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 .
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 17 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claim 17 calls for “…accessing an extracorporeal line to an individual's circulatory system with a catheter…” This language is ambiguous because the method accesses the patient’s circulatory system instead of the line. Examiner suggests to rephrase this as
“… [[accessing]] connecting an extracorporeal line to an individual's circulatory system with a catheter…” or
“… accessing [[an extracorporeal line to]] an individual's circulatory system with a catheter and an extracorporeal line …”
Claim 17 calls for “…providing the extracorporeal system, wherein said system has an inlet port and an outlet port …
… filtering the blood through the hollow fibers of said extracorporeal system …
… to pass through the pores and into said extra-lumen space; and contacting said filtered circulating cytokines, CytoVesicles, cytokine aggregates, and bacterial endotoxins with said adsorbent …”
There is insufficient antecedent basis for each of these limitations in the claim.
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 of this title, 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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-3 and 10-14 are rejected under 35 U.S.C. 103 as being unpatentable over Handelman; Garry et al. (US 20190117869 A1) in view of Brady, James et al. (US 20020146413 A1).
Regarding claim 1, Handelman discloses an extracorporeal system for the removal of inflammatory agents from blood (¶ [0002], [0014], [0018], a device for removing one or more toxin molecules from a stream of blood; ¶ [0020] FIG. 1 … device 100);
comprising: a housing (¶ [0020], housing 175);
a hollow fiber filter disposed within said housing (¶ [0020], hollow fiber 150 extending longitudinally through the receiving space 185 of housing 175);
said filter comprising a plurality of pores sized between about 200-6000 Angstroms (¶ [0025], The pores 165 may have an average diameter of from about 100 nanometer to about 1 micron, or from about 650 nanometers to about 1 micron, or from about 350 nanometers to about 1 micron, or from about 400 nanometers to about 700 nanometers); and
configured to permit passage of inflammatory agents having a diameter less than 0.60 microns from within the filter to an extra lumen space disposed within the housing and outside the filter (¶ [0023], the plasma elements, including plasma protein-bound toxins, may temporarily pass through pores 165 to the receiving space 185 within the housing 175; ¶ [0025], The pores 165 may have an average diameter of from about 100 nanometer to about 1 micron, or from about 650 nanometers to about 1 micron, or from about 350 nanometers to about 1 micron, or from about 400 nanometers to about 700 nanometers); and
at least one adsorption component positioned inside the housing and outside the hollow fiber in an extra-lumen space (¶ [0020], a plurality of beads 115 disposed within the receiving space 185 and external to the hollow fiber 150);
wherein at least one adsorption component comprises an adsorptive resin (¶ [0030], FIG. 3 depicts the use of amino sepharose beads (1 micron in diameter) which contain a succinimide leaving group; ¶ [0066] Statement 28 … amino sepharose beads with a succinimide leaving group); and
wherein the inflammatory agents include endotoxins or exotoxins (¶ [0023], The toxins that may be removed from the blood stream by device 100 may include urea, creatinine, indoxyl sulfate, bilirubin, a pharmaceutical drug, an ingested toxic substance, and uremic toxins).
Handelman does not explicitly disclose a non-ionic exchange resin selected from the claimed group, and does not explicitly remove an inflammatory agent from the selected group. Brady discloses a system for treating patients with bacterial infections (¶ [0001], [0002], [0010], [0025]);
comprising a housing and at least one adsorption component positioned inside the housing (¶ [0025], FIG. 1, the inner space 2 of the container 1 is filled with a plurality of polymer particles, which can be formed as beads, fibers, etc.);
wherein the at least one adsorption component comprises a non-ionic exchange resin selected from the group consisting of non-aliphatic ester resins, non-ionic polystyrene divinyl benzene resins, and other non-biologic adsorptive resins (¶ [0021] The hydrophobic cores of the particles of the both groups can be composed, for example, of crosslinked polymeric materials prepared by polymerization or copolymerization of the following monomers: styrene, ethylstyrene, .alpha.-methylstyrene, divinylbenzene, diisopropenylbenzene, trivinylbenzene, alkyl methacrylate as methyl methacrylate, buthyl methacrylate … The hydrophilic hemocompatible coatings or the shell of the particles of the both groups can be composed for example of the following materials: polyvinylpyrrolidone, polyhydroxyethyl methacrylate, carboxymethylcellulose, polyurethane; ¶ [0025], The polymer particles 6 of the second group preferably have pores of a smaller size and they are not charged); and
wherein the inflammatory agents are selected from the group consisting of cytokines, proteins with surface-bound cytokines, cytovesicles with encapsulated cytokine cargos, cytovesicles with surface-bound cytokines, pathogens, bacterial endotoxins, and bacterial exotoxins (¶ [0011], uncharged particles which are hydrophobic in their interior and have pore sizes, such that cytokines and superantigens penetrate to the pores and adhere to the uncharged particles; ¶ [0019] The inventive system further includes through a second group of polymeric particles. The particles of the second group are formed so as to retain cytokines and superantigens. These toxins are electrically neutral proteins; ¶ [0022], when the blood thusly purified of endotoxin passes through the second group of polymer particles, cytokines and superantigens adhere to the polymer particles of the second group).
Brady reduces an amount of cytokines and superantigens in a patient’s blood to resolve septic shock or toxic shock syndrome (¶ [0005], huge amounts of cytokines are made … can have direct toxic effects; ¶ [0012], therefore blood is purified from endotoxins, cytokines and superantigens, so that septic shock is reliably prevented). One would be motivated to modify Handelman with Brady’s non-ionic exchange resin to capture cytokines and superantigens since Handelman calls for removing toxins from a patient’s blood (¶ [0017], [0039], [0068]). A skilled artisan would have been able to modify Handelman with Brady’s non-ionic exchange resin by adding or incorporating Brady’s non-ionic exchange resin inside Handelman’s extra-lumen space. Therefore, it would have been obvious to modify Handelman with Brady’s non-ionic exchange resin in order to treat symptoms of an infection by removing cytokines and superantigens from a patient’s blood.
Regarding claim 10, Handelman discloses a method for treating a disease or disorder in an individual in need thereof (¶ [0002], methods and apparatus for removing toxins from blood; ¶ [0014], [0018], [0020] FIG. 1 … device 100);
comprising: providing an extracorporeal adsorptive toxin removal device (¶ [0020] FIG. 1 … device 100);
said device having: a housing (¶ [0020], housing 175);
a hollow fiber plasma filter having a plurality of pores sized between 200-6000 Angstrom disposed within the housing (¶ [0025], The pores 165 may have an average diameter of from about 100 nanometer to about 1 micron, or from about 650 nanometers to about 1 micron, or from about 350 nanometers to about 1 micron, or from about 400 nanometers to about 700 nanometers); and
an adsorbent positioned inside the housing and outside the fiber filter in the extra lumen space (¶ [0020], a plurality of beads 115 disposed within the receiving space 185 and external to the hollow fiber 150);
filtering the plasma of an individual in need thereof through said adsorptive toxin removal device (¶ [0022], Therefore, hollow fiber 150 permits the plasma elements of the blood stream to flow into the receiving space 185 and contact the plurality of beads 115);
wherein said filtering causes an inflammatory causing agent with a diameter less than 0.60 microns to pass through said pores (¶ [0023], the plasma elements, including plasma protein-bound toxins, may temporarily pass through pores 165 to the receiving space 185 within the housing 175; ¶ [0025], The pores 165 may have an average diameter of from about 100 nanometer to about 1 micron, or from about 650 nanometers to about 1 micron);
contacting said inflammatory causing agent with said absorbent; wherein said inflammatory causing agent binds to said adsorbent; and capturing said inflammatory causing agent in said adsorbent (¶ [0023], Once the plasma proteins pass back to the hollow fiber 150, the toxins remain bound to the beads 115);
wherein the adsorbent comprises an absorptive resin (¶ [0030], FIG. 3 depicts the use of amino sepharose beads (1 micron in diameter) which contain a succinimide leaving group; ¶ [0066] Statement 28 … amino sepharose beads with a succinimide leaving group).
Handelman lacks a non-ionic exchange resin selected from the claimed group which removes an inflammatory agent from the selected group. Brady discloses a system for treating patients with bacterial infections (¶ [0001], [0002], [0010], [0025]);
comprising: providing an extracorporeal adsorptive toxin removal device, said device having: a housing and an adsorbent positioned inside the housing (¶ [0025], FIG. 1, the inner space 2 of the container 1 is filled with a plurality of polymer particles, which can be formed as beads, fibers, etc.);
filtering the plasma of an individual in need thereof through said adsorptive toxin removal device (¶ [0025], The container has an inlet 3 for introducing a blood … and an outlet 4 through which a blood … introduced back into the patient's body);
contacting said inflammatory causing agent with said absorbent, wherein said inflammatory causing agent binds to said adsorbent, and capturing said inflammatory causing agent in said adsorbent (¶ [0011], cytokines and superantigens penetrate to the pores and adhere to the uncharged particles; ¶ [0019] The particles of the second group are formed so as to retain cytokines and superantigens; ¶ [0022], when the blood … passes through the second group of polymer particles, cytokines and superantigens adhere to the polymer particles of the second group);
wherein the adsorbent comprises a non-ionic exchange resin selected from the group consisting of non-ionic aliphatic ester resins, non-ionic polystyrene divinyl benzene resins, and other non-biologic adsorptive resins (¶ [0021] The hydrophobic cores of the particles of the both groups can be composed, for example, of crosslinked polymeric materials prepared by polymerization or copolymerization of the following monomers: styrene, ethylstyrene, .alpha.-methylstyrene, divinylbenzene, diisopropenylbenzene, trivinylbenzene, alkyl methacrylate as methyl methacrylate, buthyl methacrylate … The hydrophilic hemocompatible coatings or the shell of the particles of the both groups can be composed for example of the following materials: polyvinylpyrrolidone, polyhydroxyethyl methacrylate, carboxymethylcellulose, polyurethane; ¶ [0025], The polymer particles 6 of the second group preferably have pores of a smaller size and they are not charged); and
wherein the inflammatory agents are selected from the group consisting of cytokines, proteins with surface bound cytokines, cytovesicles with encapsulated cytokine cargos, cytovesicles with surface bound cytokines, pathogens, bacterial endotoxins, and bacterial exotoxins (¶ [0011], cytokines and superantigens penetrate to the pores and adhere to the uncharged particles; ¶ [0019] The particles of the second group are formed so as to retain cytokines and superantigens; ¶ [0022], cytokines and superantigens adhere to the polymer particles of the second group).
Brady captures cytokines and superantigens and thereby resolves symptoms of an infection (¶ [0005], [0012]). Regarding the rationale and motivation to modify Handelman with Brady’s non-ionic exchange resin, see the discussion of claim 1 above.
Regarding claims 2, 3 and 11, Handelman discloses an extracorporeal system wherein the at least one adsorption component further comprises at least one of activated carbon and ion exchange resin (¶ [0030] FIG. 3 … beads 115 depicted in FIGS. 1-2. As depicted in FIG. 3, bead 115 may be an agarose resin bead having reactive groups on the surface. In particular, FIG. 3 depicts the use of amino sepharose beads (1 micron in diameter) which contain a succinimide leaving group);
wherein said plurality of pores are sized and dimensioned to prevent a blood agent having a diameter greater than 0.60 microns to pass through the fiber walls and interact with adsorption components in the extra-lumen space (¶ [0023], the plasma elements, including plasma protein-bound toxins, may temporarily pass through pores 165 to the receiving space 185 within the housing 175; ¶ [0025], The pores 165 may have an average diameter of from about 100 nanometer to about 1 micron); and
a method wherein the capture of said inflammatory causing agent prevents said agent from reentering circulation (¶ [0023], Once the plasma proteins pass back to the hollow fiber 150, the toxins remain bound to the beads 115).
Regarding claims 12-14, Handelman does not explicitly remove cytokines from the selected groups. Brady discloses a method wherein said cytokines are selected from the group consisting of: IL-1, TNF-a, IL-11, IL-8, G-CSF, and GM-CSF. IL-3, IL-5, IL-7, IL-9, and transforming growth factor-b (TGF-b) (¶ [0033] When blood with endotoxin and superantigens passes through such a material … also the following cytokines were efficiently removed: interlukine IL-1-beta, IL-6-alpha, IL-10, and tumor necrose factor TNF alpha); or
wherein said cytokines are selected from the group consisting of IL-1, IL-2, IL-3, IL-4, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, interferons (IFNs), IFN-g inducing factor (IGIF), TGF-b, and TNF-a and -b (¶ [0033] When blood with endotoxin and superantigens passes through such a material … the following cytokines were efficiently removed: interlukine IL-1-beta, IL-6-alpha, IL-10, and tumor necrose factor TNF alpha);
wherein said disease or disorder is selected from the group consisting of cytokine storm syndrome (CSS), virus induced cytokine storm, bacteria induced cytokine storm, acute respiratory distress syndrome (ARDS), cytokine release syndrome (CRS), graft-versus-host disease (GVHD), sepsis, systemic inflammatory response syndrome (SIRS), hepatic encephalopathy, acute kidney injury (AKI) and pneumonia (¶ [0012], blood is purified from endotoxins, cytokines and superantigens, so that septic shock is reliably prevented).
Brady captures cytokines and superantigens and thereby resolves symptoms of toxic or septic shock (¶ [0005], [0012]). Regarding the rationale and motivation to modify Handelman by removing cytokines as taught by Brady, see the discussion of claim 1 above.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Handelman and Brady in view of Roberts; Craig P. et al. (US 20070181499 A1).
Regarding claim 4, Handelman and Brady lack activated carbon. Roberts discloses devices and associated methods for plasma detoxification (¶ [0002], [0021], [0059], FIG. 3 depicts another embodiment of methods for practicing the present invention), comprising:
an adsorption component comprising particles and positioned inside a housing (¶ [0059], first toxin removal device 214 … second toxin removal device 218); wherein the adsorption component comprises activated carbon (¶ [0062], In one embodiment of the present invention the first toxin removal device 214 comprises activated charcoal and the second toxin removal device 218 comprises one or more non-ionic resins; ¶ [0062], In yet still another embodiment both toxin removal devices are the same and may contain both activated charcoal and/or non-ionic resins);
wherein said activated carbon comprises coated or uncoated coconut shell granule or synthetic charcoal (¶ [0071], The activated carbon component … It can be produced by heat treatment, or "activation," of … wood, coal, peat and coconuts … Carbomix ™ … and Ultracarbon ™).
Roberts removes toxins with a mixture of non-ionic resin and activated charcoal (¶ [0072], [0073]), and also removes a broader range of toxins including protein-bound toxins (¶ [0054], The purpose of the adsorptive toxin removal device is to remove both protein-bound and soluble toxins). Roberts demonstrates that non-ionic resin and activated charcoal can be combined in a single filter device, and will work independently to capture different toxins (¶ [0054], The purpose of the adsorptive toxin removal device is to remove both protein-bound and soluble toxins; ¶ [0062], In yet still another embodiment both toxin removal devices are the same and may contain both activated charcoal and/or non-ionic resins; ¶ [0082], the use of an adsorption column allows for the targeted removal of both protein-bound and soluble toxins).
One would be motivated to modify Handelman and Brady with Roberts’s activated carbon to remove other toxic agents from a patient’s blood since Handelman calls for removing protein-bound toxins (¶ [0008], methods and apparatus for removing protein-bound toxic drugs and protein-bound ingested toxic substances from the blood of a patient is desirable). A skilled artisan would have been able to modify Handelman and Brady with Roberts’s activated carbon by adding activated carbon to the adsorption component within Handelman’s extra-lumen space. Therefore, it would have been obvious to modify Handelman and Brady with Roberts’s activated carbon in order to remove a broader range of toxins.
Claims 5-8 are rejected under 35 U.S.C. 103 as being unpatentable over Handelman and Brady in view of Gogotsi; Yury et al. (US 20200316281 A1).
Regarding claims 5-8, Handelman discloses an adsorption component having a mean particle diameter of about 35-120 microns or 300-500 microns (¶ [0029], the beads may have an average diameter of from about 50 microns to about 500 microns, or from about 75 microns to about 125 microns).
Handelman lacks non-ionic aliphatic ester resins and non-ionic polystyrene divinyl benzene resins. Brady discloses adsorption components including non-ionic aliphatic ester resins and non-ionic polystyrene divinyl benzene resins (¶ [0021] The hydrophobic cores of the particles of the both groups can be composed, for example, of crosslinked polymeric materials prepared by polymerization or copolymerization of the following monomers: styrene, ethylstyrene, .alpha.-methylstyrene, divinylbenzene, diisopropenylbenzene, trivinylbenzene, alkyl methacrylate as methyl methacrylate, buthyl methacrylate … The hydrophilic hemocompatible coatings or the shell of the particles of the both groups can be composed for example of the following materials: polyvinylpyrrolidone, polyhydroxyethyl methacrylate, carboxymethylcellulose, polyurethane); and
an average surface area of approximately 600-700 m2/g (¶ [0030] In order to produce polymer particles of the second group … The polymer displayed apparent inner surface area of 650 sq. m/g).
Handelman and Brady do not explicitly disclose an average surface area and average pore size in the claimed ranges. Gogotsi discloses materials and techniques for removing cytokines from blood and blood products (¶ [0003], [0006], [0052], [0061]), comprising:
an adsorption component comprising particles and positioned inside a housing (¶ [0051], Adsorption … by blood perfusion through a cartridge or column containing a material selective for cytokines);
wherein said adsorption component has an average surface area of approximately 500 m2/g, 700 m2/g or 600 m2/g (¶ [0063], the carbon forms have graphitic surface areas in a range of … from 500 to 600 m2/g, from 600 to 700 m2/g … or having a range defined by two or more of these ranges); and
an average pore size of approximately 300-600 Angstroms, 300 Angstroms or 100-400 Angstroms (¶ [0064], so-called “accordion” structure, formed by the stacks of dozens to hundreds graphene sheets separated by meso- and macropores of slit geometry See, e.g., FIG. 35; ¶ [0068], the pore size dimensions are preferably chosen to interact with protein having a number averaged molecular weight in a range of from 5 to 10 kDa, from 10 to 20 kDa … from 90 to 100 kDa, or having a range defined by two or more of these ranges).
Gogotsi optimizes an adsorption component for removing cytokines from a patient’s blood (¶ [0005], [0069], the targeted proteins are cytokines; ¶ [0146] FIGS. 4A-4D show the adsorption of cytokines by PDC-CDC A Low MW, and PDC-CDC B High MW). One would be motivated to modify Handelman and Brady with Gogotsi’s average surface area and average pore size to effectively absorb cytokines since both Handelman and Brady call for removing toxins (Handelman ¶ [0023], [0030]; Brady ¶ [0017], [0018], [0022], [0026]). Therefore, it would have been obvious to modify Handelman and Brady with Gogotsi’s average surface area and average pore size in order to capture cytokines during extracorporeal treatment.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Handelman and Brady in view of Tennison; Stephen Robert et al. (US 20190022623 A1).
Regarding claim 9, Handelman and Brady lack activated carbon with Micropore, Mesopore and Macropore regions. Tennison discloses an adsorption component for use in the extracorporeal treatment of blood (¶ [0002], [0033], [0034], [0036]);
comprising activated carbon (¶ [0006], methods for making carbonised and optionally activated monoliths from phenolic resin precursors; ¶ [0027], a carbonisable shaped resin body; ¶ [0035] A carbonised monolith is provided comprising mesoporous and/or macroporous carbon particles dispersed in a matrix of microporous carbon particles);
wherein the activated carbon has a pore size distribution of a Micropore region of less than 100 Angstroms, a Mesopore region of between 100 and 1,000 Angstroms, and a Macropore region of greater than 1,000 Angstroms (¶ [0034], the carbon comprising particles of microporous and mesoporous and/or macroporous carbon dispersed in a matrix of microporous carbon; ¶ [0036] The invention further provides carbon having mesopores and micropores / macropores in a bimodal pore distribution; ¶ [0088]-[0090]; ¶ [0147], It has been found that “physical” activation with carbon dioxide at the temperatures in the range 850-900° C. gives rise predominantly to microporosity; ¶ [0156] The 3-point bend test results are shown in FIG. 8 and show the impact of cured resin content and degree of cure of the microporous resin binder on strength of the carbonised extrudate; ¶ [0165] FIG. 12 shows the pore volume in the 10-1000 nm pore size range. The diamond-pattern points are the measured pore volumes whilst the square pattern points are the expected pore volume based simply on dilution of the mesoporous resin with the microporous lignin derived material).
Tennison assembles an adsorption component into a high strength, attrition-resistant structure (¶ [0017], [0034]). Tennison also efficiently removes endotoxins and cytokines from blood (¶ [0119], the monoliths can also remove TNFα, the most difficult of the SIRS related molecules to remove, from both blood and plasma). One would be motivated to modify Handelman, Brady and Roberts with Tennison’s Micropore, Mesopore and Macropore regions on an activated carbon substrate to physically reinforce the adsorption component and to configure it to remove toxins as called for by Handelman (¶ [0023], [0030]), and to more effectively capture cytokines, as called for by Brady (¶ [0019], [0020], [0022]). Therefore, it would have been obvious to modify Handelman, Brady and Roberts with Tennison’s Micropore, Mesopore and Macropore regions in order to more effectively remove toxins and cytokines with a physically stable adsorbent.
Claims 15 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Handelman and Brady in view of Brady ‘152; James A. et al. (US 20110004152 A1).
Regarding claims 15 and 16, Handelman and Brady do not explicitly remove a bacterial endotoxin or exotoxin. Brady ‘152 discloses a method that removes a biologic toxin; wherein said toxin is a bacterial endotoxin or exotoxin (¶ [0178] For example, the adsorption medium 88 can be constructed to remove LPS endotoxin, which is released into the blood of an individual suffering from a gramnegative bacterial infection. In the blood, LPS endotoxin coalesce into vesicles ranging in size from 300,000 to 1,000,000 daltons. Phosphoryl groups contained within the LPS endotoxin give it an overall negative charge at physiologic pH. The release of LPS endotoxin into the blood can cause fever, low blood pressure, and organ failure).
Brady ‘152 removes cytokines and superantigens from a patient’s blood to minimize septic shock or toxic shock syndrome (¶ [0025], prevent, control, reduce, modulate, or alleviate the severity of many physiologic conditions and disease states; ¶ [0026], prevent an overly robust endogenous response, such as occurs, e.g., during septic shock; ¶ [0027], to prevent, e.g., septic shock or other conditions that may occur).
One would be motivated to modify Handelman and Brady with Brady ‘152’s LPS endotoxin targets since Handelman calls for removing toxins from a patient’s blood (¶ [0017], [0039], [0068]). Brady further calls for addressing bacterial infections and the inflammation they cause (¶ [0005] In serious Gram-negative and Gram-positive infections, bacteria and the toxins they produce enter the bloodstream, causing massive activation of the body's immune system).
A skilled artisan would have been able to modify Handelman and Brady with Brady ‘152’s LPS endotoxin target by adding or incorporating one or more of Brady ‘152’s adsorbents inside Handelman’s extra-lumen space. Therefore, it would have been obvious to modify Handelman and Brady with Brady ‘152’s LPS endotoxin target in order to treat symptoms of an infection by directly removing bacterial toxins from a patient’s blood.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Handelman; Garry et al. (US 20190117869 A1) in view of Brady ‘152; James A. et al. (US 20110004152 A1).
Regarding claim 17, Handelman discloses a method of removing circulating toxins from the blood of an individual in need thereof (¶ [0002], methods and apparatus for removing toxins from blood; ¶ [0014], [0018], [0020] FIG. 1 … device 100);
comprising: accessing an individual's circulatory system (¶ [0021] The hollow fiber 150 is operable to receive a stream of blood from an inlet 108; ¶ [0023] During operation of device 100, a blood stream having one or more plasma protein-bound toxins may be passed through hollow fiber 150);
providing the extracorporeal system, wherein said system has an inlet port and an outlet port (¶ [0021] The hollow fiber 150 is operable to receive a stream of blood from an inlet 108 at a first end 101 of device 100 into the inner bore 155 of hollow fiber 150; ¶ [0023], The purified blood stream may then exit device 100 at outlet port 109 proximal to a second end 102 of device 100);
controlling the flow of blood through said extracorporeal system with a pump (¶ [0026] Device 100 may be coupled to one or more pumps (not shown) configured to cause the blood stream to pass through hollow fiber 150 and device 100);
filtering the blood through the hollow fibers of said extracorporeal system; wherein said filtering causes said circulating toxins to pass through the pores and into said extra-lumen space (¶ [0023], the plasma elements, including plasma protein-bound toxins, may temporarily pass through pores 165 to the receiving space 185 within the housing 175); and
contacting said filtered toxins with said adsorbent (¶ [0020], a plurality of beads 115 disposed within the receiving space 185 and external to the hollow fiber 150; ¶ [0030], FIG. 3 depicts the use of amino sepharose beads (1 micron in diameter) which contain a succinimide leaving group; ¶ [0066] Statement 28 … amino sepharose beads with a succinimide leaving group);
wherein said adsorbent captures toxins (¶ [0023], The toxins that may be removed from the blood stream by device 100 may include urea, creatinine, indoxyl sulfate, bilirubin, a pharmaceutical drug, an ingested toxic substance, and uremic toxins.
Handelman does not explicitly disclose first and second extracorporeal lines. However, Handelman discloses that the extracorporeal system receives and returns blood at its inlet and outlet (¶ [0021], [0023]). This implies that at least first and second extracorporeal lines connect to the inlet and outlet. Conversely, omitting the first and second extracorporeal lines will cause a leak at the inlet or outlet, and fail to constrain inside the system.
Handelman does not explicitly access the individual's circulatory system with a catheter or remove circulating cytokines, CytoVesicles, cytokine aggregates, and bacterial endotoxins.
Brady ‘152 discloses a method of simultaneously removing circulating cytokines, CytoVesicles, cytokine aggregates, and bacterial endotoxins from the blood of an individual in need thereof (¶ [0021], devices, systems, and methods that serve to reduce or otherwise modulate levels of proinflammatory or anti-inflammatory stimulators or mediators; ¶ [0025] The invention provides devices, systems, and methods for reducing levels of cytokines or other species of proinflammatory or anti-inflammatory stimulators or mediators in the blood);
comprising: accessing an extracorporeal line to an individual's circulatory system with a catheter (¶ [0110], FIGS. 4A and 4B, the housing 32 … can be releasably coupled to a conventional intravenous blood access catheter 40, e.g., of the type widely used in intensive care units; ¶ [0114] As FIG. 7 shows, either device 18 or 30 can comprise a component 50 … The catheter 52 is surgically attached to the circulatory system of the individual, e.g., between an artery and a vein, to form a loop through which the blood continuously circulates);
providing the extracorporeal system, wherein said system has an inlet port and an outlet port (¶ [0111] In this arrangement, the inlet 33 and 36 of the exchangeable component 38 and the catheter 40 (or inlet and outlet lines 26 and 27) would include, e.g., convention mating luer fittings 42);
controlling the flow of blood through said extracorporeal system with a pump (¶ [0108], an external pump can be used to convey the blood through the housing 32; ¶ [0109], an external pump (identified as P in FIG. 2) is typically present to convey the blood through the blood processing assembly 24; ¶ [0162] Peristaltic pumps P1 and P2 in the channels 302 and 304 (or a single, double tube peristaltic pump) convey the blood through the housings 310 and 314); and
contacting said circulating cytokines, CytoVesicles, cytokine aggregates, and bacterial endotoxins with an adsorbent (¶ [0105], The housing 32 contains a medium 34 that removes cytokines or other species of proinflammatory or anti-inflammatory stimulators or mediators by adsorption; ¶ [0114] As FIG. 7 shows, either device 18 or 30 can comprise a component 50 … the component 50 carries the adsorption medium 34 that serves to remove cytokines or other species of proinflammatory or anti-inflammatory stimulators or mediators from the individual's blood traversing the catheter 52; ¶ [0127], In the embodiment shown in FIG. 11 … the adsorption medium 34 is contained in the second compartment 66; ¶ [0174] FIG. 13 … The device 82 includes a first compartment 84, which contains the adsorption medium 34 … a second compartment 86, which contains a different medium 88);
wherein said adsorbent captures said cytokines, CytoVesicles, cytokine aggregates, and endotoxins (¶ [0025] The invention provides devices, systems, and methods for reducing levels of cytokines or other species of proinflammatory or anti-inflammatory stimulators or mediators in the blood; ¶ [0028], devices, systems, and methods serve to reduce the population of cytokines or other species of proinflammatory or anti-inflammatory stimulators or mediators by removing such stimulators or mediators from the blood circulation; ¶ [0178] For example, the adsorption medium 88 can be constructed to remove LPS endotoxin, … In the blood, LPS endotoxin coalesce into vesicles ranging in size from 300,000 to 1,000,000 daltons; ¶ [0180], the adsorption medium 88 includes a group of polymer particles 96 comprising hydrophobic porous core to which LPS endotoxin binds).
Brady ‘152 accesses a patient’s circulatory system with conventional equipment. One would be motivated to modify Handelman with Brady ‘152’s catheters since Handelman requires accessing the patient’s bloodstream.
Brady ‘152 also removes cytokines and superantigens from a patient’s blood to minimize septic shock or toxic shock syndrome (¶ [0025], prevent, control, reduce, modulate, or alleviate the severity of many physiologic conditions and disease states; ¶ [0026], prevent an overly robust endogenous response, such as occurs, e.g., during septic shock; ¶ [0027], to prevent, e.g., septic shock or other conditions that may occur). One would be motivated to modify Handelman with Brady ‘152’s cytokine targets since Handelman calls for removing toxins from a patient’s blood (¶ [0017], [0039], [0068]). A skilled artisan would have been able to modify Handelman with Brady ‘152’s cytokine targets by adding or incorporating Brady ‘152’s non-ionic exchange resin inside Handelman’s extra-lumen space. Therefore, it would have been obvious to modify Handelman with Brady ‘152’s cytokine targets in order to treat symptoms of an infection by removing cytokines from a patient’s blood.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Mitchell, Michael Donovan et al. US 20020150686 A1
Brady, James A. et al. US 20020197252 A1
Seidel, Dietrich et al. US 20050009001 A1
Kiriyama; Kentaro et al. US 20170173231 A1
Sakata; Masayo et al. US 20180178192 A1
Kanda; Shungo et al. US 20210213421 A1
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/Adam Marcetich/
Primary Examiner, Art Unit 3781
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