte, while teaching a high sensitivity (due in part to
`greater surface area of the electrode) needle-type sensor with
`a spear-shaped point, acknowledges the need for more
`protection against abrasion. Design and In Vitro Studies of
`a Needle-Type Glucose Sensor for Subcutaneous Monitor-
`35 ing by Dilbir S. Bindra, Yanan Zhang, George S. Wilson,
`Robert Sternberg, Daniel R. Thevenot, Dinah Moatti and
`Gerard Reach sets forth yet another needle-type glucose
`microsensor having a 26-gauge (0.45-mm) outside diameter.
`Additional needle-type implantable biosensors are dis-
`40 closed in certain United States patent documents. Relevant
`documents include: "Subcutaneous Glucose Electrode" to
`Heller et al., U.S. Pat. No. 6,329,161 B1; "Subcutaneous
`Implantable Sensor Set Having The Capability To Remove
`Deliver Fluids To An Insertion Site" to Mastrototaro et al.,
`45 U.S. Pat. No. 5,951,521; "Transcutaneous Sensor Insertion
`Set" to Halili et al., U.S. Pat. No. 5,586,553; "Transcutane(cid:173)
`ous Sensor Insertion Set" to Cheney, II et al., U.S. Pat. No.
`5,568,806; "Transcutaneous Sensor Insertion Set" to Lord
`et. al., U.S. Pat. No. 5,390,671; and "Implantable Glucose
`50 Sensor" to Wilson et al., U.S. Pat. No. 5,165,407.
`To provide continuous measurement, biosensors can be
`placed for extended periods of time in various locations
`within the body. One method of placement is percutaneously
`with an indwelling sensor having an attached external wire
`55 associated with a readout device. A risk of infection is
`associated with percutaneous biosensors, and they must
`typically be replaced at regular intervals because of the risk
`of infection at the insertion site.
`Another problem with implanted sensors is irritation of
`60 the tissues surrounding the implanted biosensors. Such
`irritation is typically due, in part, to the lateral rigidity of
`prior art biosensors. Related to this problem is the scarring
`of surrounding tissue due not only to rigidity but also to
`abrupt edges associated with the implants. Scar tissue sur-
`65 rounding reference electrodes of the prior art is not desir(cid:173)
`able, but may be tolerated in some cases. However, scar
`tissue can be materially detrimental to the sensor function in
`
`Dexcom Inc. v. WaveForm Technologies, Inc.
`IPR2017-01051
`Exhibit 1028
`
`

`

`US 6,965,791 Bl
`
`3
`the vicinity of the working electrode because it impedes the
`diffusion of oxygen and glucose.
`Further, to protect itself against a perceived invader, the
`body commonly experiences a foreign body reaction by
`encapsulating the implanted biosensors with protein, which 5
`may shorten the life of the implant and adversely affect the
`accuracy of information provided. The size of the sensor
`may also be regarded as a problem; smaller is better for
`comfort. Further yet, interfering compounds, such as for
`example, ascorbic acid, and acetaminophen, can reduce the 10
`accuracy of prior art amperometric glucose sensors given the
`membranes selected historically to envelope such sensors.
`Additionally the quantity of dissolved oxygen is limited at
`high glucose concentrations thus leading to non-linear out(cid:173)
`put of sensor signals at high glucose concentrations.
`A need remains for a sensor including a miniaturized
`probe of suitable materials and characteristics that may
`facilely be placed percutaneously. A need exists for a min(cid:173)
`iaturized, albeit durable, implantable biosensor percutane(cid:173)
`ously deployable wherein irritation to tissues surrounding 20
`the biosensor is minimized. A need also exists to achieve a
`rough exterior of the portion of an implantable biosensor
`exposed to surrounding tissue so that foreign body reaction
`may reduced. Similarly, there is a need for a selected
`membrane or membrane combination suitable to correction 25
`of non-linear diffusion of glucose. Further needed is a
`method of manufacturing such a miniaturized yet strong and
`durable implantable biosensor with resilient flexibility and
`minimal surface relief while achieving a microscopically
`porous surface.
`
`BRIEF SUMMARY OF THE INVENTION
`
`The invention includes an implantable needle-type bio(cid:173)
`sensor wherein an electric signal is produced between first
`and second electrical contacts responsive to an electro(cid:173)
`chemical reaction in a body. A needle-like probe element is
`typically inserted through an introducer cannula into tissues
`of a subject's body. An implantable needle element of an
`exemplary biosensor includes an elongate core having a
`distal end spaced apart axially from a proximal end. A
`workable core may be formed as a single element, or may
`include a plurality of axially oriented fibers arranged in a
`bundle. Certain cores are nonconductive to electric current.
`Workable cores may be made from natural and synthetic
`fibers, metal, polymers, and plastics. Currently preferred
`cores are made from polymer material.
`In general, a working electrode is associated with a distal
`end of the core. Desirably, the working electrode is arranged
`to protrude, beyond a distal end of an introducer cannula,
`into intimate contact with tissue of a subject's body. A
`reference electrode is included in a biosensor to produce an
`electrical signal, in combination with the working electrode,
`to
`the electrochemical reaction. Structure
`responsive
`included in a biosensor is adapted to resist direct physical
`contact between the working electrode and the reference
`electrode to prevent forming a direct electrical short between
`those electrodes.
`A first electrically conductive path exists between the
`working electrode and a first electrical contact. Similarly, a
`second electrically conductive path exists between the ref(cid:173)
`erence electrode and a second electrical contact. The first
`and second electrical contacts typically are associated with
`a hub operable to secure a probe in relation to a cannula. A
`signal may be received from the first and second contacts for
`data reduction and correlation to a physiological state in a
`body, such as glucose concentration. In general, the signal is
`
`4
`transmitted through a sensor cable affixed to structure of the
`hub. A workable sensor cable includes first and second
`wires, each wire having a first end arranged to make
`respective electrical connections with one of the first or
`second electrical contacts, and a second end of each wire
`typically being affixed to a sensor module operable to
`impose a conditioning signal on the biosensor probe.
`A working electrode can include a metal element (usually
`including platinum) formed as a wrap about a portion of the
`core. An exemplary working electrode includes a length of
`a first wire arranged to circumscribe a plurality of revolu-
`tions about the core. In such an exemplary working elec(cid:173)
`trode, a diameter of the first wire is between about 0.001 and
`about 0.005 inches. Desirably, the first wire is arranged to
`15 form a spiral path. Usually, at least a portion of the core is
`disposed substantially coaxial with an axis of the spiral. A
`currently preferred spiral path has an axial spacing, between
`the centerlines of a pair of adjacent wire wraps, sized
`between about one and about two diameters of the first wire.
`A larger spacing, up to about five diameters (or even more
`in some cases), is also workable, although it is recognized
`that the electrode's active surface area decreases with larger
`pitch spacing. Typically, the working electrode is arranged to
`reinforce the core so as to enable a reinforced core to carry
`an axial compression load permitting insertion of a distal tip
`of the biosensor through an introducer catheter for place-
`ment of the working electrode into intimate contact with
`tissue of the subject's body.
`The reference electrode typically includes a metal element
`30 (usually including Silver, and preferably including chlorided
`Silver) and can also be associated with the distal end of a
`core. A reference electrode may alternatively be associated
`with an introducer cannula, or some other structure. In the
`latter case, a reference electrode may sometimes be recessed
`35 into an exterior surface of the introducer cannula. In any
`event, it is currently preferred for a reference electrode to be
`placed into intimate contact with tissue of a subject's body.
`One embodiment of a reference electrode includes a length
`of a second wire formed as a wrap about a portion of the
`40 core. Another embodiment of a reference electrode may be
`fashioned as a length of wire, wire coil, foil, film, or coating
`associated with a cannula.
`A preferred electrode (either working or reference) may
`be characterized as having: an axially interrupted load path
`45 between first and second ends, a maximum equivalent
`outside diameter, a minimum equivalent inside diameter,
`and a surface texture disposed between the first and second
`ends that has a radially oriented component. Such an elec(cid:173)
`trode has a larger reactive surface area and a lower bending
`50 stiffness compared to a hollow cylinder structured from an
`equivalent material and having equivalent maximum outside
`and minimum inside diameters.
`The core of a biosensor probe according to the instant
`invention, can function to assist in retraction of the various
`55 components of the biosensor probe. One structure operable
`to assist in such retraction includes a plug carried on a distal
`end of the core. The plug can be structured as a stopper that
`is too large to pass through an electrode. Such a stopper
`operates to resist extraction of the core from within a portion
`60 of the working electrode as the biosensor is removed from
`the subject's body, so as not to leave a detached portion of
`the working electrode in the body. One functional plug is
`preferably formed, at least in part, with a polymer coating.
`Another functional plug can include a droplet of dielectric
`65 adhesive. A functional plug typically forms an enlargement
`in a cross-section of the core, with a portion of the enlarge(cid:173)
`ment being disposed distal to the working electrode.
`
`Dexcom Inc. v. WaveForm Technologies, Inc.
`IPR2017-01051
`Exhibit 1028
`
`

`

`US 6,965,791 Bl
`
`5
`
`5
`In probes carrying both working and reference electrodes,
`a dielectric spacer is usually interposed between the elec(cid:173)
`trodes to resist direct physical contact between them. A
`functional dielectric spacer can be made from a droplet of
`dielectric adhesive bonded to a portion of the core. Such a
`droplet desirably also is arranged as a stopper to resist
`extraction of the core from within a portion of the reference
`electrode as a biosensor is removed from a subject's body,
`so to not leave a detached portion of the reference electrode
`in the body.
`A probe portion of a biosensor includes a sensor shaft
`disposed between the working electrode and the hub. The
`sensor shaft generally includes a cylinder disposed circum(cid:173)
`ferentially about an axial length of the core proximal to the
`working electrode. A currently preferred cylinder includes a
`plurality of circumferential wrappings of a component wire
`having a smaller diameter than a diameter of the formed
`cylinder. Wrappings forming the cylinder desirably are
`closely spaced, or even touching, in an axial direction along
`an axis of the cylinder whereby to enable the shaft to carry 20
`an axial compression load effective to install the biosensor
`probe portion through an introducer cannula and into a body.
`Usually, a dielectric spacer is disposed at a distal end of the
`cylinder to resist direct physical contact between the shaft
`and an electrode. One such dielectric spacer can be formed 25
`from a droplet, or small quantity, of dielectric adhesive
`bonded to a portion of the core.
`Desirably, an exterior coating of a negatively charged
`polymer is applied to the working electrode. One operable
`negatively charged polymer includes sulfonated polyether- 30
`sulfone. It is also sometimes desirable to provide a micro(cid:173)
`scopically roughed-up surface to the outer surface of the
`coating to enhance biocompatibility of the biosensor with
`tissue of the subject's body. Desirable surface texture is
`formed by elements having a size of between about 5 and 50 35
`microns. Multifiber cores typically include a plurality of
`spaces between the fibers operable to carry glucose oxidase
`whereby to enhance a volume of glucose oxidase associated
`with a working electrode.
`The instant invention may be embodied broadly as an 40
`implantable biosensor including an introducer cannula and a
`probe element. The introducer cannula includes a lumen
`extending axially between its proximal and distal ends. The
`cannula's proximal end carries affixing structure adapted to
`resist motion of the proximal end relative to a skin surface 45
`of a subject and either carries holding structure configured to
`receive a probe. A distal end of the cannula carries a first
`electrode. A probe includes an elongate core having a distal
`end spaced apart axially from a proximal end, and is
`structured for sliding installation, through the cannula 50
`lumen, into a subject. A proximal end of the probe is
`associated with a hub adapted to be held by the cannula
`holding structure. The distal end of the probe carries a
`second electrode. The probe and cannula are cooperatively
`structured on assembly to resist direct physical contact 55
`between the first electrode and the second electrode. Desir-
`ably, the first and second electrodes are installed to be in
`intimate contact with the tissue of a subject.
`A method for manufacturing an implantable, needle-type
`biosensor probe with a transversely flexible first electrode 60
`effective to resist irritation at a site of implantation in a
`subject, includes the steps of: a) providing a core comprising
`a first nonconductive material; b) disposing a first electrode
`in a reinforcing path about the core; c) disposing a first
`electrical conductor between the first electrode and a hub 65
`associated with a proximal end of the probe; and d) dispos(cid:173)
`ing a second electrical conductor between a second electrode
`
`6
`and the hub. The method can also include the step of: e)
`forming a stopper carried by the core, a portion of the
`stopper being disposed distal to the first electrode and
`operable to resist extraction of the core from within an
`interior of the electrode, whereby to retain an association
`between the core and the electrode to resist leaving a portion
`of the electrode in a subject subsequent to removal of the
`probe.
`Sometimes, step b) includes: forming the first electrode as
`10 an axially interrupted first cylinder having a first length
`between a first end and a second end, a maximum equivalent
`outside diameter, and a minimum equivalent inside diam(cid:173)
`eter. The first cylinder desirably includes a surface texture
`disposed between its first and second ends that has a radially
`15 oriented component so as to provide a larger reactive surface
`area and a lower bending stiffness than a second cylinder
`having an equivalent maximum outside diameter and first
`length. An exemplary electrode having such conformation
`can be formed from a wire of between about 0.001 and about
`0.005 inches in diameter, with the wire being disposed to
`occupy a spiral path about the core.
`In some cases, the method may further include disposing
`a second wire circumferentially about the core in a spiral
`reinforcing path operable to enhance an axial load carrying
`capability of the core, whereby to form the second electrode.
`Typically, the step of applying an insulation to a conductive
`path extending proximally from one or both electrodes is
`further included. When two electrodes are carried on a core,
`the method additionally can include affixing a dielectric
`element between the working and the reference electrodes.
`Such dielectric element desirably is also adapted to resist
`extraction of the core from retention in an electrode,
`whereby to resist leaving a portion of that electrode inside a
`subject subsequent to extraction of the probe. Generally, the
`method includes the step of wrapping, or otherwise dispos(cid:173)
`ing, a third wire circumferentially about the core in a spiral
`reinforcing path to form a shaft of the probe. Furthermore,
`the method includes affixing the hub to a proximal portion
`of the shaft.
`Coatings are typically applied in additional steps subse(cid:173)
`quent to assembly of basic probe structure. An inner exclu(cid:173)
`sion membrane is formed in a first coating step by applying
`a solution, such as 5% polyethersulfone, to the working
`electrode. A second coating step includes applying a solu(cid:173)
`tion, such as 1% glucose oxidase, 0.6% albumin and 0.0.5%
`glutaraldehyde, to the working electrode to form a middle
`enzymatic membrane. In a third coating step, a solution,
`such as 5% polyurethane is applied to both the working and
`the reference electrodes to form an outer polymer mem(cid:173)
`brane. The final polyurethane coating desirably is micro(cid:173)
`scopically roughed-up by performing a phase inversion
`polymerization procedure. In general, a workable phase
`version polymerization procedure includes immediately dip(cid:173)
`ping the final polyurethane layer into a water bath to largely
`rinse away the miscible solvent soon after the first of the
`polymer molecules comprising the 5% solution have begun
`to bond with the second-to-last layer. Desirably, the resulting
`surface includes protruding particles sized between about 5
`and 50 microns.
`
`BRIEF DESCRIPTION OF THE SEVERAL
`VIEWS OF THE DRAWINGS
`
`In the drawings, which illustrate what are currently
`regarded as the best modes for carrying out the invention:
`FIG. 1 is a schematic of one configuration of a preferred
`embodiment;
`
`Dexcom Inc. v. WaveForm Technologies, Inc.
`IPR2017-01051
`Exhibit 1028
`
`

`

`7
`FIG. 2A is a perspective side view in elevation of a first
`implantable biosensor according to the present invention;
`FIG. 2B is an enlarged perspective view in elevation of a
`probe portion of the implantable biosensor illustrated in
`FIG. 2A;
`FIG. 2C is a perspective side view in elevation of the
`implantable biosensor of FIG. 2A, in a partially assembled
`configuration;
`FIG. 2D is a perspective side view in elevation of the
`implantable biosensor of FIG. 2A, in an assembled configu(cid:173)
`ration;
`FIG. 3 is a side view illustrating a stage of construction of
`a probe portion of the implantable biosensor of the inven-
`tion;
`FIG. 4 is a side view of an assembled but uncoated 15
`miniature probe portion of the biosensor of the invention;
`FIG. 5 is an enlarged cross-sectional side view of a
`miniature, flexible probe portion of the implantable biosen(cid:173)
`sor;
`FIG. 6Ais a perspective side view in elevation of a second
`implantable biosensor according to the present invention;
`FIG. 6B is an enlarged perspective view in elevation with
`greater resolution of a portion of the embodiment illustrated
`in FIG. 6A;
`FIG. 6C is a perspective view in elevation of the embodi(cid:173)
`ment of FIG. 6A in a partially assembled configuration; and
`FIG. 6D is a perspective view in elevation of the embodi(cid:173)
`ment of FIG. 6A in an assembled configuration.
`
`BEST MODE OF THE INVENTION
`
`FIG. 1 illustrates a preferred embodiment in which an
`implantable biosensor, generally 10, and associated sensor
`cable 20 is provided. Miniaturized and highly flexible, the
`biosensor 10 may be placed into a subject subcutaneously
`through a cannula such as an introducer catheter 30. The
`biosensor 10 as illustrated is associated percutaneously
`through the sensor cable 20 with a sensor module 40 which
`in turn is associated via a module cable 50 with a Sensor
`Display Unit ("SDU") 60. The SDU 60 can be structured to 40
`be interactive across SDU cable 70 with computer hardware
`and other software, generally 80.
`The foregoing biosensor system may include a single use
`portion and a reusable portion. The single use portion
`includes the introducer catheter 30, the biosensor 10, the 45
`sensor cable 20, the sensor module 40 and the module cable
`50. The introducer catheter 30 can generally be regarded as
`a separate component, although certain embodiments may
`incorporate the catheter to carry a portion of a biosensor
`probe. The biosensor 10, sensor cable 20, sensor module 40 50
`and module cable 50 desirably are all be permanently affixed
`to each other. Module cable 50 typically is removably
`attached at disconnect 55 to a sensor display unit (SDU) 60.
`The SDU 60 and SDU cable 70 may be reused. When
`attached to the SDU 60, the SDU cable 70 allows the glucose 55
`information to be downloaded to a personal computer 80
`that is loaded with the sensor download software 80.
`To install a preferred embodiment of a biosensor 10,
`introducer catheter 30 can be inserted into the subcutaneous
`tissue of a subject on a supporting needle (not illustrated).
`The supporting needle is removed to leave an opening
`through the cannula, and typically, a short path extension
`into the subject's tissue. Then, the biosensor 10 may be
`placed into the catheter 30 such that a portion of the
`biosensor 10 protrudes beyond the catheter 30. The working 65
`electrode 100 and reference electrode 110 of the presently
`preferred embodiment are designed to be deployed 3-10 nm
`
`US 6,965,791 Bl
`
`8
`into the su