thDETAILED 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 .
Summary
Claims 1-7, 9-13, 15-16, 18-20, and 22-25 are pending in this office action. Claims 8, 14, 17, 21, and 26-52 are cancelled. All pending claims are under examination in this application.
Priority
The current application filed on January 2, 2024 is a 371 of PCT/US2022/036120 filed July 5, 2022. The current application claims domestic priority to a provisional patent application 63/217,834 filed on July 2, 2021.
Information Disclosure Statement
Receipt of the Information Disclosure Statement filed on January 31, 2024 is acknowledged. A signed copy of the document is attached to this office action.
Objection to the Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because the tables on the far right of Figure 5 are blurry and unclear to the reader. Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Claim Objections
Claims 6, 8, 14, 17, 21, and 26-52 are objected to because of the following informalities:
Claim 6: The text of the claim states, “least at,” please correct to “at least.”
Claims 8, 14, 17, 21, and 26-52: Please add a “period” at the end of the text “(Cancelled).” For example, Claim 8 should read, “(Cancelled).”
Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 non-obviousness.
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 1-7, 9-13, 15-16, 18-20, and 22-25 are rejected under 35 U.S.C. 103 as being unpatentable over Hainfeld (US2007/0243137A1) in view of Exner et al. (US2019/0175766A1), Wald (WO2018/213828A1), Rosen et al. (US2019/0125795A1), and Neelapu et al. (WO2021/034982A1, published in February 2021).
[The Examiner is going to introduce each new reference and then combine them where appropriate.]
1. Hainfeld
Hainfeld is the closest prior art to the present application as it teaches cell and sub-cell methods for imaging and therapy (see title). Furthermore, Hainfeld discloses that methods are disclosed to rapidly form and load cells and cell-derived vesicles. Loaded materials can include imaging agents, drugs and magnetic particles. Methods are also presented to additionally target the loaded cells or vesicles, leading to new forms of imaging, treatment, diagnosis, and detection by a large number of techniques. The preparation and use of reduced sized cells that retain subset characteristics of the parent cell are also described (see abstract).
2. Exner et al.
Exner et al. teach stabilized crosslinked nanobubbles for diagnostic and therapeutic applications (see title). Additionally, Exner et al. disclose a composition includes a plurality of stabilized crosslinked nanobubbles, each nanobubble having a membrane that defines at least one internal void, which includes at least one gas, the membrane including at least one lipid, at least one nonionic triblock copolymer that is effective to control the size of the nanobubble without compromising in vitro and in vivo echogenicity of the nanobubble, and an interpenetrating crosslinked biodegradable polymer (see abstract).
3. Wald
Wald teaches compositions and methods for expanding ex vivo natural killer cells and therapeutic uses thereof (see title). In addition, Wald discloses that the present disclosure relates to methods for expanding and increasing the cytotoxic activity of natural killer cells comprising co-culturing, as feeder cells, a population of myeloid leukemia cells engineered to express one or more of membrane-bound IL-21 (mbIL- 21) or membrane-bound IL-15 (mbIL-15) in the presence of cytokine support. The present disclosure also relates to a population of acute myeloid leukemia cells engineered to express one or more of membrane-bound IL-21 (mbIL-21) or membrane-bound IL-15 (mbIL-15). The present disclosure also relates to methods of treating cancer employing the step of expanding natural killer cells using feeder cells engineered to express one or more of membrane-bound IL-21 (mbIL-21) or membrane-bound IL-15 (mbIL-15) (see abstract).
4. Rosen et al.
Rosen et al. teach compositions and methods for immune cell modulation in adoptive immunotherapies (see title). Also, Rosen et al. disclose compounds that either produced a higher proportion or greater absolute number of phenotypically identified nave, stem cell memory, central memory T cells, adaptive NK cells, and type 1 NKT cells are identified. Compositions and methods for modulating immune cells including T, NK, and NKT cells for adoptive cell therapies with improved efficacy are provided (see abstract).
5. Neelapu et al.
Neelapu et al. teach immune cells for adoptive cell therapies (see title). Further, Neelapu et al. disclose that provided are methods for the production of infinite immune cells with an increased lifespan and high proliferation rates by engineering them to express BCL6 and a cell survival-promoting gene. Further provided herein are methods for the production and use of the infinite immune cells for the treatment of diseases, such as cancer (see abstract).
Combination of Hainfeld and Exner et al.
Regarding instant claim 1, Hainfeld and Exner et al. teach an adoptive immunotherapy composition. The necessary citations within Hainfeld and Exner et al. that correspond to instant claim 1 are compiled within Table I.
Table I
Instant Claim 1
Hainfeld and Exner et al. Citations
An adoptive immunotherapy composition comprising: an enriched population of immune cells,
Hainfeld discloses an adoptive immunotherapy composition (Adoptive immunotherapy extracts particular lymphocytes that can affect tumors, proliferates these cells ex vivo, and then reinjects them to the patient to provide a large number of specialized cells ... Some of the obstacles in imaging and therapy might be overcome by packaging the contrast agent or therapeutic drug in a vesicle or cell so that more is delivered to the site of interest, see paragraphs [0033-0034] within Hainfeld) comprising: an enriched population of immune cells, wherein immune cells include intracellular nanobubbles (Since the disclosed methods may be used to load many types of compounds, biomolecules, drugs and agents into cells and cell-derived vesicles, materials can be loaded that would enhance other forms of imaging, including, but not limited to … ultrasound. Materials useful for these other forms of detection include... molecules or particles useful for ultrasound detection including but not limited to: gas bubbles of various gasses, see paragraph [0082] within Hainfeld); An example of the benefits of this approach is shown for adoptive immunotherapy. In this approach, killer T cells that can destroy patient tumor cells are removed from the patient, isolated, and grown ex-vivo to high numbers and injected back into the patient (see paragraph [0093] within Hainfeld).
Hainfeld fails to explicitly disclose wherein at least about 50% or more immune cells include intracellular nanobubbles.
wherein at least about 50% or more immune cells include intracellular nanobubbles.
However, Exner et al. is in the field of using nanobubbles for ultrasound imaging of cancer (stabilized crosslinked nanobubbles for diagnostic, therapeutic, and/or theranostic applications, see paragraph (0050] within Exner et al.).
Exner et al. teach mixing cells and the plurality of nanobubbles until cells internalize the nanobubbles (LS174-T cells were grown in a 12-well cell culture plate at a cell concentration of 2.5x104 cells/ml one day before the treatment. The treatment groups were the same as cell toxicity test above. After 2 h treatment in incubator, the drugs were aspirated and washed with sterile PBS 3 times. The attached cells were fixed with 3% formaldehyde solution for 10 min. After 3 times wash with PBS, the cells of different treatment groups were imaged at 5x and 20x on the Zeiss Axio Observer Z1 motorized FL microscope with the same parameter and scanned zones, see paragraph [0171] and Figure 17 both within Exner et al.).
It would have been obvious to one of ordinary skill in the art [skilled artisan; POSITA (person of ordinary skill in the art)] prior to the effective filing date of the claimed invention to modify Hainfeld with the teaching of Exner et al. to disclose a method of generating an adoptive immunotherapy composition, the method comprising: mixing an enriched population of immune cells with a plurality of nanobubbles; incubating the mixture of immune cells and the plurality of nanobubbles until the immune cells internalize the nanobubbles to provide intracellular labeled immune cells. The motivation for doing so would have been utilizing the phagocytosis nature of immune cells and the lipophilic nature of the nanobubbles to increase the labeling efficiency of immune cells by engulfment and thereby increasing the signal to noise ratio in the images of the regions of interest.
The combination of Hainfeld and Exner et al. teach all the elements of instant claim 1 and are therefore applied either directly or indirectly to each independent claim.
Combination of Hainfeld, Exner et al., and Wald
Regarding instant claim 2, Hainfeld, Exner et al., and Wald teach wherein at least 70% of the immune cells of the population include T-cells and/or natural killer (NK) cells that are optionally genetically modified.
Wald is in the field of NK cell immunotherapy (adoptive immunotherapy with NK cells has emerged as a promising anti-cancer treatment, see paragraph [0093] within Wald) and teaches at least 70% of the immune cells of the population include T-cells and/or natural killer (NK) cells that are optionally genetically modified (In a second aspect, there is a method for expanding natural killer cells ex vivo, said method comprising harvesting donor cells from a donor subject; isolating the NK cells; and expanding the NK cells in the presence of OCI-AML3 feeder cells, see paragraph [0018] within Wald; In an example of the second aspect, the NK cells are genetically modified to express one or proteins capable of providing cytokine support. In certain exemplary aspects, the proteins capable of providing cytokine support are selected from the group consisting of mblL-15, soluble IL-15, soluble IL-21, mblL-21, mblL-2, or soluble IL-2, see paragraph [0021] within Wald).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Hainfeld and Exner et al. with the teaching of Wald to disclose the composition, wherein at least 70% of the immune cells of the population include T-cells and/or natural killer (NK) cells that are optionally genetically modified. The motivation for doing so would have been utilizing the types of immune cells that have already been shown to be effective against certain types of cancers and tumors and thereby increasing the effectiveness and safety of adoptive immunotherapy.
Regarding instant claims 3 and 4, Hainfeld, Exner et al., and Wald teach herein at least 70% of the immune cells are NK cells optionally genetically modified to express one or more proteins capable of providing cytokine support.
Wald is in the field of NK cell immunotherapy and teaches at least 70% of the immune cells are NK cells optionally genetically modified to express one or more proteins capable of providing cytokine support (In a second aspect, there is a method for expanding natural killer cells ex vivo, said method comprising harvesting donor cells from a donor subject; isolating the NK cells; and expanding the NK cells in the presence of OCI-AML3 feeder cells, see paragraph [0018] within Wald; In an example of the second aspect, the NK cells are genetically modified to express one or proteins capable of providing cytokine support. In certain exemplary aspects, the proteins capable of providing cytokine support are selected from the group consisting of mblL-15, soluble IL-15, soluble IL-21, mbll-21, mblL-2, or soluble IL-2, see paragraph [0021] within Wald).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Hainfeld and Exner et al. with the teaching of Wald to disclose the composition, wherein at least 70% of the immune cells are NK cells optionally genetically modified to express one or more proteins capable of providing cytokine support. The motivation for doing so would have been using cytokines that have been shown to increase the proliferation and activation of natural killer cells and thereby increasing the yield of natural killer cells that can be used for adoptive immunotherapy.
Regarding instant claim 5, Hainfeld, Exner et al., and Wald teach wherein at least 70% of the immune cells are NK cells genetically modified to express one or more proteins capable of inhibiting TGFb signaling.
Wald is in the field of NK cell immunotherapy and teaches at least 70% of the immune cells are NK cells genetically modified to express one or more proteins capable of inhibiting TGFb signaling (In a second aspect, there is a method for expanding natural killer cells ex vivo, said method comprising harvesting donor cells from a donor subject; isolating the NK cells; and expanding the NK cells in the presence of OCI-AML3 feeder cells, see paragraph [0018] within Wald; In another aspect of the second embodiment, the NK cells are genetically modified to express one or proteins capable of inhibiting TGFb signaling, see paragraph [0022] within Wald).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Hainfeld and Exner et al. with the teaching of Wald to disclose the composition, wherein at least 70% of the immune cells are NK cells genetically modified to express one or more proteins capable of inhibiting TGFb signaling. The motivation for doing so would have been inhibiting a signaling pathway that is known to decrease the potency and cytolytic potential of the natural killer cells and thereby increasing the effectiveness of the natural killer cells in adoptive immunotherapy.
Combination of Hainfeld, Exner et al., and Rosen et al.
Regarding instant claims 6 and 7, Hainfeld, Exner et al., and Rosen et al. teach wherein at least 70% of the immune cells are CD4+ T-cells and/or CD8+ T-cells.
Rosen et al. is in the field of using subsets of immune cells for adoptive immunotherapy (compositions and methods for modulating one or more populations or subpopulations of immune cells to improve their therapeutic potential for adoptive immunotherapies, see paragraph [0011] within Rosen et al.) and teaches at least 70% of the immune cells are CD4+ T-cells and/or CD8+ T-cells (the cell subtypes, going into the patient can be defined in large part by the manufacturing process … maintaining or expanding cell subpopulations having a desired differentiation state, and/or adaptive immune cell characteristics during cell culture and expansion could be extremely beneficial for enhancing the efficacy of cell-based therapies. Thus, a manufacturing approach that can enhance the desired T, NK or NKT cell subsets both in quantity and quality could provide a significant enhancement of their therapeutic efficacy, see paragraph [0009] within Rosen et al.; In some other embodiments, the genetically modified modalities include one or more of…introduced or increased expression of... CD4, CD8... In some embodiments, the T, NK or NKT cells comprise an exogenous nucleic acid…In some other embodiments, the exogenous nucleic acid is introduced to the immune cells... In some embodiments, the exogenous nucleic acid for a T cell can encode…a CAR (Chimeric Antigen Receptor), see paragraph [0186] within Rosen et al.).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Hainfeld and Exner et al. with the teaching of Rosen et al. to disclose the composition, wherein at least 70% of the immune cells are CD4+ T-cells and/or CD8+ T-cells. The motivation for doing so would have been using T-cells that have been shown to have superior anti-tumor reactivity and thereby increasing the effectiveness of the adoptive immunotherapy.
Combination of Hainfeld and Exner et al.
Regarding instant claim 9, Hainfeld and Exner et al. teach wherein the enriched population of cells includes an amount of intracellular nanobubbles effective to detect the enriched population of cells by ex vivo ultrasound contrast imaging upon administration of the enriched population of cells to a subject.
Please see the discussion and citations within instant claim 1. Exner et al. disclose wherein the enriched population of cells includes an amount of intracellular nanobubbles effective to detect the enriched population of cells by ex vivo ultrasound contrast imaging upon administration of the enriched population of cells to a subject (Ultrasound can then be applied to a region of interest of the subject that includes the neoplastic cells and nanobubbles to cause release of the chemotherapeutic agent from the nanobubbles in the region of interest to the neoplastic cells, see paragraph [0016] and Figures 12A-C both within Exner et al.).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Hainfeld with the teaching of Exner et al. to disclose the use of ultrasound to detect the nanobubbles of the enriched population of cells by upon administration to a subject. The motivation for doing so would have been to employ the use of ultrasound therapy to enhance the therapeutic relevance of the nanobubbles.
Regarding instant claim 10, Hainfeld and Exner et al. teach wherein each of the immune cells that includes intracellular nanobubbles includes at least about 100 or more intracellular nanobubbles.
Please see the discussion and citations within instant claim 1. Although Exner does not disclose a numerical value for the nanobubbles within the cells of choice, the overall count ≥100 of intracellular nanobubbles would be within the scope of a skilled artisan (POSITA). By modifying the exposure to the nanobubble source, the optimal count per cell could be ascertained.
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Hainfeld with the teaching of Exner et al. to disclose wherein each of the immune cells that includes at least about 100 or more intracellular nanobubbles. The motivation for doing so would have been to optimize the therapeutic within a subject based on the count of the nanobubbles.
Regarding instant claims 11 and 16, Hainfeld and Exner et al. teach wherein each of the nanobubbles includes a lipid membrane that defines an internal void, which includes at least one gas.
Exner et al. disclose nanobubbles including a lipid membrane that defines an internal void, which includes at least one gas (Figure I).
Figure I
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(see Fig. 1 within Exner et al.). The gas can have a low solubility in water and include, for example, a perfluorocarbon, such as perfluoropropane, carbon doxide, and air (see paragraph [0009] within Exner et al.).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Hainfeld with the teaching of Exner et al. to disclose wherein each of the nanobubbles includes a lipid membrane that defines an internal void, which includes at least one gas. The motivation for doing so would have been to design a nanobubble for enhanced cell delivery.
Regarding instant claims 12-13, 15, and 18, Hainfeld and Exner et al. teach wherein the lipid membrane further includes at least one of glycerol, propylene glycol, pluronic (poloxamer), alcohols or cholesterols, that change the modulus and/or interfacial tension of the bubble membrane.
Exner et al. disclose that the lipid membrane can compromise glycerol, PEG, poloxamer, alcohols or cholesterols, and phospholipids of varying acyl chain lengths (see paragraphs [0059-0064] within Exner et al.). Furthermore, Exner et al. disclose that longer chains increase lateral cohesion forces, which increases the bending modulus and decreasing lateral density fluctuations of the bubble. The decreased bending modulus lessens buckling of the lipid monolayer, which prevents dissolution (see paragraph [0151] within Exner et al.).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Hainfeld with the teaching of Exner et al. to disclose wherein the lipid membrane further includes at least one of glycerol, propylene glycol, pluronic (poloxamer), alcohols or cholesterols, that change the modulus and/or interfacial tension of the bubble membrane. The motivation for doing so would have been to modify and adjust the membrane within the nanobubble to increase the therapeutic impact (or cell delivery).
Regarding instant claim 19, Hainfeld and Exner et al. teach the nanobubbles having an average diameter of about 30 nm to about 600 nm.
Exner et al. disclose the nanobubbles having an average diameter of about 30 nm to about 300 nm (see paragraph [0010] within Exner et al.).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Hainfeld with the teaching of Exner et al. to disclose the nanobubbles having an average diameter of about 30 nm to about 600 nm.
The motivation for doing so would have been to obtain the correct diameter of the nanobubbles to maximize their cellular penetration and therapeutic value to the patient.
Regarding instant claim 20, Hainfeld and Exner et al. teach further comprising at least one targeting moiety that is linked to the membrane of each nanobubble and/or microbubble.
Exner et al. disclose at least one targeting moiety that is linked to the membrane of each nanobubble and/or microbubble (see paragraph [0011] within Exner et al.).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Hainfeld with the teaching of Exner et al. to disclose at least one targeting moiety that is linked to the membrane of each nanobubble and/or microbubble. The motivation for doing so would have been to enhance the selectivity of the nanobubble within a biological system.
Regarding instant claims 22 and 23, Hainfeld and Exner et al. teach a method comprising: providing an adoptive immunotherapy composition as recited in instant claim 1; administering the adoptive immunotherapy composition to a subject; and generating at least one image of a region of interest (ROI) of the subject by ultrasound contrast imaging immune cells of the adoptive immunotherapy composition in the ROI of the subject.
Please see the discussion and citations within instant claims 1 and 9. Additionally, Exner et al. disclose that after administering the composition to the subject, at least one image of the ROI can be generated (see paragraphs [0014] and [0100; cancer] within Exner et al.).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Hainfeld with the teaching of Exner et al. to disclose a ROI image using the adoptive immunotherapy composition of instant claim 1. The motivation for doing so would have been to successfully image a region within a subject.
Regarding instant claim 24, Hainfeld and Exner et al. teach wherein ultrasound contrast imaging includes applying ultrasound energy to the ROI at a duty cycle of about 1% to about 100%, an ultrasound frequency of about 0.2 kHz to about 50 MHz, an intensity of about 0.1 W/cm2 to about 5 W/cm2, a pressure amplitude of about 50 kPa to about 10 MPa, and a time of about 1 minute to about 30 minutes.
Exner et al. disclose ultrasound parameters within the regions of instant claim 24:
Duty cycle: 20% (see paragraphs [0161] and [0170] within Exner et al.)
Ultrasound frequency: 1-18 MHz (see paragraphs [0050-0051], [0123], [0154], [0161], [0170], and [0186] within Exner et al.)
Intensity: 2 W/cm2 (see paragraphs [0161], [0170], and [0186] within Exner et al.)
Pressure amplitude: 0.96 MPa (see paragraph [0186]; Crum et al., within Exner et al.)
Time: 1 minute (see paragraphs [0161] and [0170] within Exner et al.)
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Hainfeld with the teaching of Exner et al. to disclose the desired ultrasound parameters. The motivation for doing so would have been to optimize the ultrasound usage with the nanobubbles.
Combination of Hainfeld, Exner et al., and Neelapu et al.
Regarding instant claim 25, Hainfeld, Exner et al., and Neelapu et al. teach wherein the adoptive immunotherapy composition administered to the subject includes at least about 1 million immune cells.
Neelapu et al. disclose wherein the adoptive immunotherapy composition administered to the subject includes at least about 1 million immune cells (see paragraph [0013] within Neelapu et al.).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify Hainfeld with the teaching of Exner et al. to disclose wherein the adoptive immunotherapy composition administered to the subject includes at least about 1 million immune cells. The motivation for doing so would have been to use a significant amount of immune cells to positively impact the patient during treatment.
Analogous Art
The Hainfeld, Exner et al., Wald, Rosen et al., and Neelapu et al. references are directed to the same field of endeavor as the instant claims, that is, an adoptive immunotherapy composition, as disclosed within instant claim 1.
Obviousness Analysis
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the cell and sub-cell methods for imaging and therapy disclosed by Hainfeld, using the teachings of Exner et al., Wald, Rosen et al., and Neelapu et al. in order to arrive at the subject matter of the instant claims.
The Hainfeld, Exner et al., Wald, Rosen et al., and Neelapu et al. references all have considerable overlap in the immunotherapy arts. In this instance, Hainfeld supplies the general template for cell and sub-cell methods for imaging and therapy, Exner et al. supplies the nanobubbles for diagnostic and therapeutic applications, while Wald, Rosen et al., and Neelapu et al. supply the detailed cellular and biological applications. All references are directed to the immunotherapy arts and therefore constitute analogous art under MPEP §2141.01(a). A POSITA would have reasonably consulted the five references when seeking to develop an adoptive immunotherapy composition.
Given these teachings, a POSITA would have been motivated to combine the cell and sub-cell methods for imaging and therapy as disclosed by Hainfeld into the nanobubbles for diagnostic and therapeutic applications taught by Exner et al. The additional disclosures of Wald, Rosen et al., and Neelapu et al. to supply the necessary biology and cellular applications. The overarching motivation for all the references would be to construct an enhanced adoptive immunotherapy composition.
These modifications constitute a simple substitution of one known element for another to obtain a predictable result [MPEP §2143(I)(B)].
The combination represents the use of a known technique to improve a similar device in the same way [MPEP §2143(I)(C)].
The art provides a finite number of identified, predictable solutions, and the POSITA would have pursued the claimed configuration with a reasonable expectation of success [MPEP §2143(I)(E); KSR].
The combination of the cell and sub-cell methods for imaging and therapy taught by Hainfeld along with the use of the necessary claim limitations taught by Exner et al., Wald, Rosen et al., and Neelapu et al. would allow a research and development scientist (POSITA) to develop the invention taught in the instant application.
Furthermore, the additional claim limitations taught by Exner et al., Wald, Rosen et al., and Neelapu et al. would have been viewed by a POSITA as routine design optimizations or known modifications for adoptive immunotherapy compositions. The motivation for doing so would have been utilizing the phagocytosis nature of immune cells and the lipophilic nature of the nanobubbles to increase the labeling efficiency of immune cells by engulfment and thereby increasing the signal to noise ratio in the images of the regions of interest. Implementing these features in Hainfeld’s cell and sub-cell methods for imaging and therapy would not require more than ordinary skill or routine experimentation.
Accordingly, the combination of Hainfeld, supplemented by Exner et al., Wald, Rosen et al., and Neelapu et al. provides all the elements of the claimed invention. The resulting adoptive immunotherapy composition constitutes no more than the predictable outcome of combining familiar prior art components, and therefore the claimed subject matter would have been obvious to a POSITA prior to the effective filing date of the invention.
Conclusion
No claims are allowed.
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