DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Rejections - 35 USC § 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.
Claims 1-4, 12, 14, 17, 19, and 47 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hossack et al (US Pub 2018/0099059 -cited by applicant) in view of “Union” (CN 111569092 -cited by applicant).
Re claim 1: Hossack discloses a method comprising:
introducing and labeling a phagocytotic cell with an echogenic microbubble of a gas stabilized by a shell to form a labeled phagocytotic cell, wherein the labeling includes internalizing the microbubble within the phagocytotic cell by phagocytosis [0030, 0034, claim 16, figure 5; see the droplet 20 that is phagocytized/ingested by donor cells ex vivo and then injected into a patient and converted to a microbubble by application of energy]; and
determining a location of the labeled phagocytotic cell in the patient [0030; a location of the cells within the patient are provided with an imaging system].
Hossack discloses that the droplets are converted to microbubbles after being injected in the patient, such that the labeled phagocytotic cell with microbubble is not introduced into the patient (it is converted to a microbubble in the patient). However, Union teaches of preparing ultrasound contrast agents wherein nano-fluorocarbon droplets are prepared and phagocytosed by macrophages, wherein energy is applied to the droplets to trigger a phase transformation into microbubbles and to subsequently inject the agent into the patient [0006, 0102, 0104; see conversion of the droplet to microbubble and subsequent injection]. It would have been obvious to the skilled artisan to modify Hossack, to convert the droplet to a microbubble prior to injection as taught by Union, in order to improve safety as the vaporization process of converting to microbubble in a patient can easily damage normal cells and tissues [see 0006 of Union].
Re claim 2: Hossack discloses isolating the phagocytotic cell from the patient [0030; the cells can be isolated cells such as dendritic cells, macrophages, T-cells, B-cells].
Re claims 3, 4: Hossack discloses all features but does not disclose: placing the phagocytotic cell in a solution comprising the echogenic microbubble, the solution contained in a sealable container; fixing the phagocytotic cell to a bottom surface of the sealable container; sealing the sealable container; inverting the sealable container; incubating the phagocytotic cell for 4 hours; and washing the phagocytotic cell. However, Union teaches placing the phagocytotic cell in a solution comprising the echogenic microbubble, the solution contained in a sealable container; fixing the phagocytotic cell to a bottom surface of the sealable container; sealing the sealable container; inverting the sealable container; incubating the phagocytotic cell for 4 hours; and washing the phagocytotic cell (page 9 paragraph 5; page 10 paragraphs 6 & 8; see the agent that is co-incubated for 2 to 12 hours with macrophages, PBS is washed 3 times, cells are scraped, and new agents are collected by washing, wherein droplets are composed of inert compound perfluorocarbon which will be vaporized into microbubbles). It would have been obvious to the skilled artisan to modify Hossack, to label as taught by Union, in order to label cells with microbubbles in order to track the labeled cellos using ultrasound imaging. Further, incubating the cell at approximately 100 degrees Fahrenheit.
Re claim 12: Hossack discloses characterizing a trafficking pattern of the labeled phagocytotic cell; wherein the determining comprises ultrasound imaging the patient to determine the location of the labeled phagocytotic cell in the patient [0030, 0031; see the imaging and that the droplets are used to track the movement of phagocytotic cells].
Re claim 14: Hossack discloses the determining comprises determining the location of the labeled phagocytotic cells in the patient [0030; a location of the cells within the patient are provided with an imaging system]; and the method further comprises: labeling the phagocytotic cells with echogenic microbubbles [0034, claim 16; see the cells labeled with PFC droplets that are introduced and ingested by target cells in a test region]; and ultrasound imaging the patient to determine a characterization of one or more trafficking patterns of the labeled phagocytotic cells [0030, 0031; see the ultrasound imaging and tracking the cells]; wherein the characterization comprises one or more of: determining accumulation of the labeled phagocytotic cells [0030, 0031; wherein the imaging determined how much is accumulated]; determining a flux of the labeled phagocytotic cells [0031; the droplets are used to track movement of the cells to and from the organ or region of injection]; or determining a distribution of the labeled phagocytotic cells [0030, 0034; see the tracking of different B-cell types].
Re claim 17: Hossack discloses the phagocytotic cells comprise macrophages [0030; see the macrophages].
Re claims 19, 47: Hossack discloses the echogenic microbubbles comprise a fluorocarbon compound (i.e. perflourobutane) in a lipid shell the echogenic microbubble and the phagocytotic cell remains labeled with the echogenic microbubble for at least
approximately 4 hours after the labeling [0022, 0045; see the lipid shell with PFC that remains labeled until the tracking is performed].
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Hossack/Union, as applied to claim 3, in view of Toma et al (US Pub 2011/0208113 -cited by applicant).
Re claim 6: Hossack discloses the echogenic microbubble is one of a plurality of echogenic microbubbles; the phagocytotic cell is one of a plurality of phagocytotic cells [0031; see the tracking of the phagocytotic cells]; and Union teaches the placing comprises placing the plurality of phagocytotic cells in a solution comprising the plurality of echogenic microbubbles, the solution contained in a sealable container; the fixing comprises fixing the plurality of phagocytotic cells to a bottom surface of the sealable container; the incubating comprising incubating the plurality of phagocytotic cells for a period of time (page 9 paragraph 5; page 10 paragraphs 6 & 8; see the agent that is co-incubated for 2 to 12 hours with macrophages, PBS is washed 3 times, cells are scraped, and new agents are collected by washing, wherein droplets are composed of inert compound perfluorocarbon which will be vaporized into microbubbles). Hossack/Union do not teach the solution comprises a ratio of phagocytotic cells to echogenic microbubbles of between approximately 1:1 and 1:50. However, Toma teaches the solution comprises a ratio of phagocytotic cells to echogenic microbubbles of between approximately 1:1 and 1:50 [0318, 0319; see the cells mixed with increasing ratios of cationic microbubbles such as 1:1 or 1:40]. It would have been obvious to the skilled artisan to modify Hossack/Union, to use the ratio as taught by Toma, in order to facilitate tracking using ultrasound imaging.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Hossack/Union, as applied to claim 1, in view of Hendrick et al (US Pub 2021/0340218 -cited by applicant).
Re claim 13: Hossack/Union discloses the introducing comprises introducing labeled phagocvtotic cells into the patient; the determining comprises determining the location of one or more of the labeled phagocytotic cells in the patient [0030; a location of the cells within the patient are provided with an imaging system]; and the method further comprises: labeling the phagocvtotic cells with one or more echogenic microbubbles to form the labeled phagocvtotic cells; and characterizing one or more trafficking patterns of the labeled phagocytotic cells in the patient over a time period, the characterizing comprising: detecting one or more of the labeled phagocytotic cells in a patient with the SNR > 5;discriminating at least a portion of the labeled phagocytotic cells from background cells; resolving one or more single respective labeled phagocytotic cells from among the labeled phagocytotic cells using a spatial resolution equal to or better than 20 m; and imaging the target anatomy with a FOV on the order of one or more centimeters the determining comprises determining the location of the labeled phagocytotic cells in the patient [0030, 0031, 0034, claim 16; see the labeling, tracking, and ultrasound imaging that includes detecting at a SNR > 5 and spatial resolution better than 20 microns]. Hossack/Union do not disclose determining a respective velocity of at least a portion of the respective resolved single labeled phagocytotic cells, wherein a low velocity correlates with a strength of an interaction of the respective resolved single labeled phagocytotic cell with a target anatomy. However, Hendrick teaches determining a respective velocity of at least a portion of the respective resolved single labeled phagocytotic cells, wherein a low velocity correlates with a strength of an interaction of the respective resolved single labeled phagocytotic cell with a target anatomy [0155, figure 1B; see the patrolling speed and number of Nur77-GFPhigh monocytes]. It would have been obvious to the skilled artisan to modify Hossack/Union, to determine velocity as taught by Hendrick, in order to indicate the strength of interaction between the phagocytotic cell and the target anatomy.
Claims 18, 23, 24, 39, 40, 45, and 46 are rejected under 35 U.S.C. 103 as being unpatentable over Hossack/Union or Hossack/Union/Hendrick, further in view of Hong et al (US Pub 2019/0307794 -cited by applicant).
Re claims 18, 23, 24, 39, 40, 45, 46: Hossack/Union or Hossack/Union/Hendrick disclose all features including labeling and introducing the cells and ultrasound imaging to determine locations and trafficking patterns, and echogenic microbubbles comprises a fluorocarbon compound in a shell selected from group consisting of a lipid shell and a mannose shell [0030, 0034, 0045, claim 16; see the labeling and ultrasound imaging and also see the droplets converted to microbubbles in a controlled manner with a lipid shell] except that the phagocytotic cells comprise bone marrow-derived macrophages, performing cell engineering on the phagocytotic cells, isolating at least a portion of the labeled phagocytotic cells from the patient, wherein echogenic microbubbles comprises a fluorocarbon compound in a shell selected from group consisting of a lipid shell and a mannose shell, and changing a phenotype of the phagocytotic cells [0084, 0130; see the treating the M2 macrophage with the exosomes in vitro and see the changing of the phenotype]. It would have been obvious to the skilled artisan to modify Hossack/Union or Hossack/Union/Hendrick, in order to produce a phagocytotic cell with a desired phenotype.
Claims 20-22 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Hossack/Union or Hossack//Union/Hendrick/Hong, further in view of Nagy et al (US Pub 2013/0129635 -cited by applicant).
Re claims 20-22, 42: Hossack/Union or Hossack/Union/Hendrick/Hong disclose all features except that the compound comprises one or more of octoflouropropane and perflourobutane, wherein the echogenic microbubbles comprise a fluorocarbon compound in a mannose shell. However, Nagy teaches compound comprises one or more of octoflouropropane and perflourobutane, wherein the echogenic microbubbles comprise a fluorocarbon compound in a mannose shell [0072, 0098; see the mannose shell and fluorocarbon and perfluorocarbon gases]. It would have been obvious to the skilled artisan to modify Hossack/Union or Hossack/Union/Hendrick/Hong, to use the compound as taught by Nagy, in order to provide an improved contrast agent for ultrasound detection.
Response to Arguments
Applicant’s arguments with respect to claims 1-4, 6, 12-14, 17-24, 39, 40, 42, and 45-47 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument. The new limitations now require that there is a microbubble as part of a labeled phagocytotic cell that is introduced into a patient. Examiner agrees with Applicant that in Hossack’s ex vivo embodiment that the droplets are converted to microbubbles only after in-patient acoustic vaporization, thereby not meeting the claimed limitation of “introducing the labeled phagocytotic cell into a patient”. However, Union (CN 111569092) is now applied to teach this limitation as obvious.
Regarding claim 2, the rejection is maintained as Hossack discloses the donor cells are of a specific type that are then imaged. Selecting a particular cell type or imaging the labeled cell is isolating the cell, given broadest reasonable interpretation. In regard to claims 12 and 14, the rejection is maintained as Hossack specifically discloses that the various embodiments can be combined, thereby providing sufficient disclosure of the limitations as cited. Regarding claim 19, Examiner maintains that Hossack discloses conversion of the droplet to a microbubble, which changes the liquid core to a gas filled microbubble. In regard to claims 3 and 4, Applicant discusses Xie et al (the Union CN 111569092 reference) and argues that it teaches against the use of preformed microbubbles for cell labeling. The Examiner disagrees with this assertion and finds that Union specifically teaches converting the droplets to microbubbles prior to injection in order to avoid the damage that the vaporization process can cause to normal cells if performed within the patient. This provides motivation to modify Hossack, thereby meeting the claimed limitations. The rejections of other claims using additional references are also maintained. It is noted that Applicant cannot show nonobviousness by attacking references individually wherein the rejections are based on combinations of references.
The prior specification objections and claim objections are withdrawn due to amendments.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL T ROZANSKI whose telephone number is (571)272-1648. The examiner can normally be reached Mon - Fri 8:00-4:00.
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/MICHAEL T ROZANSKI/Primary Examiner, Art Unit 3797
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