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 .
DETAILED ACTION
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.
Response to Amendments
Applicant’s amendments and response filed Nov. 11, 2025 have been received and entered into the case.
Status of the Claims
Claims 1-4 and 20-37 are currently pending.
Claims 1, 36 and 37 are amended.
Claims 5-19 are cancelled.
Claims 1-4 and 20-37 have been considered on the merits.
Claim Rejections - 35 USC § 112
The claim rejections under 35 USC § 112, (a) or first paragraph (pre-AIA ), are withdrawn due to amendment.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are withdrawn due to amendment. New claim rejections under 35 USC § 103 have been added to address the claim amendments.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-3, 20, 22, 23, 25-27, 31, 32, and 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over King (US 4,568,328) (ref. of record) in view of Briggs et al. (WO 2016/205511 A1) (ref. of record) and Girardi et al. (Leukemia & lymphoma, 2006) as evidenced by Durazzo et al. (Transfusion and Apheresis Science, 2014).
With respect to claims 1, 36 and 37, King teaches a method of treating leukocytes or white blood cells (mononuclear cells) by extracorporeal photopheresis (abstract). King teaches a central control means which controls and adjusts the system using a central processing unit and memory stored software (a computer, driven and adjusted by a microprocessor-based controller) (Col. 6 lines 21-40 and Col. 8 lines 13-58). With respect to the first recited step of claims 1, 36 and 37, King teaches priming the fluid circuit with a priming fluid (Col. 5 lines 40-45, Col. 6 lines 12-17 and Col. 8 lines 26-30). With respect to the second recited step of claims 1, 36 and 37, King teaches connecting a patient to the system and withdrawing whole blood from a patient and directing it through the system (directing whole blood derived from a blood source into the fluid circuit) (Col. 4 lines 33-41). With respect to the third recited step of claims 1, 36 and 37, King teaches separating the whole blood into a red blood cell component, leukocytes (white blood cells or mononuclear component) and a plasma component in a centrifuge bowl (a separation chamber) (Col. 4 lines 48 to Col. 5 line 18). With respect to the fourth recited step of claims 1, 36 and 37, King teaches returning the erythrocyte enriched portion and excess plasma back to the patient (returning a first portion of the red blood cell component and a first portion of the plasma component to the whole blood) (Col. 5 lines 31-34 and Col. 8 line 67 to Col. 9 line 7). With respect to the fifth recited step of claims 1, 36 and 37 and claim 20, King teaches adding a photoactivable reagent to the desired blood portion (biological agent that is a photoactivation agent) including the leukocyte fraction and tubing attaching the container containing the leukocyte enriched portion to the centrifuge bowl (separation chamber) and tubing attaching the leukocyte container to a treatment cassette (an illumination container fluidically connected to the separation chamber) (Col. 1 lines 7-12 and 43-55, Col. 4 lines 3-5, Col. 6 lines 33-50, and Col. 7 lines 10-15 and Fig. 1 and 2). With respect to the sixth and seventh recited steps of claims 1 and 37, the sixth recited step of claim 36 and claim 20, King teaches exposing the leukocyte fraction combined with the photoactivable compound with irradiation within the fluid circuit for certain exposure time which would be understood that the leukocytes with the photoactivable reagent would be incubated together during this exposure time (incubating for a period of time the agent-added mononuclear cell component to create an incubated agent-added mononuclear cell component) (Col. 6 lines 21-40). With respect to the seventh recited step of claims 1 and 37, the sixth recited step of claim 36 and claim 22, King teaches that the patient is preferably disconnect from the machine during the irradiation treatment (Col. 3 lines 50-62 and Col. 6 line 66 to Col. 7 line 7).
With respect to the first recited step of claim 2, King teaches the red blood cells and plasma are retained after separation (Col. 4 lines 48 to Col. 5 Col. 5 lines 31-34 and Col. 8 line 67 to Col. 9 line 7). With respect to the second recited step of claim 2, King teaches reinfusing the red blood cells and plasma back to the patient (Col. 4 lines 48 to Col. 5 line 18, Col. 5 lines 31-34 and Col. 8 line 67 to Col. 9 line 7).
With respect to claim 23, King teaches reinfusing a portion of the incubated photoactivated mononuclear cell component into the patient (blood source) (Col. 3 lines 50-62 and Col. 6 lines 41-67). With respect to claims 26, 27, 31 and 32, King teaches reinfusing the photoactivated leukocytes or the incubated mononuclear cell component back to the patient or blood source which would include a first portion and a second portion (Col. 3 lines 50-62 and Col. 6 lines 41-67).
With respect to claim 35, King teaches the blood is collected from the patient by connecting them to the system by venipuncture methods (whole blood is directed into the fluid circuit via an access device of the fluid circuit connected to the blood source) and the patient is disconnected from the system during the photoactivation (the blood source is disconnected from the access device of the fluid circuit for at least a portion of the period of time) (Col. 3 lines 50 to Col. 4 line 12, Col. 4 lines 33-37 and Col. 6 line 66 to Col. 7 line 7).
King does not teach the method where the first portion of the red blood cell component and a first portion of the plasma component is returned to the whole blood at the same time as the mononuclear cell component is accumulating in the separation container as recited in fourth recited step of claims 36 and 37.
However, Briggs teaches a similar method of treating leukocyte-enriched blood including white blood cells (mononuclear cells) by extracorporeal photopheresis (pg. 10 last three para.). Briggs teaches returning certain components of the whole blood from the centrifuge to the patient as whole blood is directed is directed into the centrifuge bowl and, in particular, teaches the red blood cells and plasma may be returned to the patient simultaneously with the whole blood being drawn from the patient and while certain blood components including the buffy coat (which includes mononuclear cells) accumulate in the centrifuge bowl (pg. 1 para. 4 and pg. 11 para. 2). Briggs teaches returning the blood to the patient may be important for some patients such as pediatric patients (pg. 43 last para.). In further support, King teaches returning the erythrocyte enriched portion between cycles of separation and the cycles are repeated a number of times until the desired volume of leukocyte enriched blood and plasma is obtained for further treatment (Col. 5 lines 19-34).
Accordingly, at the effect time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the teachings of King so that a first component of red blood cells and plasma is returned to the whole blood or patient while the mononuclear component is accumulating for the benefit of maintaining the blood volume of the patient as taught by Briggs. Furthermore, it would have been obvious to one skilled in the art to have further modified King such that a first component of red blood cells and plasma is returned to the whole blood or patient, since methods of extracorporeal photopheresis were known to return red blood cells and plasma back to the patient while whole blood is continuously drawn from the patient and separated and where the mononuclear cells accumulate in the separation chamber as taught by Briggs. For these reasons one of ordinary skill in the art would have had a reasonable expectation of success in modifying King to include continuous processing and accumulation of the mononuclear cells in the separation chamber.
King does not teach the method where there is a step of incubating of the agent-added mononuclear cell component after the irradiation of the cells as recited in the seventh recited step of claims 1 and 37. Likewise, King does not teach the method wherein the period of time of incubation is sufficiently long to allow for apoptotic T-cells generated in the agent-added mononuclear cell component by irradiation to induce differentiation of monocytes in the first portion of the agent-added mononuclear cell component into dendritic cells as recited in claims 1 and 37.
However, Girardi teaches a method of treating mononuclear cells for an extracorporeal photopheresis procedure where after ECP (extracorporeal photochemotherapy) treatment the cells are incubated overnight to increase the efficiency with which the apoptotic CTCL cells (cutaneous T cell lymphoma) and newly formed DC (dendritic cells) within the treated cell population can interact instead of immediately returning the cells to the patient after irradiation (abstract and pg. 1496 Col. 1 para. 3). Girardi teaches ECP product or treated cells were incubated overnight and then reinfused the next day (pg. 1496 Col. 1 para. 4 to Col. 2 para. 1). Girardi teaches that the beneficial effects of ECP are enhanced after ex vivo culture of the cells following ECP treatment and further enhanced by incubating the newly formed dendritic cells formed during the photochemical induction of monocytes with malignant cells in an overnight incubation (pg. 1495 last para. to pg. 1496 para. 2). Girardi further teaches that “transimmunization” (the overnight incubation of the cells after ECP treatment) can be applied for other malignancies and the prevention/treatment of GVHD by further manipulating the treated cells to maximize their tolerogenic capacity (pg. 1496 Col. 1 para. 1 and pg. 1502 last para.).
Accordingly, at the effective time of filing of the claimed invention one of ordinary skill in the art would have been motivated to modify the method of King to including incubating the irradiated mononuclear cells for a period of time following irradiation to further enhance the beneficial effects of ECP as taught by Girardi. It would have been obvious to one of ordinary skill in the art to modify the method of King to including incubating the irradiated mononuclear cells for a period of time following irradiation, since incubating or culturing the cells after irradiation and prior to returning the cells to the subject was known in the art and known to improve the effects of the cells as taught by Girardi. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification, since Girardi teaches a similar method of treating mononuclear cells for an extracorporeal photopheresis procedure and King and teaches the successful incubation of mononuclear cells following irradiation and return to the subject (abstract).
With respect to the limitation that the period of time of incubation is sufficiently long to allow for apoptotic T-cells generated in the agent-added mononuclear cell component by irradiation to induce differentiation of monocytes in the first portion of the agent-added mononuclear cell component into dendritic cells this is an inherent outcome of irradiating an agent-added mononuclear cell component as evidenced by Durazzo. Specifically, Durazzo reports that extracorporeal photochemotherapy (ECP), where the patient’s blood is extracorporeally routed as a thin film between parallel transparent plates to allow for site-focused targeting of passaged leukocytes by UVA irradiation, induces extracorporeally passaged monocytes to differentiate in dendritic cells (DC) (abstract and pg. 370 para. 2). Accordingly, the irradiation period is a sufficient period of time to incubate the agent-added mononuclear cell component to differentiate into dendritic cells and this would have occurred before a separate incubating time after irradiation.
King does explicitly teach the method where a single fluid circuit is used for both separating the whole blood and incubating the first portion of the agent-added mononuclear cell component as recited in claims 36 and 37. However, Briggs teaches a similar method of treating leukocyte-enriched blood including white blood cells (mononuclear cells) by extracorporeal photopheresis (pg. 10 last three para.). Briggs teaches the method where the process occurs within a single, closed sterile circuit and reduces the extracorporeal volume deficit and reduce the potential for infection, and ensures that a patient’s autologous cells are returned to them (pg. 11 para. 2 and pg. 15 para. 4).
Accordingly, at the effect time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the teachings of King so that a single fluid circuit is used for both separating the whole blood and incubating the first portion of the agent-added mononuclear cell component for the benefits of reducing the extracorporeal volume deficit, reducing the chances of infection and ensuring the return of the cells to the patient as taught by Briggs. Furthermore, it would have been obvious to one skilled in the art to have further modified King such that a single fluid circuit is used for both separating the whole blood and incubating the first portion of the agent-added mononuclear cell component, since methods of extracorporeal photopheresis were known to use single circuits as taught by Briggs. For these reasons one of ordinary skill in the art would have had a reasonable expectation of success in modifying King to include continuous processing.
King does not teach the priming fluid comprises albumin and/or a blood component as recited in claim 3. However, Briggs teaches a similar method of treating leukocyte-enriched blood including white blood cells (mononuclear cells) by extracorporeal photopheresis (pg. 10 last three para.). Briggs teaches purging the air bubbles from the centrifuge bowl by filling it with a fluid such as blood or water (priming the fluid circuit with a priming fluid) (pg. 22 para. 3). At the time of the claimed invention, one of ordinary skill in the art would have been motivated to modify the teachings of King in such a way that the priming fluid is blood for the purpose being able prime the fluid circuit and remove air bubbles. Furthermore, it would have been obvious to one skilled in the art to have further modified King such that priming fluid is blood, since methods of priming fluid circuits for extracorporeal photopheresis were known to use blood as taught by Briggs. Such a modification merely involves the substitution of one known type of priming fluid for another for the purpose being able prime the fluid circuit and remove air bubbles.
King does not teach returning a portion of the priming fluid to the blood source as recited in claim 25. However, Briggs teaches a method of extracorporeal photopheresis where the priming fluid is returned back to the patient (pg. 6 para. 4-5). Accordingly, at the effective time of filing of the claim invention, one of ordinary skill in the art would have been motivated to modify the method of King to include returning a portion of the priming fluid to the patient when the priming solution is a blood component, since Briggs teaches a similar method where blood is used as the priming solution and is returned back to the patient. It would have been within the purview of one of ordinary skill of the art to arrive at the claimed configuration based on the volume need of the returned blood components of the patients. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of King, so that a portion of the priming fluid is returned , since Briggs teaches a similar method where blood is used as the priming solution and is returned back to the patient.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 21, 28, 30 and 33 are rejected under 35 U.S.C. 103(a) as being unpatentable over King in view of Briggs and Girardi (as applied to claims 1-3, 20, 22, 23, 25-27, 31, 32, and 35-37 above), and further in view of Nguyen et al. (US 2018/0256805 A1) (ref. of record).
The teachings of King, Briggs and Girardi can be found in the previous rejection above.
Although, King teaches returning treated blood, untreated blood components, treated blood components and other fluids back to the patient, and teaches returning the cells through an infusion line (abstract, Col. 3 lines 50-62, Col. 3 line 50 to Col. 4 line 12, Col. 4 lines 48 to Col. 5 line 18, Col. 5 lines 31-34, Col. 6 lines 41-67, and Col. 8 line 67 to Col. 9 line 7), King does not explicitly teach retaining a second portion of the red blood cell component and a second portion of the plasma component within the fluid circuit prior to adding the photoactivation agent, and reinfusing into the blood source the second portion of the red blood cell component and the second portion of the plasma component at the same time as irradiating the agent-added mononuclear cell component) as recited in claim 30. King does not teach the method including collecting a second portion of the incubated photoactivated mononuclear cell component without reinfusion to the blood source as recited in claim 33, collecting a second portion of the incubated agent-added mononuclear cell component without reinfusion to the blood source as recited in claim 28, or retaining a second portion of the red blood cell component and a second portion of the plasma component within the fluid circuit without returning to the blood source as recited in claim 21.
However, Nguyen teaches a similar method of separating blood for the treating of mononuclear cells with extracorporeal photopheresis (abstract). Nguyen teaches flowing a portion of the mononuclear fraction into a mononuclear cell collection chamber where the cells are irradiated (0020) (collecting a second portion of the incubated photoactivated mononuclear cell component without reinfusion to the blood source). Nguyen teaches if additional mononuclear cell (MNC) product needs to be collected, alternating build-up and harvest phases may be repeated so that a sufficient amount of MNC product is collected (0045). Nguyen further teaches that red blood cells may be either collected or returned to the blood source, or a portion of the red blood cells may be collected while another portion is returned to the blood source (0045).
Accordingly, at the effective time of filing of the claim invention, one of ordinary skill in the art would have been motivated to modify the method of King to include the claimed different configurations of collecting, portioning the different blood components, treating or not treating portions of the blood components, reinfusing certain components together or separately, and saving portions, since Nguyen teaches possible different configurations. It would have been within the purview of one of ordinary skill of the art to arrive at the claimed configuration based on the need of the treated of mononuclear cells and the particular type of treatment of the mononuclear cells. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of King, so that to include the claimed different configurations of collecting, portioning the different blood components, treating or not treating portions of the blood components, reinfusing certain components together or separately, and saving portions, since Nguyen teaches many different possible configurations where different portions are saved, treated or reinfused.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 1, 2, 4, 20, 22-27, 31, 32, and 34-37 are rejected under 35 U.S.C. 103 as being unpatentable over King (US 4,568,328) (ref. of record) in view of Gara et al. (US 2006/0155236 A1) (ref. of record) and Girardi et al. (Leukemia & lymphoma, 2006) as evidenced by Durazzo et al. (Transfusion and Apheresis Science, 2014).
With respect to claims 1, 36 and 37, King teaches a method of treating leukocytes or white blood cells (mononuclear cells) by extracorporeal photopheresis (abstract). King teaches a central control means which controls and adjusts the system using a central processing unit and memory stored software (a computer, driven and adjusted by a microprocessor-based controller) (Col. 6 lines 21-40 and Col. 8 lines 13-58). With respect to the first recited step of claims 1, 36 and 37, King teaches priming the fluid circuit with a priming fluid (Col. 5 lines 40-45, Col. 6 lines 12-17 and Col. 8 lines 26-30). With respect to the second recited step of claims 1, 36 and 37, King teaches connecting a patient to the system and withdrawing whole blood from a patient and directing it through the system (directing whole blood derived from a blood source into the fluid circuit) (Col. 4 lines 33-41). With respect to the third recited step of claims 1, 36 and 37, King teaches separating the whole blood into a red blood cell component, leukocytes (white blood cells or mononuclear component) and a plasma component in a centrifuge bowl (a separation chamber) (Col. 4 lines 48 to Col. 5 line 18). With respect to the fourth recited step of claims 1, 36 and 37, King teaches returning the erythrocyte enriched portion and excess plasma back to the patient (returning a first portion of the red blood cell component and a first portion of the plasma component to the whole blood) (Col. 5 lines 31-34 and Col. 8 line 67 to Col. 9 line 7). With respect to the fifth recited step of claims 1, 36 and 37 and claim 20, King teaches adding a photoactivable reagent to the desired blood portion (biological agent that is a photoactivation agent) including the leukocyte fraction and tubing attaching the container containing the leukocyte enriched portion to the centrifuge bowl (separation chamber) and tubing attaching the leukocyte container to a treatment cassette (an illumination container fluidically connected to the separation chamber) (Col. 1 lines 7-12 and 43-55, Col. 4 lines 3-5, Col. 6 lines 33-50, and Col. 7 lines 10-15 and Fig. 1 and 2). With respect to the sixth and seventh recited steps of claims 1 and 37, the sixth recited step of claim 36 and claim 20, King teaches exposing the leukocyte fraction combined with the photoactivable compound with irradiation within the fluid circuit for certain exposure time which would be understood that the leukocytes with the photoactivable reagent would be incubated together during this exposure time (incubating for a period of time the agent-added mononuclear cell component to create an incubated agent-added mononuclear cell component) (Col. 6 lines 21-40). With respect to the seventh recited step of claims 1 and 37, the sixth recited step of claim 36 and claim 22, King teaches that the patient is preferably disconnect from the machine during the irradiation treatment (Col. 3 lines 50-62 and Col. 6 line 66 to Col. 7 line 7).
With respect to the first recited step of claim 2, King teaches the red blood cells and plasma are retained after separation (Col. 4 lines 48 to Col. 5 Col. 5 lines 31-34 and Col. 8 line 67 to Col. 9 line 7). With respect to the second recited step of claim 2, King teaches reinfusing the red blood cells and plasma back to the patient (Col. 4 lines 48 to Col. 5 line 18, Col. 5 lines 31-34 and Col. 8 line 67 to Col. 9 line 7).
With respect to claim 23, King teaches reinfusing a portion of the incubated photoactivated mononuclear cell component into the patient (blood source) (Col. 3 lines 50-62 and Col. 6 lines 41-67). With respect to claims 26, 27, 31 and 32, King teaches reinfusing the photoactivated leukocytes or the incubated mononuclear cell component back to the patient or blood source which would include a first portion and a second portion (Col. 3 lines 50-62 and Col. 6 lines 41-67).
With respect to claim 35, King teaches the blood is collected from the patient by connecting them to the system by venipuncture methods (whole blood is directed into the fluid circuit via an access device of the fluid circuit connected to the blood source) and the patient is disconnected from the system during the photoactivation (the blood source is disconnected from the access device of the fluid circuit for at least a portion of the period of time) (Col. 3 lines 50 to Col. 4 line 12, Col. 4 lines 33-37 and Col. 6 line 66 to Col. 7 line 7).
King does not teach the method where the first portion of the red blood cell component and a first portion of the plasma component is returned to the whole blood at the same time as the mononuclear cell component is accumulating in the separation container as recited in fourth recited step of claims 36 and 37.
However, Gara teaches a similar method of treating leukocytes or white blood cells (mononuclear cells) by extracorporeal photopheresis (0001-0002, 0010-0011 and 0207). Gara teaches the method where the whole blood is separated in a bowl with three separate fluid conduits (an inlet port and two outlet ports) that continuously spins which allows for reduced buffy coat collection process time, smaller blood volumes to be processed, red blood cells can be returned to the patients continuously, better separation of the different components of blood due to increased spinning or rotation time, and ability to separate high density red blood cells fractions from the whole blood (0221). Gara teaches the method where the buffy coat (contains mononuclear cells) accumulates or builds up in the separator as more whole blood is added (0031). In further support, King teaches returning the erythrocyte enriched portion between cycles of separation and the cycles are repeated a number of times until the desired volume of leukocyte enriched blood and plasma is obtained for further treatment (Col. 5 lines 19-34).
Accordingly, at the effect time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the teachings of King so that a first component of red blood cells and plasma is returned to the whole blood or patient while the mononuclear component is accumulating in the separation chamber for the benefits of maintaining the blood volume of the patient, reducing the processing times, and improved separation of the components as taught by Gara.
Furthermore, it would have been obvious to one skilled in the art to have further modified King such that a first component of red blood cells and plasma is returned to the whole blood or patient, since methods of extracorporeal photopheresis were known to return red blood cells and plasma back to the patient while whole blood is continuously drawn from the patient and separated and where the mononuclear cells accumulate in the separation chamber as taught by Gara. For these reasons one of ordinary skill in the art would have had a reasonable expectation of success in modifying King to include continuous processing. For these reasons one of ordinary skill in the art would have had a reasonable expectation of success in modifying King to include continuous processing and accumulation of the mononuclear cells in the separation chamber.
King does not teach the method where there is a step of incubating of the agent-added mononuclear cell component after the irradiation of the cells as recited in the seventh recited step of claims 1 and 37. Likewise, King does not teach the method wherein the period of time of incubation is sufficiently long to allow for apoptotic T-cells generated in the agent-added mononuclear cell component by irradiation to induce differentiation of monocytes in the first portion of the agent-added mononuclear cell component into dendritic cells as recited in claims 1 and 37.
However, Girardi teaches a method of treating mononuclear cells for an extracorporeal photopheresis procedure where after ECP (extracorporeal photochemotherapy) treatment the cells are incubated overnight to increase the efficiency with which the apoptotic CTCL cells (cutaneous T cell lymphoma) and newly formed DC (dendritic cells) within the treated cell population can interact instead of immediately returning the cells to the patient after irradiation (abstract and pg. 1496 Col. 1 para. 3). Girardi teaches ECP product or treated cells were incubated overnight and then reinfused the next day (pg. 1496 Col. 1 para. 4 to Col. 2 para. 1). Girardi teaches that the beneficial effects of ECP are enhanced after ex vivo culture of the cells following ECP treatment and further enhanced by incubating the newly formed dendritic cells formed during the photochemical induction of monocytes with malignant cells in an overnight incubation (pg. 1495 last para. to pg. 1496 para. 2). Girardi further teaches that “transimmunization” (the overnight incubation of the cells after ECP treatment) can be applied for other malignancies and the prevention/treatment of GVHD by further manipulating the treated cells to maximize their tolerogenic capacity (pg. 1496 Col. 1 para. 1 and pg. 1502 last para.).
Accordingly, at the effective time of filing of the claimed invention one of ordinary skill in the art would have been motivated to modify the method of King to including incubating the irradiated mononuclear cells for a period of time following irradiation to further enhance the beneficial effects of ECP as taught by Girardi. It would have been obvious to one of ordinary skill in the art to modify the method of King to including incubating the irradiated mononuclear cells for a period of time following irradiation, since incubating or culturing the cells after irradiation and prior to returning the cells to the subject was known in the art and known to improve the effects of the cells as taught by Girardi. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in making such a modification, since Girardi teaches a similar method of treating mononuclear cells for an extracorporeal photopheresis procedure and King and teaches the successful incubation of mononuclear cells following irradiation and return to the subject (abstract).
With respect to the limitation that the period of time of incubation is sufficiently long to allow for apoptotic T-cells generated in the agent-added mononuclear cell component by irradiation to induce differentiation of monocytes in the first portion of the agent-added mononuclear cell component into dendritic cells this is an inherent outcome of irradiating an agent-added mononuclear cell component as evidenced by Durazzo. Specifically, Durazzo reports that extracorporeal photochemotherapy (ECP), where the patient’s blood is extracorporeally routed as a thin film between parallel transparent plates to allow for site-focused targeting of passaged leukocytes by UVA irradiation, induces extracorporeally passaged monocytes to differentiate in dendritic cells (DC) (abstract and pg. 370 para. 2). Accordingly, the irradiation period is a sufficient period of time to incubate the agent-added mononuclear cell component to differentiate into dendritic cells and this would have occurred before a separate incubating time after irradiation.
King does explicitly teach the method where a single fluid circuit is used for both separating the whole blood and incubating the first portion of the agent-added mononuclear cell component as recited in claims 36 and 37. However, Gara teaches a similar method of treating leukocytes or white blood cells (mononuclear cells) by extracorporeal photopheresis (0001-0002, 0010-0011 and 0207). Gara teaches the method where the blood is treated in a closed-loop process and returning the blood back in one medical treatment (0002, 0006, 0008 and 0125). Gara teaches the method reduces the amount of time it takes to process the blood, the amount of blood needed and the costs (0010). Accordingly, at the effect time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the teachings of King so that a single fluid circuit is used for both separating the whole blood and incubating the first portion of the agent-added mononuclear cell component for the benefits of reducing the amount of time needed, the amount of blood needed and costs as taught by Gara. Furthermore, it would have been obvious to one skilled in the art to have further modified King such that a single fluid circuit is used for both separating the whole blood and incubating the first portion of the agent-added mononuclear cell component, since methods of extracorporeal photopheresis were known to use single circuits as taught by Gara. For these reasons one of ordinary skill in the art would have had a reasonable expectation of success in modifying King to include continuous processing.
King does not teach the priming fluid is saline as recited in claim 4. However, Gara teaches a similar method of treating leukocytes or white blood cells (mononuclear cells) by extracorporeal photopheresis (0001-0002, 0010-0011 and 0207). Gara teaches the method is controlled by a processor system and teaches the system where the controller analyzes data and adjusts speed of the blood pump (0186, 0188, 0251) (driven and adjusted by a microprocessor-based controller). Gara teaches priming the fluid circuit with a priming fluid containing saline (0032, 0162, and Fig. 26A). Gara teaches priming the fluid circuit to remove gas bubbles (0162 and 0289). At the time of the claimed invention, one of ordinary skill in the art would have been motivated to modify the teachings of King in such a way that the priming fluid is saline for the purpose being able prime the fluid circuit and remove air bubbles. Furthermore, it would have been obvious to one skilled in the art to have further modified King such that priming fluid is blood, since methods of priming fluid circuits for extracorporeal photopheresis were known to use blood as taught by Gara. Such a modification merely involves the substitution of one known type of priming fluid for another for the purpose being able prime the fluid circuit and remove air bubbles.
King does not teach washing at least a portion of the incubated agent-added mononuclear cell component as recited in claim 24. However, Gara teaches filtering the untreated and treated blood components by filtering or washing at least a portion of the incubated agent-added mononuclear cell component (0161 and 0187). Gara teaches the filtering removes contaminants and other undesired materials from the fluid and facilitates the release of trapped gasses in the fluid (0161). Accordingly, at the effective time of filing of the claimed invention one of ordinary skill in the art would have been motivated to modify the method of King to include a step of further washing the incubated agent-added mononuclear cell component for the benefits of removing contaminants, undesired materials and trapped gasses as taught by Gara. It would have been obvious to one of ordinary skill in the art to include this step of filtering or washing in the method of King, since similar methods of extracorporeal photopheresis include such a step filtering or washing the blood components as taught by Gara. Furthermore, one of ordinary skill in art would have had a reasonable expectation of success in making such a modification, since it was a known step in the art as taught by Gara.
King does not teach returning a portion of the priming fluid to the blood source as recited in claim 25. However, Gara teaches returning a portion of the priming fluid to the blood source (0143 and 0164). Accordingly, at the effective time of filing of the claim invention, one of ordinary skill in the art would have been motivated to modify the method of King to include returning a portion of the priming fluid to the patient when the priming solution is a blood component, since Gara teaches a similar method where blood is used as the priming solution and is returned back to the patient. It would have been within the purview of one of ordinary skill of the art to arrive at the claimed configuration based on the volume need of the returned blood components of the patients. Additionally, Gara teaches the addition of saline or other compatible components to add enough volume for the centrifuge process and adjusting the volume of the returned blood components according to the size or condition of the patient (0215 and 0301). Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of King, so that a portion of the priming fluid is returned, since Gara teaches a similar method where blood is used as the priming solution and is returned back to the patient.
King does not teach method where none of the incubated agent-added mononuclear cell component is returned back to the patient or blood source as recited in claims 29 and 34. However, Gara teaches a similar method of treating leukocytes or white blood cells (mononuclear cells) by extracorporeal photopheresis where the platelets, leukocytes and other buffy coat fraction can be further separated and along with red blood cells can be collected rather than being returned with the plasma to the patient (reinfusing none of the incubated photoactivated mononuclear cell component to the blood source) (0001-0002, 0010-0011, 0207, and 0295). Accordingly, at the effective time of filing of the claim invention, one of ordinary skill in the art would have been motivated to modify the method of King to include the step of not returning the incubated agent-added mononuclear cell component, since Gara teaches a similar method where the incubated agent-added mononuclear cell component is not returned to the patient but saved. It would have been within the purview of one of ordinary skill of the art to arrive at the claimed configuration based purpose of the extracorporeal photopheresis procedure. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of King, so that the incubated agent-added mononuclear cell component is not returned to the patient but saved, since Gara teaches a similar method where the incubated agent-added mononuclear cell component is not returned to the patient but saved.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 21, 28, 30 and 33 are rejected under 35 U.S.C. 103(a) as being unpatentable over King in view of Gara and Girardi evidenced by Durazzo (as applied to claim 1, 2, 4, 20, 22-27, 31, 32, and 34-37 above), and further in view of Nguyen et al. (US 2018/0256805 A1) (ref. of record).
The teachings of King, Gara and Girardi can be found in the previous rejection above.
Although, King teaches returning treated blood, untreated blood components, treated blood components and other fluids back to the patient, and teaches returning the cells through an infusion line (abstract, Col. 3 lines 50-62, Col. 3 line 50 to Col. 4 line 12, Col. 4 lines 48 to Col. 5 line 18, Col. 5 lines 31-34, Col. 6 lines 41-67, and Col. 8 line 67 to Col. 9 line 7), King does not explicitly teach retaining a second portion of the red blood cell component and a second portion of the plasma component within the fluid circuit prior to adding the photoactivation agent, and reinfusing into the blood source the second portion of the red blood cell component and the second portion of the plasma component at the same time as irradiating the agent-added mononuclear cell component) as recited in claim 30. King does not teach the method including collecting a second portion of the incubated photoactivated mononuclear cell component without reinfusion to the blood source as recited in claim 33, collecting a second portion of the incubated agent-added mononuclear cell component without reinfusion to the blood source as recited in claim 28, or retaining a second portion of the red blood cell component and a second portion of the plasma component within the fluid circuit without returning to the blood source as recited in claim 21.
However, Nguyen teaches a similar method of separating blood for the treating of mononuclear cells with extracorporeal photopheresis (abstract). Nguyen teaches flowing a portion of the mononuclear fraction into a mononuclear cell collection chamber where the cells are irradiated (0020) (collecting a second portion of the incubated photoactivated mononuclear cell component without reinfusion to the blood source). Nguyen teaches if additional mononuclear cell (MNC) product needs to be collected, alternating build-up and harvest phases may be repeated so that a sufficient amount of MNC product is collected (0045). Nguyen further teaches that red blood cells may be either collected or returned to the blood source, or a portion of the red blood cells may be collected while another portion is returned to the blood source (0045).
Accordingly, at the effective time of filing of the claim invention, one of ordinary skill in the art would have been motivated to modify the method of King to include the claimed different configurations of collecting, portioning the different blood components, treating or not treating portions of the blood components, reinfusing certain components together or separately, and saving portions, since Nguyen teaches possible different configurations. It would have been within the purview of one of ordinary skill of the art to arrive at the claimed configuration based on the need of the treated of mononuclear cells and the particular type of treatment of the mononuclear cells. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of King, so that to include the claimed different configurations of collecting, portioning the different blood components, treating or not treating portions of the blood components, reinfusing certain components together or separately, and saving portions, since Nguyen teaches many different possible configurations where different portions are saved, treated or reinfused.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed Nov. 11, 2025 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 103, Applicant argues that it is not clear from Durazzo when the differentiation of the monocytes into dendritic cells occurs and the language suggests that it happens after irradiation (Remarks pg. 10 para. 2). However, this argument was not found to be persuasive, since Durazzo teaches that extracorporeal photochemotherapy (ECP) “promotes platelet immobilization and activation, initiating stepwise receptor-ligand interactions with monocytes, which then differentiate into DC” (abstract). Durazzo teaches that the shear-stress-dependent platelet monocyte interaction that may reflect a physiologic method of induction of DC or platelets induce monocyte-to-DC differentiation under conditions of flow (pg. 372 last para.). In other words, Durazzo teaches that the monocyte differentiation occurs during the irradiation of the monocytes. Additionally, it is noted that the claims only require the time period to be sufficient for the differentiation to happen.
Applicant argues that King does not teach an intentional delay between the end of irradiation and when the cells are returned to the patient and instead teaches disconnecting the patient from the system during the irradiation period to avoid any risks of the “energized high voltage” used during irradiation (Remarks pg. 10 para. 3). The Applicant’s amendments limiting claims 1 and 37 to include an incubation step after the irradiation necessitated new rejections. Applicant’s arguments are drawn to King failing to teach this new limitation. However, this new limitation is addressed in the new rejections.
Applicant argues that there is no teaching in King to incubate the cells prior to returning the cells to the patient and after irradiation which allow for enough time for the inducement of monocytes to differentiate into dendritic cells and, therefore, this differentiation described by Durazzo is not an inherent outcome (Remarks pg. 10-11 bridging para.). Applicant further argues that the claim has been amended to make it clear that there is a separate incubation period following the irradiation so that the irradiation and incubation steps do not occur simultaneously. Applicant argues that the time between the beginning of the irradiation stage of King the time cell return to the patient is not long enough to inherently result in differentiation (Remarks pg. 11 para. 2). Applicant’s amendments limiting claims 1 and 37 to include an incubation step after the irradiation necessitated new rejections. Applicant’s arguments are drawn to King failing to teach this new limitation. However, this new limitation is addressed in the new rejection. Additionally, it is maintained that the differentiation is still inherent to the method of King, since Durazzo teaches that the monocyte differentiation occurs during the irradiation of the monocytes and therefore would not require a separate incubation time to have occurred.
Applicant argues that Durazzo provides evidence that King does not teach an incubation stage that would inherently result in differentiation (Remarks pg. 11 para. 3). However, this argument was not found to be persuasive, since as stated above, Durazzo teaches that extracorporeal photochemotherapy (ECP) “promotes platelet immobilization and activation, initiating stepwise receptor-ligand interactions with monocytes, which then differentiate into DC” (abstract). Durazzo teaches that the shear-stress-dependent platelet monocyte interaction that may reflect a physiologic method of induction of DC or platelets induce monocyte-to-DC differentiation under conditions of flow (pg. 372 last para.). In other words, Durazzo teaches that the monocyte differentiation occurs during the irradiation of the monocytes. Additionally, it is noted that the claims only require the time period to be sufficient for the differentiation to happen.
Applicant argues that Briggs, Gara and Nguyen do not remedy King and do not teach an incubation step (Remarks pg. 11 para. 3). However, this argument was not found to be persuasive, since the arguments with respect to the rejections over King were not found to be persuasive as explained above.
With respect to claim 36, Applicant argues that it would not be obvious to adapt King’s system or method so that it is a single fluid circuit (Remarks pg. 11 para. 4). Specifically, Applicant argues that King teaches separate “separation” and “irradiation” circuits and a centrifuge bowl where red blood cells accumulate while the other components are conveyed out of the centrifuge bowl (Remarks pg. 12 para. 1). However, this argument was not found to be persuasive, since claims 1 and 37 require the accumulation of mononuclear cells in the separation chamber while a first portion of red blood cells and plasma are returned to the whole blood. Therefore, it is unclear how the system and method of King which has similar collection of blood components in separate containers as the claimed invention cannot be in a single circuit.
Applicant argues that the system and method of King would require completely redesigning the fluid circuit and the hardware component and the flow of the procedure and this is not a simple matter of providing an appropriate number of pumps (Remarks pg. 12 para. 2). Additionally, Applicant argues that it would not have been obvious to modify the system of King to be a single circuit, since the changes to the “fluid circuit” of King would require significant changes in the hardware components, the stages of the procedure which would require different oversight by the operator and different involvement of the patient, and these changes would result in other changes to aspects of the system such as insuring the patient is qualifies for the procedure, the hardware components have the appropriate sensors and other safeguards (Remarks pg. 12-13 bridging para.). However, these arguments were not found to be persuasive, and it is maintained that it would have been obvious to one of ordinary skill in art, to modify King to be in a single circuit, since both Briggs and Gara teach similar extracorporeal photopheresis procedures treating mononuclear cells where single fluid circuits are used for the benefits of reducing chances of infection, ensuring return of the cells to the subject and reducing costs and time.
With respect to claim 37, Applicant argues that the claim requires a separate incubation step like claim 1 which is not taught by King and where the first portions of the red blood cell component and the plasma component are returned to the whole blood at the same time as the mononuclear cell component is accumulating in the separation container which would require significant changes to the system of King (Remarks pg. 13 para. 3-4). Applicant’s amendments limiting claims 1 and 37 to include an incubation step after the irradiation necessitated new rejections. Applicant’s arguments are drawn to King failing to teach this new limitation. However, this new limitation is addressed in the new rejections.
Conclusion
No claims are allowed.
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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/EMILY A CORDAS/Primary Examiner, Art Unit 1632