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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/13/2026 has been entered.
Response to Amendment
Claims 1 and 39 have been amended. Claims 66-67 have been added. Claims 1, 3, 4, 39, 40, 52, and 66-67 remain pending; no new matter has been entered.
Claim 39 was previously objected to and has been amended to overcome the previous objection; the previous objection is thus withdrawn.
Claim Rejections - 35 USC § 103
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.
The factual inquiries 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.
Claim(s) 1, 3-4, 39-40, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over El-Khatib et al. (WO 2015061693, henceforth El-Khatib et al.) in view of Gorman et al. (US 20040116866, henceforth Gorman et al.), Shimabukuro-Vornhagen et al. (“Cytokine release syndrome”, Journal for ImmunoTherapy of Cancer, published 15 June 2018, henceforth Shimabukuro-Vornhagen), Anderson (US 20170087299, henceforth Anderson), Galley et al. (US 20060276771, henceforth Galley et al.), and Bengtsson (US 20040162521, henceforth Bengtsson).
Regarding claim 1, El-Khatib et al. discloses a system (infusion system 10, Fig. 2) comprising: a housing attachable to a patient’s skin (External shell of infusion pump 12 shown in Fig. 2; Examiner notes that the housing shown in Fig. 2 is capable of being attached to a patient’s skin as it could be secured to the skin using tape or a rubber band); a first reservoir disposed at least partially within the housing (Medicament reservoir 16A, Fig. 4, pg. 17 lines 9-25) and filled with a first drug product (insulin, see pg. 21 line 21); a second reservoir disposed at least partially within the housing (Medicament reservoir 16B, Fig. 4, pg. 17 lines 9-25) and filled with a second drug product (glucagon, see pg. 21 lines 22-23), wherein the second drug product comprises an agent for treating a response induced by administration of the first drug product (glucagon is known to have the opposite effect of insulin, see pg. 21 lines 17-18); at least one administration member (cannula 196A, Fig. 10C) insertable into the patient and connected or connectable in fluid communication (see infusion set 20, Fig. 2) with at least one of the first reservoir and the second reservoir; a fluid delivery system (infusion pump 12, Fig. 2) operable to deliver at least one of the first drug product from the first reservoir and the second drug product from the second reservoir (see pg. 14 lines 25-29) to the patient via the at least one administration member (cannula 196A, Fig. 10C); a sensor (glucose sensor, pg. 14 line 24) operable to sense a biological condition of the patient (blood glucose level, pg. 14 line 23); and a controller (controller, see pg. 14 line 30) coupled with the housing (see pg. 14 lines 29-31, the controller is coupled with the infusion pump 12 and thus the external shell thereof) configured to analyze output from at least the sensor (see pg. 14 lines 17-31) to determine if the patient experiences a medical condition which needs treatment (see pg. 14 line18-29 especially 18-20), wherein a determination is based at least partly on the sensed biological condition being within or outside of a predetermined range of values or greater or less than a predetermined value (Damiano et al., US Pat. No. 7806854, henceforth Damiano et al., which is incorporated by reference on pg. 15 lines 1-3 of El-Khatib et al., discloses y(t) establishes a target level, see col. 2 lines 50-67 and col. 3 lines 1-24. See also El-Khatib et al. pg. 3 lines 1-4 and pg. 14 lines 25-29, it is the Examiner’s position that it is known in the art a closed-loop glucose control system has a predetermined value or range of values to compare with measured values), and operate the fluid delivery system to initiate delivery of the second drug product (see pg. 14, lines 17-31 and pg. 15 lines 1-3, it is the Examiner’s position that when the controller controls the pump to deliver glucagon the delivery of glucagon is initiated) to the patient in response to the determination that the patient is experiencing the medical condition (see pg. 14, lines 17-31 and pg. 15 lines 1-3).
El-Khatib et al. does not disclose the system comprising an adhesive attached to an exterior surface of the housing for attaching the housing to a patient's skin. Gorman et al. teach the use of an adhesive attachment apparatus to comfortably and reliably adhere fluid devices such as insulin infusion devices to a patient for treatment of diabetes ([0013], [0109]). Gorman et al. also teaches that ambulatory infusion pumps are used to deliver insulin and result in better efficacy of the drug and therapy and less toxicity to the patient's system ([0006]), and that existing adhesives at the time of filing of Gorman et al. needed improved comfort and reliability for ambulatory infusion pumps ([0011]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added the adhesive attachment apparatus of Gorman et al. to the housing of El-Khatib et al. for providing a comfortable and reliable means to transport the housing to allow the system of El-Khatib et al. to deliver insulin and result in better efficacy of the drug and therapy and less toxicity to the patient's system.
El-Khatib et al. as modified by Gorman additionally discloses that sensing of the biological condition serves as an indicator for diagnosing the response to the administration of the first agent (see at least pg. 14 lines 17-31) and that the first agent and second agent can be replaced with different agents (see pg. 11 lines 5-15) where the device can be used for multiple indications (pg. 18 lines 5-12).
El-Khatib et al. as modified does not disclose that the first drug product comprises a bispecific T cell engaging antibody construct and/or a chimeric antigen receptor (CAR) T cell receptor; that the second drug product comprises an agent for treating cytokine release syndrome (CRS) induced by administration of the bispecific T cell engaging antibody construct and/or a chimeric antigen receptor (CAR) T cell receptor, or that the sensed biological condition should be a cytokine parameter which is an indicator of CRS as measured by a cytokine sensor. Shimabukuro-Vornhagen teaches administration of a drug product comprising a bispecific T cell engaging antibody construct (BiTE constructs such as blinatumomab, see Abstract and the last paragraph of the left column of pg. 10) which can induce CRS (see at least the first paragraph of the right column of pg. 2, in a study using blinatumomab there were patients with CRS) which can be treated with appropriate administration of a second drug product (tocilizumab, see at least the second paragraph of the right column of pg. 10) which is used for treating CRS (see at least the second paragraph of the right column of pg. 10, tocilizumab is taught as a treatment for severe CRS which is previously taught to be a possible outcome of blinatumomab), and that CRS can be detected at least in part based on sensing of a cytokine parameter in a biological fluid (serum CRP can be used as a biomarker for determining severity of CRS, see at least the third paragraph of the left column of pg. 10). Additionally, Anderson teaches administration of immunotherapy treatment with a first drug product (immune system suppressor, [0020]; also, a chemotherapeutic agent is taught in [0021]) and administration of a second drug product (a steroid, [0019]) which addresses a second condition (inflammation, [0019]) which is detected by a cytokine sensor (detector for C-reactive protein, [0019], which is a cytokine sensor as C-reactive protein is a biomarker for cytokines and thus it is a sensed cytokine parameter and thus the sensor is a cytokine sensor since it measures a sensed cytokine parameter). Additionally, Anderson teaches that the sensing of blood glucose is equivalent to the sensing of C-reactive protein, or CRP, depending on the conditions to be monitored and treated (see at least [0002], [0003], [0009], [0019]-[0021], and [0033], insulin is known to react with blood glucose levels in diabetes and contextualized biometric states can include either CRP measurements or blood glucose levels depending on the target conditions).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have replaced the insulin and glucagon of El-Khatib et al. with the bispecific T cell engaging antibody construct and second agent of Shimabukuro-Vornhagen for treating cancer instead of diabetes (Shimabukuro-Vornhagen teaches that BiTE therapy and CAR-T cell therapy have shown remarkable efficacy in cancer treatment, see Abstract) and to have correspondingly replaced the blood glucose sensor of El-Khatib et al. with the CRP sensor of Anderson to allow for the detection of CRS using CRP as a cytokine parameter (CRP can function at least partially as a biomarker for the detection of CRS, see Shimabukuro-Vornhagen at least at par. 3 of the left column of pg. 2 and at the third paragraph of the left column of pg. 10, meaning that it is a sensed cytokine parameter as it is a biomarker for cytokines as provided in the art) as El-Khatib et al. teaches that its apparatus can be used for multiple indications (see pg. 11 lines 5-15) and further because such a substitution would have yielded the same, predictable result of a system which is capable of administering a first agent which treats a target condition, sensing whether or not a negative symptom is occurring as a result of the administration of the first medicament with a sensor (in the disclosure of El-Khatib et al., this negative symptom is a potentially dangerous glycemic low as a result of over-administration of insulin and is detected by measuring blood glucose; in the modified device, it is a measuring of CRP to detect CRS as a result of administration of a bispecific T cell engaging antibody construct), and if needed, administering a second agent which is configured to treat the negative symptom caused by administration from the first agent (in El-Khatib et al., this second agent is glucagon to treat the potentially dangerous glycemic low; in the modified device, it is administration of an agent to treat CRS as claimed). In this modified system, the teachings of El-Khatib et al. and the references which it incorporates by reference (which are subsequently called out as appropriate) regarding the use of different administration times and changes would apply when sensing CRP instead of glucose in the blood.
El-Khatib et al. as modified does not disclose a patient temperature sensor operable to sense a patient temperature. Galley et al. teaches a first sensor (261, glucose sensor, see [0046]) and a patient temperature sensor (262, implanted body temperature sensor, see [0046]) operable to sense a temperature of the patient (patient temperature, see [0046]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the device of El-Khatib et al. by adding the subcutaneous (or implanted) temperature sensor of Galley et al. (see [0046]) for providing additional information relating to the physiological condition of the user and because Shimabukuro-Vornhagen teaches that body temperature is another significant indicator of CRS (see at least the third paragraph of the left column of pg. 2, the third paragraph of the left column of pg. 10, and the third paragraph of the right column of pg. 10) and thus an added temperature sensor would provide the benefit of being able to more reliably detect CRS if the sensed temperature was used in part for the controlling of administration of the first and second drug products (since fever is a part of the clinical presentation of CRS as taught by Shimabukuro-Vornhagen, including determination of severity of the CRS, it could be used to further the diagnosis of and thus treatment of CRS when combined with the sensing of CRP as indicated above).
El-Khatib et al. as modified does not explicitly disclose the controller being configured to analyze the output from the patient temperature sensor of Galley to determine if the patient experiences CRS where the determination is based on a sensed patient temperature being within or outside of a predetermined temperature range or greater or less than a predetermined temperature. However, Shimabukuro-Vornhagen teaches that fever is an indicator of CRS (see at least the third paragraph of the left column of pg. 2, the third paragraph of the left column of pg. 10, and the third paragraph of the right column of pg. 10) and that severe CRS is often denoted by a high fever (see at least the third paragraph of the left column of pg. 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have configured the controller of El-Khatib et al. as modified to analyzed the output from the patient temperature sensor of Galley to determine if the patient experiences CRS, wherein the determination is based at least partly on a sensed patient temperature being within or outside of a predetermined temperature range or greater or less than a predetermined temperature as this measured patient temperature from the added sensor of Galley would be an indication of a fever or high fever which is an indicator of CRS and the relative severity of said CRS (see at least the third paragraph of the left column of pg. 2, the third paragraph of the left column of pg. 10, and the third paragraph of the right column of pg. 10). The second predetermined value or range of values as claimed would then be a threshold for a fever or a high fever as compared to normal body temperatures in this modified device.
El-Khatib as modified thus discloses that the cytokine sensor is in some way in contact with the patient’s blood (see at least Anderson [0002], [0003], [0009], [0019]-[0021], and [0033] and Shimabukuro-Vornhagen at the third paragraph of the left column of pg. 10, the CRP sensor in the modified device measures the patient’s blood to determine amounts of CRP). El-Khatib as modified additionally discloses that the patient temperature sensor is in some way in contact with the interior of the patient where the sensor is called out as being implanted, meaning provided subcutaneously (see Galley [0046]). El-Khatib as modified additionally discloses that glucose sensors and CRP sensors are obvious replacements of each other and can be substituted depending on what the desired variable to be measured in the patient is (see Anderson [0002], [0003], [0009], [0019]-[0021], and [0033]).
El-Khatib et al. as modified does not explicitly disclose that the cytokine sensor and the patient temperature sensor is arranged at and/or extending from the exterior surface of the housing, or wherein the cytokine sensor is configured such that attaching the housing to the patient’s skin causes the sensor to contact and/or insert into the patient’s skin as El-Khatib does not provide the specifics of the arrangement of its sensor. Bengtsson teaches a system (system 400, figs. 9A and 9B) which includes a housing (disposable unit 413 and durable unit 414, fig. 9B, create a housing at their exterior) which is attachable to a patient’s skin (see [0093]) comprising an art-effective sensor (needle-formed sensors 412, fig. 9B) for detecting an analyte in the patient’s blood (see [0093], the sensors are for measuring blood glucose which is shown to be a known variant to the CRP sensors of El-Khatib et al. as modified as indicated previously) wherein the sensor is arranged at and extending from an exterior surface of the housing (see fig. 9B, sensors 412 are shown as being arranged and protruding from second mounting surface 411 which is an exterior surface of the housing as shown, see also [0093]) which an adhesive is attached to (see [0028] and [0030], mounting surfaces are meant to have adhesives attached to them such as to mount them to the patient’s skin) and further wherein the sensor is configured such that attaching the housing to the patient’s skin causes the sensor to contact and/or insert into the patient’s skin (see figs. 9A and 9B and [0093], the sensors 412 are configured to be inserted subcutaneously and are configured as claimed where the placement of the sensors and the attachment of the housing to the skin means that the needles contact and then insert subcutaneously into the patient’s skin).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arranged the cytokine sensor and the patient temperature sensor of El-Khatib as modified according to the arrangement of Bengtsson as the arrangement of the sensor of Bengtsson is an art-effective way to mount a sensor which measures an analyte in the patient’s blood and because such an arrangement would have yielded the same, predictable result of the system having the housing and the sensor arranged such that it can be in contact with the patient’s blood and be able to measure the desired analyte. Further, there are a limited number of options for arranging the sensor of El-Khatib within the assembly of El-Khatib such that the sensor would be able to measure an analyte in the blood, and one of these limited options is to have provided the sensor at the exterior of the housing as claimed as the housing is attachable to the patient’s skin and the patient’s blood is separated from the system by the patient’s skin; since the sensor must be in contact with the blood to be operational, it would have been obvious to have arranged the sensor such that it traverses the patient’s skin via an insertion into the skin as shown in Bengtsson.
Regarding claim 3, El-Khatib et al. as modified discloses the controller being configured to operate the fluid delivery system to suspend, terminate, or throttle delivery of the first drug product to the patient based at least partly on the sensed cytokine parameter being within or outside of the predetermined range of values or greater or less than the predetermined cytokine value (see El-Khatib et al. pg. 14, lines 17-31, and see Shimabukuro-Vornhagen at the first paragraph of the right column of pg. 10 which teaches that BiTE therapy can be interrupted if necessary; thus, in the modified device, it is the Examiner’s position that the controller would interrupt the BiTE therapy such as to deliver the second agent based on the sensed CRP levels indicating severe CRS), and the sensed patient temperature being within or outside of the predetermined temperature range or greater or less than the predetermined temperature (since the sensed patient temperature from Galley is used to detect CRS in the modified device and since Shimabukuro-Vornhagen at the first paragraph of the right column of pg. 10 teaches that BiTE therapy can be interrupted if necessary, it is the Examiner’s position that the controller would interrupt the BiTE therapy as needed such as to deliver the second agent based on the sensed patient temperature levels indicating severe CRS where the sensed patient temperatures are used in part to determine severe CRS in the modified device).
Regarding claim 4, El-Khatib et al. as modified discloses the controller (controller, see pg. 14 line 30) being configured to operate an output unit (screen reading “Infusion Pump” in Figs. 7A-7C, see also display-screen, pg. 15 lines 21-22) to notify the patient and/or a healthcare provider (see pg. 15 lines 9-19) based at least partly on the sensed cytokine parameter being within or outside of the predetermined range of values or greater or less than the predetermined cytokine value (see El-Khatib pg. 15 lines 19-22; the display is configured for displaying pump data, and since the pump actions are based on the presence of CRS as detected at least in part by the cytokine sensor, the controller is thus configured to operate the display based at least partly on the sensed cytokine parameter values as claimed), and the sensed patient temperature being within or outside of the predetermined temperature range or greater or less than the predetermined temperature (see El-Khatib pg. 15 lines 19-22; the display is configured for displaying pump data, and since the pump actions are based on the presence of CRS as detected at least in part by the patient temperature sensor, the controller is thus configured to operate the display based at least partly on the sensed patient temperature values as claimed).
Regarding claim 39, El-Khatib et al. discloses a method comprising: providing a system (infusion system 10, Fig. 2) comprising: a housing attachable to a patient's skin (External shell of infusion pump 12 shown in Fig. 2; Examiner notes that the housing shown in Fig. 2 is capable of being attached to a patient’s skin as it could be secured to the skin using tape or a rubber band), a first reservoir disposed at least partially within the housing (Medicament reservoir 16A, Fig. 4, pg. 17 lines 9-25) and filled with a first drug product (insulin, see pg. 21 line 21); a second reservoir disposed at least partially within the housing (Medicament reservoir 16B, Fig. 4, pg. 17 lines 9-25) and filled with a second drug product (glucagon, see pg. 21 lines 22-23), wherein the second drug product comprises an agent for treating a response induced by administration of the first drug product (glucagon is known to have the opposite effect of insulin, see pg. 21 lines 17-18); at least one administration member (cannula 196A, Fig. 10C) insertable into the patient and connected or connectable in fluid communication (see infusion set 20, Fig. 2) with at least one of the first reservoir and the second reservoir (see Fig. 2 and Fig. 10C), a fluid delivery system (infusion pump 12, Fig. 2) operable to deliver at least one of the first drug product from the first reservoir and the second drug product from the second reservoir (see pg. 14 lines 25-29) to the patient via the at least one administration member (cannula 196A, Fig. 10C), a sensor (glucose sensor, pg. 14 line 24) operable to sense a biological condition of the patient (blood glucose level, pg. 14 line 23); and a controller (controller, see pg. 14 line 30) coupled with the housing (see pg. 14 lines 29-31, the controller is coupled with the infusion pump 12 and thus the external shell thereof); and operating the fluid delivery system (infusion pump 12, Fig. 2) to deliver the first drug product (insulin, see pg. 21 line 21) from the first reservoir (medicament reservoir 16A, Fig. 4) to the patient via the administration member (cannula 196A, Fig. 7C); sensing, via the sensor (glucose sensor, see pg. 14 line 24), a biological condition of the patient (blood glucose level, see pg. 14 line 23) while, before, and/or after the first drug product is delivered (real-time measurements, see pg. 14 lines 23-29); and analyzing, with the controller, output from at least the sensor (see pg. 14 lines 17-31) to determine if the patient experiences a medical condition which needs treatment (see pg. 14 line18-29 especially 18-20), wherein a determination is based at least partly on the sensed biological condition being within or outside of a predetermined range of values or greater or less than a predetermined value (Damiano et al., US Pat. No. 7806854, henceforth Damiano et al., which is incorporated by reference on pg. 15 lines 1-3 of El-Khatib et al., discloses y(t) establishes a target level, see col. 2 lines 50-67 and col. 3 lines 1-24. See also El-Khatib et al. pg. 3 lines 1-4 and pg. 14 lines 25-29, it is the Examiner’s position that it is known in the art a closed-loop glucose control system has a predetermined value or range of values to compare with measured values), and operating the fluid delivery system to deliver of the second drug product (see pg. 14, lines 17-31 and pg. 15 lines 1-3, it is the Examiner’s position that when the controller controls the pump to deliver glucagon the delivery of glucagon is initiated and thus the second drug product is delivered) to the patient in response to the determination that the patient is experiencing the condition (see pg. 14, lines 17-31 and pg. 15 lines 1-3).
El-Khatib et al. does not disclose the system comprising an adhesive attached to an exterior surface of the housing for attaching the housing to a patient's skin. Gorman et al. teach the use of an adhesive attachment apparatus to comfortably and reliably adhere fluid devices such as insulin infusion devices to a patient for treatment of diabetes ([0013], [0109]). Gorman et al. also teaches that ambulatory infusion pumps are used to deliver insulin and result in better efficacy of the drug and therapy and less toxicity to the patient's system ([0006]), and that existing adhesives at the time of filing of Gorman et al. needed improved comfort and reliability for ambulatory infusion pumps ([0011]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added the adhesive attachment apparatus of Gorman et al. to the housing of El-Khatib et al. for providing a comfortable and reliable means to transport the housing to allow the system of El-Khatib et al. to deliver insulin and result in better efficacy of the drug and therapy and less toxicity to the patient's system.
El-Khatib et al. as modified by Gorman additionally discloses that sensing of the biological condition serves as an indicator for diagnosing the response to the administration of the first agent (see at least pg. 14 lines 17-31) and that the first agent and second agent can be replaced with different agents (see pg. 11 lines 5-15) where the device can be used for multiple indications (pg. 18 lines 5-12).
El-Khatib et al. as modified does not disclose that the first drug product comprises a bispecific T cell engaging antibody construct and/or a chimeric antigen receptor (CAR) T cell receptor; that the second drug product comprises an agent for treating cytokine release syndrome (CRS) induced by administration of the bispecific T cell engaging antibody construct and/or a chimeric antigen receptor (CAR) T cell receptor, or that the sensed biological condition should be a cytokine parameter which is an indicator of CRS as measured by a cytokine sensor. Shimabukuro-Vornhagen teaches administration of a drug product comprising a bispecific T cell engaging antibody construct (BiTE constructs such as blinatumomab, see Abstract and the last paragraph of the left column of pg. 10) which can induce CRS (see at least the first paragraph of the right column of pg. 2, in a study using blinatumomab there were patients with CRS) which can be treated with appropriate administration of a second drug product (tocilizumab, see at least the second paragraph of the right column of pg. 10) which is used for treating CRS (see at least the second paragraph of the right column of pg. 10, tocilizumab is taught as a treatment for severe CRS which is previously taught to be a possible outcome of blinatumomab), and that CRS can be detected at least in part based on sensing of a cytokine parameter in a biological fluid (serum CRP can be used as a biomarker for determining severity of CRS, see at least the third paragraph of the left column of pg. 10). Additionally, Anderson teaches administration of immunotherapy treatment with a first drug product (immune system suppressor, [0020]; also, a chemotherapeutic agent is taught in [0021]) and administration of a second drug product (a steroid, [0019]) which addresses a second condition (inflammation, [0019]) which is detected by a cytokine sensor (detector for C-reactive protein, [0019], which is a cytokine sensor as C-reactive protein is a biomarker for cytokines and thus it is a sensed cytokine parameter and thus the sensor is a cytokine sensor since it measures a sensed cytokine parameter). Additionally, Anderson teaches that the sensing of blood glucose is equivalent to the sensing of C-reactive protein, or CRP, depending on the conditions to be monitored and treated (see at least [0002], [0003], [0009], [0019]-[0021], and [0033], insulin is known to react with blood glucose levels in diabetes and contextualized biometric states can include either CRP measurements or blood glucose levels depending on the target conditions).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have replaced the insulin and glucagon of El-Khatib et al. with the bispecific T cell engaging antibody construct and second agent of Shimabukuro-Vornhagen for treating cancer instead of diabetes (Shimabukuro-Vornhagen teaches that BiTE therapy and CAR-T cell therapy have shown remarkable efficacy in cancer treatment, see Abstract) and to have correspondingly replaced the blood glucose sensor of El-Khatib et al. with the CRP sensor of Anderson to allow for the detection of CRS using CRP as a cytokine parameter (CRP can function at least partially as a biomarker for the detection of CRS, see Shimabukuro-Vornhagen at least at par. 3 of the left column of pg. 2 and at the third paragraph of the left column of pg. 10, meaning that it is a sensed cytokine parameter as it is a biomarker for cytokines as provided in the art) as El-Khatib et al. teaches that its apparatus can be used for multiple indications (see pg. 11 lines 5-15) and further because such a substitution would have yielded the same, predictable result of a system which is capable of administering a first agent which treats a target condition, sensing whether or not a negative symptom is occurring as a result of the administration of the first medicament with a sensor (in the disclosure of El-Khatib et al., this negative symptom is a potentially dangerous glycemic low as a result of over-administration of insulin and is detected by measuring blood glucose; in the modified device, it is a measuring of CRP to detect CRS as a result of administration of a bispecific T cell engaging antibody construct), and if needed, administering a second agent which is configured to treat the negative symptom caused by administration from the first agent (in El-Khatib et al., this second agent is glucagon to treat the potentially dangerous glycemic low; in the modified device, it is administration of an agent to treat CRS as claimed). In this modified system, the teachings of El-Khatib et al. and the references which it incorporates by reference (which are subsequently called out as appropriate) regarding the use of different administration times and changes would apply when sensing CRP instead of glucose in the blood.
El-Khatib et al. as modified does not disclose a patient temperature sensor operable to sense a patient temperature. Galley et al. teaches a first sensor (261, glucose sensor, see [0046]) and a patient temperature sensor (262, implanted body temperature sensor, see [0046]) operable to sense a temperature of the patient (patient temperature, see [0046]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the device of El-Khatib et al. by adding the subcutaneous (or implanted) temperature sensor of Galley et al. (see [0046]) for providing additional information relating to the physiological condition of the user and because Shimabukuro-Vornhagen teaches that body temperature is another significant indicator of CRS (see at least the third paragraph of the left column of pg. 2, the third paragraph of the left column of pg. 10, and the third paragraph of the right column of pg. 10) and thus an added temperature sensor would provide the benefit of being able to more reliably detect CRS if the sensed temperature was used in part for the controlling of administration of the first and second drug products (since fever is a part of the clinical presentation of CRS as taught by Shimabukuro-Vornhagen, including determination of severity of the CRS, it could be used to further the diagnosis of and thus treatment of CRS when combined with the sensing of CRP as indicated above).
El-Khatib et al. as modified does not explicitly disclose the controller being configured to analyze the output from the patient temperature sensor of Galley to determine if the patient experiences CRS where the determination is based on a sensed patient temperature being within or outside of a predetermined temperature range or greater or less than a predetermined temperature. However, Shimabukuro-Vornhagen teaches that fever is an indicator of CRS (see at least the third paragraph of the left column of pg. 2, the third paragraph of the left column of pg. 10, and the third paragraph of the right column of pg. 10) and that severe CRS is often denoted by a high fever (see at least the third paragraph of the left column of pg. 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have configured and used the controller of El-Khatib et al. as modified to analyzed the output from the patient temperature sensor of Galley to determine if the patient experiences CRS, wherein the determination is based at least partly on a sensed patient temperature being within or outside of a predetermined temperature range or greater or less than a predetermined temperature as this measured patient temperature from the added sensor of Galley would be an indication of a fever or high fever which is an indicator of CRS and the relative severity of said CRS (see at least the third paragraph of the left column of pg. 2, the third paragraph of the left column of pg. 10, and the third paragraph of the right column of pg. 10). The second predetermined value or range of values as claimed would then be a threshold for a fever or a high fever as compared to normal body temperatures in this modified device. In this modified device, then, El-Khatib as modified discloses sensing, via the patient temperature sensor, a patient temperature while, before, and/or after the first drug product is delivered as claimed where these represent all time options and where the use of the measured patient temperature is used for determining of CRS which occurs during administration of the first drug product in the modified device to confirm that BiTE therapy does not need to be paused due to CRS.
El-Khatib as modified thus discloses that the cytokine sensor is in some way in contact with the patient’s blood (see at least Anderson [0002], [0003], [0009], [0019]-[0021], and [0033] and Shimabukuro-Vornhagen at the third paragraph of the left column of pg. 10, the CRP sensor in the modified device measures the patient’s blood to determine amounts of CRP). El-Khatib as modified additionally discloses that the patient temperature sensor is in some way in contact with the interior of the patient where the sensor is called out as being implanted, meaning provided subcutaneously (see Galley [0046]). El-Khatib as modified additionally discloses that glucose sensors and CRP sensors are obvious replacements of each other and can be substituted depending on what the desired variable to be measured in the patient is (see Anderson [0002], [0003], [0009], [0019]-[0021], and [0033]).
El-Khatib et al. as modified does not explicitly disclose that the cytokine sensor and the patient temperature sensor is arranged at and/or extending from the exterior surface of the housing, or wherein the cytokine sensor is configured such that attaching the housing to the patient’s skin causes the sensor to contact and/or insert into the patient’s skin as El-Khatib does not provide the specifics of the arrangement of its sensor. Bengtsson teaches a system (system 400, figs. 9A and 9B) which includes a housing (disposable unit 413 and durable unit 414, fig. 9B, create a housing at their exterior) which is attachable to a patient’s skin (see [0093]) comprising an art-effective sensor (needle-formed sensors 412, fig. 9B) for detecting an analyte in the patient’s blood (see [0093], the sensors are for measuring blood glucose which is shown to be a known variant to the CRP sensors of El-Khatib et al. as modified as indicated previously) wherein the sensor is arranged at and extending from an exterior surface of the housing (see fig. 9B, sensors 412 are shown as being arranged and protruding from second mounting surface 411 which is an exterior surface of the housing as shown, see also [0093]) which an adhesive is attached to (see [0028] and [0030], mounting surfaces are meant to have adhesives attached to them such as to mount them to the patient’s skin) and further wherein the sensor is configured such that attaching the housing to the patient’s skin causes the sensor to contact and/or insert into the patient’s skin (see figs. 9A and 9B and [0093], the sensors 412 are configured to be inserted subcutaneously and are configured as claimed where the placement of the sensors and the attachment of the housing to the skin means that the needles contact and then insert subcutaneously into the patient’s skin).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arranged the cytokine sensor and the patient temperature sensor of El-Khatib as modified according to the arrangement of Bengtsson as the arrangement of the sensor of Bengtsson is an art-effective way to mount a sensor which measures an analyte in the patient’s blood and because such an arrangement would have yielded the same, predictable result of the system having the housing and the sensor arranged such that it can be in contact with the patient’s blood and be able to measure the desired analyte. Further, there are a limited number of options for arranging the sensor of El-Khatib within the assembly of El-Khatib such that the sensor would be able to measure an analyte in the blood, and one of these limited options is to have provided the sensor at the exterior of the housing as claimed as the housing is attachable to the patient’s skin and the patient’s blood is separated from the system by the patient’s skin; since the sensor must be in contact with the blood to be operational, it would have been obvious to have arranged the sensor such that it traverses the patient’s skin via an insertion into the skin as shown in Bengtsson.
Regarding claim 40, El-Khatib et al. as modified discloses operating the fluid delivery system (infusion pump 12, Fig. 2) to suspend, terminate, or throttle delivery of the first drug product to the patient based at least partly on the sensed cytokine parameter being within or outside of the predetermined range of values or greater or less than the predetermined cytokine value (see El-Khatib et al. pg. 14, lines 17-31, and see Shimabukuro-Vornhagen at the first paragraph of the right column of pg. 10 which teaches that BiTE therapy can be interrupted if necessary; thus, in the modified device, it is the Examiner’s position that the controller would interrupt the BiTE therapy such as to deliver the second agent based on the sensed CRP levels indicating severe CRS), and the sensed patient temperature being within or outside of the predetermined temperature range or greater or less than the predetermined temperature (since the sensed patient temperature from Galley is used to detect CRS in the modified device and since Shimabukuro-Vornhagen at the first paragraph of the right column of pg. 10 teaches that BiTE therapy can be interrupted if necessary, it is the Examiner’s position that the controller would interrupt the BiTE therapy as needed such as to deliver the second agent based on the sensed patient temperature levels indicating severe CRS where the sensed patient temperatures are used in part to determine severe CRS in the modified device).
Regarding claim 52, El-Khatib et al. as modified discloses the method comprising operating, automatically via the controller (controller, see pg. 15 lines 15-21), an output unit (display screen, pg. 15 lines 21-22) to notify the patient and/or a healthcare provider (see pg. 15 lines 9-22) based at least partly on: the sensed cytokine parameter being within or outside of the predetermined range of values or greater or less than the predetermined cytokine value (see El-Khatib pg. 15 lines 19-22; the display is configured for displaying pump data, and since the pump actions are based on the presence of CRS as detected at least in part by the cytokine sensor, the controller is thus configured to operate the display based at least partly on the sensed cytokine parameter values as claimed), and the sensed patient temperature being within or outside of the predetermined temperature range or greater or less than the predetermined temperature (see El-Khatib pg. 15 lines 19-22; the display is configured for displaying pump data, and since the pump actions are based on the presence of CRS as detected at least in part by the patient temperature sensor, the controller is thus configured to operate the display based at least partly on the sensed patient temperature values as claimed).
Claim(s) 66-67 is/are rejected under 35 U.S.C. 103 as being unpatentable over El-Khatib et al. (WO 2015061693, henceforth El-Khatib et al.) in view of Gorman et al. (US 20040116866, henceforth Gorman et al.), Shimabukuro-Vornhagen et al. (“Cytokine release syndrome”, Journal for ImmunoTherapy of Cancer, published 15 June 2018, henceforth Shimabukuro-Vornhagen), Anderson (US 20170087299, henceforth Anderson), Galley et al. (US 20060276771, henceforth Galley et al.), and Bengtsson (US 20040162521, henceforth Bengtsson) as applied to claims 1 and 39 above, respectively, and further in view of Weichel et al. (“TandAbs: potent and well-manufacturable bi-specific antibodies”, European Pharmaceutical Review, Vol. 20, Issue 1, 2015, pgs. 27-32, henceforth Weichel et al.) and Chiang et al. (US 20090028824, henceforth Chiang, previously made of record on 01/08/2024).
Regarding claims 66 and 67, El-Khatib as modified discloses the respective system and method of claims 1 and 39.
El-Khatib as modified does not disclose the respective system or method wherein the fluid delivery system comprises a reconstitution subsystem and the first drug product is initially in a lyophilized form, and wherein the method comprises reconstituting the first drug product using the reconstitution subsystem prior to delivery to the patient via the administration member.
Weichel teaches that lyophilization is an option for long-term storage of bispecific antibodies including bispecific T-cell engaging antibodies (see “Since lyophilisation is an option for long-term storage during early clinical development, conditions are also identified to support this formulation” … and “The data sets show excellent stability for the TandAb material spanning three years”, from Weichel pg. 32, second paragraph of the first column and first paragraph of the second column, respectively, and see the section “In vivo pharmacodynamics of (T cell-recruiting) TandAbs – effective tumour elimination” of pg. 31).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have formed the first drug of El-Khatib et al. as an initial lyophilized form as Weichel teaches this form to be effective for long term storage of bispecific antibodies and scalably manufacturable under good manufacturing processes (see Weichel pgs. 31 and 32 under the section “cGMP manufacturing of TandAbs – scalable process”).
El-Khatib as modified does not disclose the fluid delivery system comprising a reconstitution subsystem which is configured and used to reconstitute the first drug product prior to delivery to the patient via the first administration member.
Chiang teaches a fluid delivery system (assembly of fig. 18) comprising a reconstitution subsystem (the elements which are used to mix the lyophilized drug with a suitable fluid vehicle known in the art as in [0078] are the claimed subsystem) which is configured and used to reconstitute a lyophilized drug product ([0078]) prior to delivery of the drug product to a patient via an administration member (see [0027] and [0078], the reconstitution of [0078] must occur prior to fluid delivery otherwise the delivery is not a fluid delivery as is taught in [0027]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have added a reconstitution subsystem to the fluid delivery system of El-Khatib et al. as in Chiang as Chiang teaches that such a system is needed when a drug is lyophilized for stability during storage and needs to be delivered as a fluid as in El-Khatib et al. (see Chiang [0078]).
Response to Arguments
Applicant's arguments filed 07/13/2026 have been fully considered but they are not persuasive.
Applicant has argued that the relied upon combination of references is insufficient and unsubstantiated, particularly regarding using the system of El-Khatib for the treatment of cancer and replacing the insulin and glucagon of El-Khatib with a BiTE construct and a steroid as in Shimabukuro-Vornhagen as relied on above. This is respectfully found unpersuasive. El-Khatib discloses at pg. 11, lines 6-15, the following:
The present invention described herein relates to an infusion system 10 for subcutaneously delivering a plurality of medicaments or infusates, and preferably different types of medicaments or infusates, to a patient. Specific examples are set forth below with respect to a dual-medicament delivery and infusion system for delivering multiple medicaments, such as for example insulin and glucagon, to the patient. However, one of ordinary skill in the art will readily recognize that the infusion system 10 of the present invention may be used with other types of medicaments or infusates, and may be used, configured or designed to deliver more than or less than two medicaments.
This is an explicit disclosure from El-Khatib that the system of El-Khatib is not meant to be limited to the indication of diabetes treatment which the disclosure of El-Khatib is centered around. Thus, it is the Examiner’s position that the system of El-Khatib is capable of being configured for different indications such as cancer. Examiner also notes new reference, Stone (US 20110144587) at [0089] teaches that its pump device is capable of administering insulin for diabetes treatment, and at [0093] teaches that its pump device is alternatively capable of administering cancer therapy drugs for cancer treatment. Similar teachings exist in Shin et al. (US 20130041353) at [0152]-[0154]. El-Khatib teaches a system using a first drug product (insulin) to treat a condition (diabetes) which can have a negative side effect (glycemic emergency) which is treatable with a second drug product (glucagon) which acts against the side effect caused by the first drug product (glycemic emergency) as detected by a sensor (glucose sensor) which detects a blood analyte as a biomarker of the side effect (glucose as a glycemic index marker). Analogously, Shimabukuro-Vornhagen teaches a treatment option using a first drug product (BiTE constructs) to treat a condition (cancer) which can have a negative side effect (CRS) which is treatable with a second drug product (a steroid) which acts against the side effect caused by the first drug product (the CRS). The detection of this side effect in the modified system as relied upon is done by a sensor (CRP sensor) which detects a blood analyte (CRP) as a biomarker of the side effect (CRP is a biomarker for CRS as explained in the body of the rejection above). Thus, while the exact indications are different and system modifications would have to be made, the same system design is in place for El-Khatib as to work in the modified system as relied upon above, and since El-Khatib discloses that one of ordinary skill in the art would have recognized that its system could be used with other medicaments or infusates, Examiner respectfully finds Applicant’s argument unpersuasive.
Examiner notes and suggests that further amendments could be made to the claimed system to differentiate the cytokine sensor and the sensed cytokine parameter to further distinguish between Applicant’s disclosure and the combination of references as relied upon above.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Stone (US 20110144587) and Shin et al. (US 20130041353) are considered relevant prior art where they disclose systems similar to that of El-Khatib which are primarily disclosed as being used to treat diabetes but are also disclosed to be configurable to treat cancer, similar to the modifications made in the rejection of record above and argued to be obvious to one of ordinary skill in the art by Examiner above (see the Response to Arguments section above).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMUEL J MARRISON whose telephone number is (703)756-1927. The examiner can normally be reached M-F 7:00a-3:30p ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kevin Sirmons can be reached on (571) 272-4965. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SAMUEL J MARRISON/Examiner, Art Unit 3783
/EMILY L SCHMIDT/Primary Examiner, Art Unit 3783
Prosecution Insights