DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
The amendments filed December 29, 2025 has been entered. Claims 1, 10, and 19 have been amended. Claims 1, 3-6, 8-10, 12-19, 21-23 are pending in this application.
Response to Arguments
Applicant's arguments filed July 22, 2025 have been fully considered but they are not persuasive. Claims 1, 10, and 19 have been amended to recite “wherein the membrane is crosslinked to the sensing area.”
Mao teaches a 4-vinylpyridine and styrene membrane overcoating the sensing area (par. 55; Fig. 2A). Mao teaches that the “membrane is formed in situ by applying an alcohol-buffer solution of a crosslinker and a modified polymer over an enzyme-containing sensing layer and allowing the solution to cure for one to two days” (par. 18). There is evidence that in situ polymerization inherently forms crosslinks between the polymers in the membrane and sensing layer. Ouyang (US 2012/0296186) recites “in situ polymerization of the membrane can form crosslinks between the polymers of the membrane and the polymers in the sensing layer” (par. 29). Ouyang further teaches the same method of forming a membrane in situ (par. 128) and membrane composition (pars. 43-44), which further supports that Mao’s method of membrane formation would inherently crosslink the membrane to the sensing area.
Alternatively, if Applicant believes that Mao does not inherently teach that the membrane is crosslinked to the sensing area, then one of ordinary skill in the art before the effective filing date of the invention would be motivated to crosslink the membrane to the sensing area. One would be motivated to do so because Ouyang teaches that crosslinking of the membrane to the sensing layer facilitates a reduction in the occurrence of delamination of the membrane from the sensing layer (par. 29). Ouyang teaches a similar membrane (4-vinylpyridine and styrene copolymer, pars. 43-44) formed in a similar way (par. 128), so this modification could be successfully applied to the sensor of Say in view of Mao, Zou, and Wellinghoff.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Applicant argues that “nothing in Zou teaches or suggests a membrane comprising a copolymer of 4-vinylpyridine and styrene…wherein the membrane is crosslinked with the sensing area” and that “nothing in Wellinghoff teaches or suggests a membrane comprising a copolymer of 4-vinylpyridine…wherein the membrane is crosslinked with the sensing area” (Remarks pg. 8, paragraphs 2-3). However, Mao is the reference relied on to teach a sensor membrane comprising a copolymer of 4-vinylpyridine and styrene, and Applicant has not provided specific arguments about Mao’s teachings or about the combination of references. Thus, the argument is unpersuasive.
Regarding claims 10, 19 and the dependent claims, Applicant relies on the same arguments. Since the arguments were unpersuasive, the same references are relied on in the rejection below in addition to Ouyang.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 3-6, 8-9, 19, and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Say (U.S. Patent No. 6,565,509) in view of Mao (US 2003/0042137), Zou (US 2017/0191955), Wellinghoff (US 2006/0057191), and optionally further in view of Ouyang (US 2012/0296186). Say, Mao, Zou, and Wellinghoff have been cited previously.
Regarding claim 1, Say teaches an analyte sensor (sensor 42, Figs. 1-2) comprising:
a sensor tail substrate having a lower portion and configured for insertion into a tissue (substrate 50, Fig. 2; col. 6, lines 59-65),
a first electrode (working electrode 58) disposed on the lower portion of the sensor tail substrate (Fig. 2),
a sensing area disposed upon a surface of the first electrode (sensing layer 64 may comprise electron transfer agents and catalysts to catalyze a reaction of the analyte, col. 7, lines 47-64; Figs. 3, 6-7),
a membrane (any one of mass transport limiting layer 74, biocompatible layer 75, or interferent eliminating layer (not shown) can be considered a membrane, Fig. 9), wherein the membrane overcoats both faces of the lower portion of the sensor tail substrate, wherein the membrane overcoats the sensing area (“the sensor may be completely…coated on its exterior with a biocompatible coating,” col. 25, lines 22-23; Fig. 9 shows coatings 74 and 75 on both sides of substrate 50);
a second electrode (any of reference electrode 62, counter electrode 60, or a counter/reference electrode, col. 7, lines 22-25) disposed on the lower portion of the sensor tail substrate, wherein the second electrode is disposed on the same or the opposite side of the sensor tail substrate as the first electrode (Figs. 2, 6);
and a non-electrochemical functional layer located at the lower portion of the sensor tail substrate (any other of mass transport limiting layer 74, biocompatible layer 75, or interferent eliminating layer can be considered a non-electrochemical functional layer, Fig. 9; “interferent-eliminating layer (not shown) may be included in the sensor 42…prevents the penetration of one or more interferents into the region around the working electrodes 58,” col. 25, lines 31-40), and
wherein the analyte sensor is configured to be inserted into a tissue and in contact with a bodily fluid to detect an analyte in the bodily fluid (“an implantable sensor for the in vivo determination of a concentration of an analyte…in a fluid,” col. 5, lines 33-35).
Say explicitly teaches all limitations of claim 1 except for the membrane having a thickness from 1-500 microns, comprising a copolymer of 4-vinylpyridine and styrene, being crosslinked to the sensing area, comprising 0.1% to 50% by weight of a metal-based antimicrobial compound selected from the group consisting of silver chloride, silver iodide, and combinations thereof, and wherein the metal-based antimicrobial compound is configured to diffuse into the tissue.
Regarding the membrane polymer, Mao teaches an analogous sensor membrane for use in an analyte sensor (membrane 20, Fig. 2A). Mao teaches the membrane can comprise a copolymer of 4-vinylpyridine and styrene (“poly(heterocyclic nitrogen-co-D) polymers suitable as starting materials for the present invention are commercially available. For example…poly(4-vinylpyridine-co-styrene),” para. 55).
It would be obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Say to comprise poly(4-vinylpyridine-co-styrene) in Say’s mass transport limiting layer 74, biocompatible layer 75, or interferent eliminating layer. One would be motivated to do so because this copolymer was already known in the art for limiting analyte flux, improving biocompatibility , and blocking interferents in the sensor (“the resulting membrane is capable of limiting the flux of an analyte,” para. 43; “properties of the membrane including…biocompatibility…permeability to an analyte and its non-permeability to an undesirable, interfering component,” para. 55). Using a different known polymer to create a sensor membrane with the same functionality as Say’s mass transport limiting layer 74, biocompatible layer 75, or interferent eliminating layer would be obvious to try. Furthermore, one would be further motivated to use a membrane comprising poly(4-vinylpyridine-co-styrene) because Mao teaches advantages of the membrane include sensitivity, stability, responsivity, motion-compatibility, ease of calibration, and ease and reproducibility of manufacture (para. 110).
Regarding the thickness of the membrane, Mao teaches that the membrane thickness is controlled by the concentration of the membrane solution, the droplets applied, and the number of times the sensor is dipped in the solution (par. 18). Zou teaches an analogous analyte sensor (sensor 38) comprising a membrane (diffusion resistance domain 46 and/or biointerface domain 48, Fig. 2A) with a thickness from 1-500 microns (a diffusion-resistance layer can be 0.01-250 microns thick, par. 8; the biointerface domain can be 0.1-250 microns thick, par. 172).
It would be obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Say in view of Mao such that the membrane thickness is between 1-500 microns. Since Mao doesn’t explicitly teach how thick the membrane should be, one would be motivated to look at known sensor membranes made using the same techniques such as the membranes taught by Zou. Zou teaches similar membrane polymers to Mao (polyvinylpyridine and styrene polymers, pars. 191, 268) and the membrane is applied using similar techniques (drop-let coating and dipping, par. 76). Thus, a sensor membrane made with droplet coating and dipping techniques can have a thickness within the claimed range (“the preferred number of repeated dip processes can depend upon the polymers used, their concentration, conditions during deposition (e.g., dipping) and the desired thickness,” Zou par. 204; “the thickness of the membrane is controlled by the concentration of the solution, by the number of droplets of the solution applied, by the number of times the sensor is dipped in the solution, or by any combination of the these factors,” Mao par. 18).
Regarding the antimicrobial compound, Zou teaches the sensor membrane (diffusion resistance domain 46 and/or biointerface domain 48, Fig. 2A) comprises 0.1% to 50% by weight of a silver antimicrobial compound (“a bioactive agent can be incorporated into the membrane system,” paragraph 325; anti-infective agents include silver, paragraph 317; the level of loading of the bioactive agent can be from 1%-50% by weight, paragraphs 339-340), and wherein the metal-based antimicrobial compound is configured to diffuse into the tissue (“bioactive agents of the preferred embodiments can be optimized for short or long-term release,” Zou paragraphs 335-337). Wellinghoff teaches a polymer blend containing silver chloride or silver iodide can be used as a coating for medical devices to reduce infection (“method of making a biocidal material comprising: (1) obtaining a solution of an organosoluble silver salt…(4) dissolving an organosoluble hydrophilic polymer in the organic phase to make a mobile solution…to produce coated objects by solvent evaporation,” paragraph 18; ‘Silver’ includes all silver salts or silver compounds, including, but not limited to, silver chloride…silver iodide,” paragraph 20). Wellinghoff is analogous art because it is reasonably pertinent to the problems identified by Say and Zou (MPEP 2141.01(a)(I); “biomolecules may foul the electrodes…reducing the effectiveness of the sensor,” Say col. 25, lines 13-15; “the wound created by the incision into which an implantable device is inserted,” Zou paragraph 314). Wellinghoff also teaches that the silver salt can be configured for diffusion into the tissue (“a controlled release of silver over a wide range of rates,” Wellinghoff paragraph 65).
It would be obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Say in view of Mao and Zou such that the sensor membrane comprises silver chloride or silver iodide in an amount of 1% to 50% by weight of the membrane or layer (Zou paras. 339-340; Wellinghoff para. 20). One would be motivated to do so because Zou teaches including an antimicrobial agent can reduce an inflammatory response at a sensor implant site (“anti-infective agents are substances capable of acting against infection…which can serve to reduce an immuno-response without an inflammatory response at the implant site,” Zou paragraph 317), and silver and silver-based compounds were known in the art to provide an antimicrobial quality to a polymer coating (Zou paragraph 317; “silver ions exhibit biocidal properties,” Wellinghoff paragraph 27). The sensor of Say in view of Mao could be improved in the same way by incorporating silver chloride or silver iodide in the membrane. This modification could be carried out with a reasonable expectation of success because Zou and Wellinghoff teach similar membrane polymers to Mao (polyvinylpyridine and styrene polymers disclosed in Zou paragraphs 147, 191, 268 and Wellinghoff paragraphs 41, 43). Furthermore, Wellinghoff teaches that silver ions may associate with the pyridine group of a vinylpyridine polymer or the arene group of a styrene copolymer (para. 15), and Mao teaches that plenty of heterocyclic nitrogen atoms are left unbonded (“pyridine groups, only a few percent of which are used in crosslinking during membrane formation. The membrane thus has an excess of these groups present,” para. 83), providing additional evidence that silver iodide or silver chloride may successfully be incorporated into a membrane comprising poly(4-vinylpyridine-co-styrene).
Regarding the membrane crosslinked to the sensing area, Mao further teaches that the “membrane is formed in situ by applying an alcohol-buffer solution of a crosslinker and a modified polymer over an enzyme-containing sensing layer and allowing the solution to cure for one to two days” (par. 18). In situ polymerization on the sensing layer inherently forms crosslinks between the polymers in the membrane and sensing layer, as evidenced by Ouyang (“in situ polymerization of the membrane can form crosslinks between the polymers of the membrane and the polymers in the sensing layer,” par. 29). Ouyang further teaches the same method of forming a membrane in situ (par. 128) and membrane composition (pars. 43-44), which further supports that Mao’s method of membrane formation would inherently crosslink the membrane to the sensing area.
Alternatively, if Applicant believes that Mao does not inherently teach that the membrane is crosslinked to the sensing area, then one of ordinary skill in the art before the effective filing date of the invention would be motivated to crosslink the membrane of Say in view of Mao, Zou, and Wellinghoff to the sensing area. One would be motivated to do so because Ouyang teaches that crosslinking of the membrane to the sensing layer facilitates a reduction in the occurrence of delamination of the membrane from the sensing layer (par. 29). Ouyang teaches a similar membrane (4-vinylpyridine and styrene copolymer, pars. 43-44) formed in a similar way (par. 128), so this modification could be successfully applied to the sensor of Say in view of Mao, Zou, and Wellinghoff.
Thus, Say in view of Mao, Zou, Wellinghoff, and optionally Ouyang teach or suggest all limitations of claim 1.
Regarding claims 3 and 4, according to the broadest reasonable interpretation of the claim language, any lower region of the sensor tail can be considered the lower portion. For example, if the entire length of the sensor having narrow width 53 (Say Fig. 2) is considered a lower portion of the sensor tail (“all or only a part of this narrow portion may be subcutaneously implanted into the patient,” Say col. 9, lines 60-62), then the lower portion comprises more than 50% of the sensor tail substrate extending from the distal tip.
Regarding claim 5, Wellinghoff teaches the metal-based antimicrobial compound is chemically bound to the membrane (Wellinghoff teaches that the silver ion can bond to polymers, paras. 15, 54).
Regarding claim 6, Wellinghoff teaches the metal-based antimicrobial compound is homogeneously or spatially intermixed with the membrane (Wellinghoff teaches creating a solution or blend with the silver salt before crosslinking the membrane, paras. 18, 54, 63).
Regarding claim 8, Say in view of Mao, Zou, Wellinghoff, and optionally Ouyang teaches the metal-based antimicrobial compound is configured for bolus diffusion, sustained delivery diffusion, or dynamic diffusion into the tissue (“bioactive agents of the preferred embodiments can be optimized for short or long-term release…release of the factors can be continuous or discontinuous, linear, or non-linear…release over a period of from about a few minutes or hours to…about 7 days or more,” Zou paras. 335-337; “a controlled release of silver over a wide range of rates,” Wellinghoff paragraph 65).
Regarding claim 9, Wellinghoff teaches the metal-based antimicrobial compound can be silver iodide (“silver” includes all silver salts including silver iodide, Wellinghoff paragraph 20).
Regarding claim 19, Say teaches a system (Fig. 1) comprising:
a receiver (receiver 46 or 48) and an analyte sensor (sensor 42) in electrical communication with the receiver (col. 36, lines 64-67), the analyte sensor comprising:
a sensor tail substrate having a lower portion and configured for insertion into a tissue (substrate 50, Fig. 2; col. 6, lines 59-65), a first electrode (working electrode 58) and a second electrode (any of a second working electrode 58b, a counter electrode 60 or reference electrode 62 can be considered a second electrode) disposed on the lower portion of the sensor tail substrate, wherein the second electrode is disposed on the same side or on the opposite side of the sensor tail substrate as the first electrode (Figs. 2, 6);
a sensing area disposed upon a surface of the first electrode (sensing layer 64 may comprise electron transfer agents and catalysts to catalyze a reaction of the analyte, col. 7, lines 47-64; Figs. 3, 6-7),
a membrane, wherein the membrane overcoats both faces of the lower portion of the sensor tail substrate and the sensing area (“the sensor may be completely…coated on its exterior with a biocompatible coating,” col. 25, lines 22-23; Fig. 9 shows coatings 74 and 75 on both sides of substrate 50); and a non-electrochemical functional layer located at least at the lower portion of the sensor tail substrate (any two of mass transport limiting layer 74, biocompatible layer 75, or interferent eliminating layer (not shown) can be considered a membrane and a non-electrochemical functional layer); and
wherein the analyte sensor is configured to be inserted into a tissue and in contact with a bodily fluid to detect an analyte in the bodily fluid (“an implantable sensor for the in vivo determination of a concentration of an analyte…in a fluid,” col. 5, lines 33-35).
Say explicitly teaches all limitations of claim 19 except for the membrane having a thickness from 1-500 microns, comprising a copolymer of 4-vinylpyridine and styrene, being crosslinked to the sensing area, comprising 0.1% to 50% by weight of a metal-based antimicrobial compound selected from the group consisting of silver chloride, silver iodide, and combinations thereof, and wherein the metal-based antimicrobial compound is configured to diffuse into the tissue.
Regarding the membrane polymer, Mao teaches an analogous sensor membrane for use in an analyte sensor (membrane 20, Fig. 2A). Mao teaches the membrane can comprise a copolymer of 4-vinylpyridine and styrene (“poly(heterocyclic nitrogen-co-D) polymers suitable as starting materials for the present invention are commercially available. For example…poly(4-vinylpyridine-co-styrene),” para. 55).
It would be obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Say to comprise poly(4-vinylpyridine-co-styrene) in Say’s mass transport limiting layer 74, biocompatible layer 75, or interferent eliminating layer. One would be motivated to do so because this copolymer was already known in the art for limiting analyte flux, improving biocompatibility , and blocking interferents in the sensor (“the resulting membrane is capable of limiting the flux of an analyte,” para. 43; “properties of the membrane including…biocompatibility…permeability to an analyte and its non-permeability to an undesirable, interfering component,” para. 55). Using a different known polymer to create a sensor membrane with the same functionality as Say’s mass transport limiting layer 74, biocompatible layer 75, or interferent eliminating layer would be obvious to try. Furthermore, one would be further motivated to use a membrane comprising poly(4-vinylpyridine-co-styrene) because Mao teaches advantages of the membrane include sensitivity, stability, responsivity, motion-compatibility, ease of calibration, and ease and reproducibility of manufacture (para. 110).
Regarding the thickness of the membrane, Mao teaches that the membrane thickness is controlled by the concentration of the membrane solution, the droplets applied, and the number of times the sensor is dipped in the solution (par. 18). Zou teaches an analogous analyte sensor (sensor 38) comprising a membrane (diffusion resistance domain 46 and/or biointerface domain 48, Fig. 2A) with a thickness from 1-500 microns (a diffusion-resistance layer can be 0.01-250 microns thick, par. 8; the biointerface domain can be 0.1-250 microns thick, par. 172).
It would be obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Say in view of Mao such that the membrane thickness is between 1-500 microns. Since Mao doesn’t explicitly teach how thick the membrane should be, one would be motivated to look at known sensor membranes made using the same techniques such as the membranes taught by Zou. Zou teaches similar membrane polymers to Mao (polyvinylpyridine and styrene polymers, pars. 191, 268) and the membrane is applied using similar techniques (drop-let coating and dipping, par. 76). Thus, a sensor membrane made with droplet coating and dipping techniques can have a thickness within the claimed range (“the preferred number of repeated dip processes can depend upon the polymers used, their concentration, conditions during deposition (e.g., dipping) and the desired thickness,” Zou par. 204; “the thickness of the membrane is controlled by the concentration of the solution, by the number of droplets of the solution applied, by the number of times the sensor is dipped in the solution, or by any combination of the these factors,” Mao par. 18).
Regarding the antimicrobial compound, Zou teaches the membrane comprises 0.1% to 50% by weight of a silver antimicrobial compound (“a bioactive agent can be incorporated into the membrane system,” paragraph 325; anti-infective agents include silver, paragraph 317; the level of loading of the bioactive agent can be from 1%-50% by weight, paragraphs 339-340), and wherein the metal-based antimicrobial compound is configured to diffuse into the tissue (“bioactive agents of the preferred embodiments can be optimized for short or long-term release,” Zou paragraphs 335-337). Wellinghoff teaches a polymer blend containing silver chloride or silver iodide can be used as a coating for medical devices to reduce infection (“method of making a biocidal material comprising: (1) obtaining a solution of an organosoluble silver salt…(4) dissolving an organosoluble hydrophilic polymer in the organic phase to make a mobile solution…to produce coated objects by solvent evaporation,” paragraph 18; ‘Silver’ includes all silver salts or silver compounds, including, but not limited to, silver chloride…silver iodide,” paragraph 20). Wellinghoff is analogous art because it is reasonably pertinent to the problems identified by Say and Zou (MPEP 2141.01(a)(I); “biomolecules may foul the electrodes…reducing the effectiveness of the sensor,” Say col. 25, lines 13-15; “the wound created by the incision into which an implantable device is inserted,” Zou paragraph 314). Wellinghoff also teaches that the silver salt can be configured for diffusion into the tissue (“a controlled release of silver over a wide range of rates,” Wellinghoff paragraph 65).
It would be obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Say in view of Mao and Zou such that the sensor membrane comprises silver chloride or silver iodide in an amount of 1% to 50% by weight of the membrane or layer (Zou paras. 339-340; Wellinghoff para. 20). One would be motivated to do so because Zou teaches including an antimicrobial agent can reduce an inflammatory response at a sensor implant site (“anti-infective agents are substances capable of acting against infection…which can serve to reduce an immuno-response without an inflammatory response at the implant site,” Zou paragraph 317), and silver and silver-based compounds were known in the art to provide an antimicrobial quality to a polymer coating (Zou paragraph 317; “silver ions exhibit biocidal properties,” Wellinghoff paragraph 27). The sensor of Say in view of Mao could be improved in the same way by incorporating silver chloride or silver iodide in the membrane. This modification could be carried out with a reasonable expectation of success because Zou and Wellinghoff teach similar membrane polymers to Mao (polyvinylpyridine and styrene polymers disclosed in Zou paragraphs 147, 191, 268 and Wellinghoff paragraphs 41, 43). Furthermore, Wellinghoff teaches that silver ions may associate with the pyridine group of a vinylpyridine polymer or the arene group of a styrene copolymer (para. 15), and Mao teaches that plenty of heterocyclic nitrogen atoms are left unbonded (“pyridine groups, only a few percent of which are used in crosslinking during membrane formation. The membrane thus has an excess of these groups present,” para. 83), providing additional evidence that silver iodide or silver chloride may successfully be incorporated into a membrane comprising poly(4-vinylpyridine-co-styrene).
Regarding the membrane crosslinked to the sensing area, Mao further teaches that the “membrane is formed in situ by applying an alcohol-buffer solution of a crosslinker and a modified polymer over an enzyme-containing sensing layer and allowing the solution to cure for one to two days” (par. 18). In situ polymerization on the sensing layer inherently forms crosslinks between the polymers in the membrane and sensing layer, as evidenced by Ouyang (“in situ polymerization of the membrane can form crosslinks between the polymers of the membrane and the polymers in the sensing layer,” par. 29). Ouyang further teaches the same method of forming a membrane in situ (par. 128) and membrane composition (pars. 43-44), which further supports that Mao’s method of membrane formation would inherently crosslink the membrane to the sensing area.
Alternatively, if Applicant believes that Mao does not inherently teach that the membrane is crosslinked to the sensing area, then one of ordinary skill in the art before the effective filing date of the invention would be motivated to crosslink the membrane of Say in view of Mao, Zou, and Wellinghoff to the sensing area. One would be motivated to do so because Ouyang teaches that crosslinking of the membrane to the sensing layer facilitates a reduction in the occurrence of delamination of the membrane from the sensing layer (par. 29). Ouyang teaches a similar membrane (4-vinylpyridine and styrene copolymer, pars. 43-44) formed in a similar way (par. 128), so this modification could be successfully applied to the sensor of Say in view of Mao, Zou, and Wellinghoff.
Thus, Say in view of Mao, Zou, Wellinghoff, and optionally Ouyang teach all limitations of claim 19.
Regarding claim 21, Mao teaches a first portion of the pyridine nitrogen atoms in the 4-vinylpyridine are functionalized with a non-crosslinked poly(ethylene glycol) tail (the “B” modifier groups attached to pyridine nitrogen atoms can be poly(ethylene glycol), Mao para. 60; evidence that the polyethylene glycol is non-crosslinked is given by US 2004/0242770: “In PVP-PEG blends, only high molecular weight polymers (i.e., PVP) can be crosslinked…the PEG remains non-crosslinked,” para. 248).
Regarding claim 22, S Say in view of Mao, Zou, Wellinghoff, and optionally Ouyang teaches the analyte sensor generates a signal with a drift rate of less than 20% over 300 hours (“sensors containing the disclosed diffusion-resistance layers can have a minimum drift… a drift of less than 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% over 10 days,” Zou paragraph 198; Mao teaches the stability curve of a sensor with the membrane is about 0.06% per hour, para. 91; 10% change or less over 240 hours and 0.06%/hr are lower drift rates than 20% change over 300 hours;)
Regarding claim 23, Mao teaches a second portion of the nitrogen atoms in the 4-vinylpyridine are functionalized with an alkylsulfonic acid group (the “A” modifier groups attached to pyridine nitrogen can be sulfonate groups, Mao para. 46; Formula 5 polymer is formed through reaction with methanesulfonic acid to yield a sulfonate group attached to the pyridine nitrogen, Mao para. 66).
Claims 10, 12-18 are rejected under 35 U.S.C. 103 as being unpatentable over Zou in view of Say, Mao, Wellinghoff, and optionally further in view of Ouyang.
Regarding claims 10, Zou teaches a method comprising:
diffusing a metal-based antimicrobial compound (“bioactive agents of the preferred embodiments can be optimized for short or long-term release,” paragraph 335; bioactive agents include anti-infective agents such as silver, paragraph 317) into a tissue from an analyte sensor (sensor 38), the analyte sensor comprising:
a substrate comprising a first electrode (working electrode of sensor 38 can comprise a plated polymer such that the core 410 can be considered substrate and the first layer can be considered the electrode, paragraph 94; Fig. 3B) and a second electrode (reference electrode 414 is formed from silver/silver chloride, paragraph 103) disposed on a lower portion of the substrate and configured for insertion into a tissue (Figs. 3B-3C);
a sensing area disposed upon a surface of the first electrode (enzyme layer 44, paragraph 77, Fig. 2A),
a membrane (diffusion resistance domain 46 and/or biointerface domain 48, Fig. 2A), wherein the membrane overcoats the sensing area (Figs. 2A-2B), and wherein the membrane has a thickness from about 1 micron to about 500 microns (a diffusion-resistance layer can be 0.01-250 microns thick, par. 8; the biointerface domain can be 0.1-250 microns thick, par. 172);
a non-electrochemical functional layer located at least at the lower portion of the substrate (interference membrane 43 can be interpreted as a non-electrochemical functional layer, paragraphs 77-78)
wherein at least the membrane comprises 0.1% to about 50% by weight of the metal-based antimicrobial compound (“a bioactive agent can be incorporated into the membrane system…the bioactive agent diffuses through the membrane system,” paragraph 325; the level of loading of the bioactive agent can be from 1%-50% by weight, paragraphs 339-340);
and wherein the analyte sensor is configured to be inserted into a tissue and in contact with the bodily fluid to detect an analyte in the bodily fluid (“implantable devices, such as devices for monitoring and determining analyte levels in a biological fluid,” para. 72).
Zou teaches all limitations of claim 10 except for the second electrode being on the same side or on the opposite side of the sensor tail substrate as the first electrode, the membrane overcoats both faces of the lower portion of the sensor tail substrate, the membrane comprising a copolymer of 4-vinylpyridine and styrene and is crosslinked to the sensing area, and the metal-based antimicrobial compound being selected from the group consisting of silver chloride, silver iodide, and combinations thereof.
Regarding the sensor and membrane structure, Zou teaches concentric electrodes and membrane systems (Figs. 2A-3C) but suggests that other sensor structures may be used, such as those taught by Say (“the sensors may be implemented as planar sensors,” paragraph 71; “In one alternative embodiment, the continuous glucose sensor comprises a sensor such as described in U.S. Pat. No. 6,565,509 to Say et al.,” Zou paragraph 74). Say teaches an analogous analyte sensor (sensor 42) comprising a sensor tail substrate having a lower portion and configured for insertion into a tissue (substrate 50, Fig. 2; col. 6, lines 59-65), a first electrode (working electrode 58), a second electrode (any of a second working electrode 58b, a counter electrode 60 or reference electrode 62 can be considered a second electrode), and a membrane (coatings 74, 75, Fig. 9) disposed on the lower portion of the sensor tail substrate, wherein the membrane overcoats both faces of the lower portion of the sensor tail substrate (“the sensor may be completely…coated on its exterior with a biocompatible coating,” col. 25, lines 22-23; Fig. 9 shows coatings 74 and 75 on both sides of substrate 50) and the second electrode is disposed on the same side or on the opposite side of the sensor tail substrate as the first electrode (Figs. 2, 6).
It would be obvious to one of ordinary skill in the art before the effective filing date of the invention to modify the analyte sensor of Zou to include a planar sensor substrate comprising at least two electrodes disposed on the same or different sides of the substrate and providing the sensor membranes on two sides of the sensor substrate, as taught by Say Figs. 2, 6, 9. One would be motivated to do so because Zou explicitly teaches the sensor of Say as an alternative embodiment of an analyte sensor structure (paragraph 74). Zou also teaches “the membranes described herein can be applied to any planar or non-planar surface” (paragraph 84), further indicating this modification could be carried out with a reasonable expectation of success.
Regarding the membrane polymer, Mao teaches an analogous sensor membrane for use in an analyte sensor (membrane 20, Fig. 2A). Mao teaches the membrane can comprise a copolymer of 4-vinylpyridine and styrene (“poly(heterocyclic nitrogen-co-D) polymers suitable as starting materials for the present invention are commercially available. For example…poly(4-vinylpyridine-co-styrene),” para. 55).
It would be obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Zou to comprise poly(4-vinylpyridine-co-styrene) in diffusion resistance domain 46 or biointerface domain 48. One would be motivated to do so because this copolymer was already known in the art for limiting analyte flux and improving biocompatibility (“the resulting membrane is capable of limiting the flux of an analyte,” para. 43; “properties of the membrane including…biocompatibility…permeability to an analyte,” para. 55). Using a different known polymer to create a sensor membrane with the same functionality as diffusion resistance domain 46 or biointerface domain 48 would be obvious to try. Furthermore, one would be further motivated to use a membrane comprising poly(4-vinylpyridine-co-styrene) because Mao teaches advantages of the membrane include sensitivity, stability, responsivity, motion-compatibility, ease of calibration, and ease and reproducibility of manufacture (para. 110).
Regarding the antimicrobial compound, Wellinghoff teaches a polymer blend containing silver chloride or silver iodide can be used as a coating for medical devices to reduce infection (“method of making a biocidal material comprising: (1) obtaining a solution of an organosoluble silver salt…(4) dissolving an organosoluble hydrophilic polymer in the organic phase to make a mobile solution…to produce coated objects by solvent evaporation,” paragraph 18; ‘Silver’ includes all silver salts or silver compounds, including, but not limited to, silver chloride…silver iodide,” paragraph 20). Wellinghoff is analogous art because it is reasonably pertinent to the problems identified by Say and Zou (MPEP 2141.01(a)(I); “biomolecules may foul the electrodes…reducing the effectiveness of the sensor,” Say col. 25, lines 13-15; “the wound created by the incision into which an implantable device is inserted,” Zou paragraph 314). Wellinghoff also teaches that the silver salt can be configured for diffusion into the tissue (“a controlled release of silver over a wide range of rates,” Wellinghoff paragraph 65).
It would be obvious to one of ordinary skill in the art before the effective filing date of the invention to modify Zou in view of Say, and Mao such that silver chloride or silver iodide is used as an antimicrobial agent instead of silver or other agents disclosed in Zou paragraphs 310-313 and 317. One would be motivated to do so because silver and silver-based compounds were known in the art to provide an antimicrobial quality (Zou paragraph 317; “silver ions exhibit biocidal properties,” Wellinghoff paragraph 27), and one of ordinary skill in the art would have been able to substitute silver within the membrane of Zou for silver chloride or silver iodide. This modification could be carried out with a reasonable expectation of success because Zou and Wellinghoff teach similar membrane polymers to Mao (polyvinylpyridine and styrene polymers disclosed in Zou paragraphs 147, 191, 268 and Wellinghoff paragraphs 41, 43). Furthermore, Wellinghoff teaches that silver ions may associate with the pyridine group of a vinylpyridine polymer or the arene group of a styrene copolymer (para. 15), and Mao teaches that plenty of heterocyclic nitrogen atoms are left unbonded (“pyridine groups, only a few percent of which are used in crosslinking during membrane formation. The membrane thus has an excess of these groups present,” para. 83), providing additional evidence that silver iodide or silver chloride may successfully be incorporated into a membrane comprising poly(4-vinylpyridine-co-styrene).
Regarding the membrane crosslinked to the sensing area, Mao further teaches that the “membrane is formed in situ by applying an alcohol-buffer solution of a crosslinker and a modified polymer over an enzyme-containing sensing layer and allowing the solution to cure for one to two days” (par. 18). In situ polymerization on the sensing layer inherently forms crosslinks between the polymers in the membrane and sensing layer, as evidenced by Ouyang (“in situ polymerization of the membrane can form crosslinks between the polymers of the membrane and the polymers in the sensing layer,” par. 29). Ouyang further teaches the same method of forming a membrane in situ (par. 128) and membrane composition (pars. 43-44), which further supports that Mao’s method of membrane formation would inherently crosslink the membrane to the sensing area.
Alternatively, if Applicant believes that Mao does not inherently teach that the membrane is crosslinked to the sensing area, then one of ordinary skill in the art before the effective filing date of the invention would be motivated to crosslink the membrane of Say in view of Mao, Zou, and Wellinghoff to the sensing area. One would be motivated to do so because Ouyang teaches that crosslinking of the membrane to the sensing layer facilitates a reduction in the occurrence of delamination of the membrane from the sensing layer (par. 29). Ouyang teaches a similar membrane (4-vinylpyridine and styrene copolymer, pars. 43-44) formed in a similar way (par. 128), so this modification could be successfully applied to the sensor of Say in view of Mao, Zou, and Wellinghoff.
Thus, Zou in view of Say, Mao, Wellinghoff, and optionally Ouyang teaches or suggests all limitations of claim 10.
Regarding claim 12, according to the broadest reasonable interpretation of the claim language, any lower region of the substrate can be considered the lower portion. For example, in the combination of Zou in view of Say, Mao, Wellinghoff, and Ouyang, if the entire length of the sensor having narrow width 53 (Say Fig. 2) is considered a lower portion of the substrate(“all or only a part of this narrow portion may be subcutaneously implanted into the patient,” Say col. 9, lines 60-62), then the lower portion comprises more than 75% of the substrate extending from the distal tip.
Regarding claim 13, Zou in view of Say, Mao, Wellinghoff, and optionally Ouyang teaches the metal-based antimicrobial compound is homogeneously or spatially intermixed with the membrane (“the bioactive agent can be blended into uncured polymer…then cured and the bioactive agent thereby cross-linked,” Zou paragraph 330; “a solution including dissolved bioactive agent…to form a coating,” Zou paragraph 333; Wellinghoff teaches that creating a solution or blend with the silver salt, paragraphs 18, 54, 63).
Regarding claim 14, Zou in view of Say, Mao, Wellinghoff, and optionally Ouyang teaches the diffusing is bolus diffusing, sustained delivery diffusing, or a dynamic diffusing (“bioactive agents of the preferred embodiments can be optimized for short or long-term release…release of the factors can be continuous or discontinuous, linear, or non-linear…release over a period of from about a few minutes or hours to…about 7 days or more,” Zou paragraphs 335-337; “a controlled release of silver over a wide range of rates,” Wellinghoff paragraph 65).
Regarding claim 15, Zou in view of Say, Mao, Wellinghoff, and optionally Ouyang teaches reducing or preventing infection of the tissue as a result of the diffusing (silver acts as an anti-infective agent, Zou paragraph 317; “silver ions exhibit biocidal properties,” Wellinghoff paragraph 27).
Regarding claim 16 and 17, Zou teaches detecting glucose with the sensing area (paragraph 207).
Regarding claim 18, Wellinghoff teaches the metal-based antimicrobial compound can be silver iodide (“silver” includes all silver salts including silver iodide, paragraph 20).
As stated in the rejection of claim 10, it would be obvious to one of ordinary skill in the art before the effective filing date of the invention to substitute one antimicrobial agent for another. One would be motivated to do so because various silver-based compounds were known in the art to provide an antimicrobial quality (“silver ions exhibit biocidal properties,” Wellinghoff paragraph 27), and one would have been able to substitute one silver compound within the membrane of Zou for silver iodide with a reasonable expectation of success.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ALICE LING ZOU/Examiner, Art Unit 3791
/TSE W CHEN/ Supervisory Patent Examiner, Art Unit 3791