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 .
Election/Restrictions
Applicant elected Group II, without traverse, and cancelled the claims of Group I in the reply filed on 11/20/2025. Accordingly, claims 14-16, 18-24, and 26-30 are pending and have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/US2021/044557 (filed on 8/04/2021), which claims priority benefit of U.S. Provisional Application No. 63/061416 (filed on 8/05/2020) under 35 U.S.C. 119(e).
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 1/20/2023 and 2/22/2023 are in compliance with the provisions of 37 C.F.R. 1.97. All references cited in both IDSs have been fully considered.
Claim Objections
Claim 23 is objected to because of the following informalities: incorrect grammar. The phrase “in a growth media” (line 7) has the singular article “a” preceding the plural noun “media”. To resolve this issue, it is recommended that “media” be amended to its singular form “medium”.
Claim 28 is also objected to due to incorrect grammar. The plural noun “media” is followed by the singular verb “is”. It is recommended that “media” be amended to “medium” to correct the grammar and maintain consistency with the parent claim.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 14-16 and 18-19 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Steemers et al. (Pub. No. US 2019/0352591 A1).
Steemers et al. discloses systems and methods involving hollow beads encapsulating single cells (Abstract). The hollow beads can have pores that allow diffusion of reagents through the hollow bead while retaining the cell within (par. [0023], [0027]).
The hollow bead has a polymer shell prepared from a hydrogel composition that is crosslinked and forms an interior encapsulating a single cell. In some embodiments, the hydrogel is a biocompatible hydrogel, which is a polymer that forms a gel that is not toxic to living cells and allows sufficient diffusion of oxygen and nutrients to entrapped cells to maintain viability (par. [0029]-[0031]).
The crosslinker can be a reversible crosslinker. In some embodiments, a reversible crosslinker is capable of reversibly crosslinking the hydrogel polymer and is capable of being un-crosslinked in the presence of a cleaver. In some embodiments, a crosslinker can be cleaved by a reducing agent, an elevated temperature, or an electric field (par. [0038]).
The hollow beads can be prepared with functional groups like biotin or other ligands that can be utilized for specific capture of encapsulated cells. For example, biotin-harboring cells can be coated with magnetic streptavidin beads so that they become magnetic, thereby allowing automated and easy processing (par. [0043]). Encapsulating cells in a targeted surface-initiated polymerization method enables the user to specifically select cells of interest and simultaneously prepares the cells for subsequent downstream assays, thereby combining flow sorting with single cell assays (par. [0044]).
When performing assays, the hollow beads encapsulating a single cell can be loaded onto a surface such as a flow cell device, a microarray, a plate with wells, an etched surface, microfluidic channel, and a column. In some embodiments, a single hollow bead encapsulating a single cell is deposited into each well of a multi-well plate (par. [0054]-[0056]).
Steemers et al.’s methods read on the instant application as follows:
Regarding claim 14: using hollow beads comprising a polymer shell
is the same as “using a particle system comprisinq a plurality of hollow shell particles”.
The polymer shell being prepared from a hydrogel that is crosslinked, wherein said hydrogel can be a biocompatible hydrogel (defined as a polymer that forms a gel that is not toxic to living cells and allows sufficient diffusion of oxygen and nutrients to entrapped cells to maintain viability; par. [0029]) and can be degraded via cleaving of the crosslinker by a reducing agent, elevated temperature, or electric field (par. [0038]), meets the requirement that the hollow shell particles are “formed from a biocompatible and chemically or physically degradable crosslinked hydrogel”.
The polymer shell having an interior containing a single cell, wherein the polymer shell is formed around the cell to encapsulate it (par. [0030], [0035]-[0036]), satisfies “each hollow shell particle havinq a void or cavity formed therein and surrounded by a shell of crosslinked hydroqel, and one or more live cells contained in the void or cavity”.
The encapsulated cell being prepared with functional groups to specifically capture/select cells and prepare them for subsequent downstream assays, thereby allowing magnetic sorting or flow sorting (which is a type of cell cytometry and also referred to as fluorescence-activated cell sorting) to be performed in combination with single cell assays (par. [0043]-[0044]), fulfills “subjecting the plurality of hollow shell particles to screening and/or sorting by one of flow cytometry, fluorescence-activated cell sorter (FACS), image activated cell sorting (IACS), microscopy, mass spectrometry, filtering, and a magnetic sorter device”.
Hence, claim 14 is anticipated by Steemers et al..
Regarding claim 15: the embodiment of degrading the hollow beads to release the contents for further analysis is akin to “further comprising releasing the one or more live cells from the plurality of hollow shell particles that are screened and/or sorted”.
Regarding claim 16: the degradation of hollow beads being achieved through cleavage of crosslinks such as by a reducing agent (par. [0038]) corresponds to “wherein the releasing is performed by the presence of cleaving molecules generated by the one or more live cells or cleaving molecules exposed to the plurality of hollow shell particles”.
Regarding claim 18: the degradation of hollow beads being induced by elevated temperature or electric field meets “wherein the releasing is caused by exposing the plurality of hollow shell particles to an environmental stimulus”.
Regarding claim 19: the hollow bead being perturbed by physical force to release contents (par. [0030]) is analogous to “wherein the releasing is caused by one of pressure, shear stress, or mechanical stretching”.
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.
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 14-16, 18-19, 20-24, and 26-29 are rejected under 35 U.S.C. 103 as being unpatentable over Steemers et al. (Pub. No. US 2019/0352591 A1) in view of He et al. (Pub. No. US 2014/0127290 A1).
Steemers et al.’s teachings are set forth above and applied herein. Steemers et al. is found to anticipate claims 14-16 and 18-19.
The methods of Steemers et al. are comparable to the claims below:
Regarding claim 20: using hollow beads comprising a polymer shell made from a crosslinked hydrogel, which can be biocompatible and degradable, is identical to “using a particle system comprisinq a plurality of hollow shell particles formed from a biocompatible and chemically or physically deqradable crosslinked hydroqel”.
The polymer shell having an interior containing a single cell, wherein the polymer shell is formed around the cell, satisfies “each hollow shell particle havinq a void or cavity formed therein and surrounded by a shell of crosslinked hydrogel, and one or more live cells contained in the void or cavity”.
Steemers et al. is different from the instant claim in that it does not teach “incubating the plurality of hollow shell particles to grow the one or more cells contained therein”.
Nonetheless, it is known in the art that cells encapsulated in a polymer shell are routinely cultured and/or differentiated as substantiated by He et al. (par. [0026]). He et al. provides microcapsules comprising a core and a shell, wherein the shell is formed of crosslinked hydrogel (including biodegradable and biocompatible polymers (par. [0052]-[0053]) and the core contains a cell or cell aggregate suspended in a matrix that is either a viscous aqueous liquid or hydrogel (par. [0027], [0035]). The microcapsules can further contain one or more bioactive agents like a growth factor or chemokine to promote the growth, survival, or differentiations of the cell or cell aggregate within (par. [0061]). He et al.’s working examples show that encapsulating a single cell or multiple cells in the microcapsule’s shell made of crosslinked hydrogel shell and suspending the cell-containing microcapsules in culture medium resulted in cell proliferation and formation of a single cell aggregate or multiple aggregates after several days (par. [0158], [0160], [0165], [0169]-[0170], [0176], [0185]).
Accordingly, a person with ordinary skill in the art before the effective filing date of the claimed invention would have modified Steemers et al.’s method by incorporating an additional step of incubating the hollow beads in a culture medium. It can be predicted that the single cell within the shell of the hollow beads would successfully grow after a few days of being immersed in a culture medium based on He et al.’s teachings. Obviousness is based on the rationale that all claimed elements were known in the prior art and their combination would have yielded nothing more than predictable results. See MPEP § 2143 and KSR, 550 U.S. 398, 82 USPQ2d at 1395; Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976).
Claim 20 is therefore obvious over Steemers et al. in view of He et al..
Regarding claims 21-22: He et al. teaches staining encapsulated cells with a fluorescent agent for cell markers, which allows determination of cell viability (par. [0165]-[0166], [0178]). Since Steemers et al.’s hollow beads are porous that allow diffusion of nutrients into the shell to maintain viability of the cell, one with ordinary skill in the art would have further altered the modified method by incubating said hollow beads in a solution containing a fluorescent agent for a cell marker with reasonable expectation that the encapsulated cell would be stained and could be evaluated. Combining prior art elements according to known methods to yield predictable results. Id.
Regarding claim 23: Steemers et al. and He et al.’s modified method involving encapsulating a single cell with a hollow bead prepared from crosslinked hydrogel that is biocompatible, degradable, and having an interior in which the single cell is contained is the same as the step “providing plurality of hollow shell particles formed from a biocompatible and chemically or physically degradable crosslinked hydrogel, each hollow shell particle having a void or cavity formed therein and surrounded by a shell of crosslinked hydrogel and having a single cell contained in the void or cavity of at least some of the plurality of particles”.
Incubating the hollow beads in a culture medium for several days such that the single cell in the shell of each hollow bead proliferates to form a single cell aggregate is analogous to “incubating the plurality of hollow shell particles in a growth media for a time period to obtain multicellular colonies contained in the void or cavity of at least some of the plurality of hollow shell particles”.
Further incubating the hollow beads in a solution with a fluorescent agent for a cell marker is equivalent to “optionally labeling the cells and/or the hollow shell particle with a fluorescent label or fluorogenic substrate”.
Capturing/selecting cells and preparing them for subsequent downstream assays via flow sorting, which is known to sort optically based on fluorescence and/or scatter signal, corresponds to “passing the plurality of hollow shell particles through a fluorescence activated cell sorter and sorting hollow shell particles containing multicellular colonies based on a fluorescence and/or scatter signal of each hollow shell particle”.
Regarding claim 24: the method of claim 23 has the additional limitation “further comprising loading the sorted hollow shell particles into a plurality of separate sample volumes, wherein each sample volume contains a single hollow shell particle”.
Although Steemers et al. does not specifically teach where to put the cells after sorting, the prior art teaches that the hollow beads can be loaded onto a surface like a flow cell device having a multi-well plate such that each well contains a single hollow bead (par. [0056]). Thus, it would have been obvious to perform flow sorting using said device and place the sorted cells into the wells of its multi-well plate.
Regarding claims 26-27: Steemers et al. teaches carrying out assays on the single cell-containing hollow bead in each well. And as discussed above, He et al. teaches analyzing encapsulated cells with the aid of a cell marker probe such as a fluorescent stain that can determine cell viability. Given that the disclosed method can entail performing multiple assays on the hollow bead, a person with ordinary skill in the art would have combined Steemers et al.’s teachings with He et al. and treat the sorted cells with a fluorescent agent for further characterization. Combining prior art elements according to known methods to yield predictable results is the rationale supporting the conclusion of obviousness. Id.
Regarding claim 28: He et al. teaches culturing cells using a culture medium containing antibiotics and leukemia inhibiting factor (which is considered a selective growth medium since said components remove unwanted microorganisms and prevent cell differentiation, respectively; par. [0158]), thereby satisfying “wherein the growth media is a selective growth medium”.
Regarding claim 29: Steemers et al. teaches performing assays on a number of single cells such as 10,000-1,000,000 cells (par. [0026]) and thus fulfills “wherein the plurality of hollow shell particles comprises greater than 10,000 hollow shell particles”.
Claims 14-16, 18-19, 20-24, and 26-30 are rejected under 35 U.S.C. 103 as being unpatentable over Steemers et al. (Pub. No. US 2019/0352591 A1) in view of He et al. (Pub. No. US 2014/0127290 A1) and Brix et al. (Pub. No. WO 2009003492 A1).
The teachings of Steemers et al. and He et al. are described previously and applied herein. Steemers et al. anticipates claims 14-16 and 18-19, while Steemers et al. and He et al. render claims 14-16, 18-19, 20-24, and 26-29 obvious.
Steemers et al. is similar to the following claim:
Regarding claim 30: the hollow shell particles in the method of claim 23 are further required to be “not labelled and the hollow shell particles containing multicellular colonies are sorted based on a scatter signal of each hollow shell particle”.
Steemers et al. differs from the instant claim in that it does not specifically teach flow sorting based on scatter signal of unlabeled hollow beads.
Flow sorting based on scatter signal of unlabeled particles, however, is a known technique in the art. According to Brix et al., light scatter is typically utilized to identify a cell/particle population of interest while fluorescence intensity provides specific information about individual cells (lines 26-28, page 154). Flow cytometry is a powerful technique since it can measure various parameters to sort cells. Aside from measuring fluorescence, it can also measure the amount of light scattered. Forward and side scatter data are used for preliminary identification of cells including differentiation of sub-populations of cells as well as exclusion of debris and dead cells (lines 11-30, page 155). A person with ordinary skill in the art before the effective filing date of the claimed invention would have applied the known technique of flow cytometry on unlabeled hollow beads and expect that sub-populations of cells encapsulated within said hollow beads would be differentiated based on characteristics such as size. Applying a known technique to a known method ready for improvement yields predictable results. See MPEP 2143 and KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007).
Hence, claim 30 is obvious over Steemers et al. in view of He et al. and Brix et al..
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 14 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 33-43 of co-pending Application No. 17/996927 in view of Steemers et al. (Pub. No. US 2019/0352591 A1).
The co-pending application is directed to a method of performing a cell secretion assay using shaped particles, wherein each shaped particle has a void or cavity formed therein. The method comprises: providing a plurality of shaped particles; loading at least one cell into the void or cavity of the at least one shaped particle; adding an affinity capture agent to the at least one shaped particle specific to a cell secretion of interest; incubating the at least one shaped particle with the at least one cell loaded therein for a period of time such that the cell secretion of interest is secreted from the at least one cell and binds to the affinity capture agent; adding a stain, dye, label, or other secondary affinity capture agent specific to the cell secretion of interest on or in the at least one shaped particle; and analyzing or sorting the at least one shaped particle based on a signal formed or property generated by the stain, dye, label, or other secondary affinity capture agent.
Although the claims at issue are not identical, they are not patentably distinct from each other because an embodiment further comprises flowing the at least one shaped particle through a flow cytometer, fluorescence activated cell sorter, or other single-cell analysis instrument, and then sorting the at least one shaped particle based on a threshold or gate in fluorescence intensity, scatter intensity, or other signal measured with the flow cytometer, fluorescence activated cell sorter, or other single-cell analysis instrument. In another embodiment, the method further entails culturing the at least one cell loaded therein.
Unlike the claims of the instant application, the co-pending application does not explicitly indicate that the plurality of shaped particles comprises hollow shell particles are made from a biocompatible and degradable crosslinked hydrogel.
Despite this, encapsulating one or more cells using such particles is known in the art. Steemers et al., for example, discloses a hollow bead comprising (i) a polymer shell prepared from a crosslinked hydrogel composition and (ii) an interior surrounded by the polymer shell, wherein said hydrogel can be a biocompatible and degradable polymer (par. [0029]-[0030]). The disclosed hollow beads have a size sufficient to encapsulate a single cell such as a diameter of 20-200 µm (par. [0035]-[0036]). The hollow beads’ polymer shell can be prepared to contain functional groups such as biotin or other ligands for specific capture, and can also be permeabilized or lysed, to allow flow sorting and cell assays (par. [0043]-[0044], [0056]-[0057]). Since these hollow beads are designed to encapsulate a single cell and can be labeled for sorting and assaying, one with ordinary skill in the art before the effective filing date of the claimed invention would have used Steemers et al.’s hollow beads as the plurality of shaped particles in the co-pending application’s method. It can be expected that a single cell would be successfully loaded into the interior of each hollow bead, labeled, and sorted.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 14 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13-34 of co-pending Application No. 18/560103.
Co-pending application 18/560103 is drawn to a method of screening B or T cells for one or more secretions of interest, as well as a method of sorting shaped particles loaded with cells. The two disclosed methods are not distinct from the claims of the instant application as both use three-dimensional shaped particles having voids or cavities loaded with single cells and employ a flow cytometer or FACS instrument to sort them.
The screening method comprises: loading single B or T cells into respective voids or cavities formed in the plurality of three-dimensional shaped particles; capturing the one or more secretions of interest with one or more capture agents disposed on or in the plurality of three-dimensional shaped particles; labeling the one or more captured secretions of interest with fluorescent reporters; sorting the three-dimensional shaped particles using a flow cytometer or fluorescence activated cell sorter based on a fluorescence signal from the fluorescent reporters to create a sorted population of three-dimensional shaped particles.
Similarly, the sorting method comprises: providing a population of shaped particles loaded with single cells into respective voids or cavities formed in the plurality of three-dimensional shaped particles; capturing a secretion from the cells on one or more of the shaped particles containing single cells therein; exposing the one or more shaped particles with the captured secretion to a fluorescent reporter; flowing the population of shaped particles loaded with single cells through the flow cytometer or FACS instrument; optically interrogating the shaped particles in the flow cytometer or FACS instrument to measure a fluorescence signal for each shaped particle that comprises two or more of: a fluorescence peak area, fluorescence peak height, and fluorescence peak width; and identifying and sorting a sub-population of the shaped particles based at least in part on a threshold or gate on two or more of: fluorescence peak area, fluorescence peak height, and fluorescence peak width.
The co-pending application differs from the instant claims in that the screening method and sorting method do not specify that the plurality of three-dimensional shaped particles are hollow shell particles comprising biocompatible and degradable crosslinked hydrogel.
Steemers et al., however, teaches using hollow beads to encapsulate single cells and performing assays on the encapsulated cells or materials derived from said cells like DNA, RNA, and proteins (par. [0006], [0056]). The hollow beads include (i) a polymer shell having pores that allow diffusion of reagents (par. [0007]) and are made of crosslinked hydrogel that can comprise a biocompatible and degradable polymer, as well as (ii) an interior surrounded by the polymer shell (par. [0029]-[0030]). The hollow beads’ polymer shell can be prepared to contain functional groups such as biotin or other ligands for specific capture, and can also be permeabilized or lysed, to allow flow sorting and cell assays (par. [0043]-[0044], [0056]-[0057]). A person with ordinary skill in the art would have used Steemers et al.’s hollow beads as the plurality of three-dimensional shaped particles in the co-pending application’s method with reasonable expectation that the single cells would be successfully sorted and analyzed.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHELLE F PAGUIO FRISING whose telephone number is (571)272-6224. The examiner can normally be reached Monday-Friday, 8:00 a.m. - 4:00 p.m..
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/Michelle F. Paguio Frising/Primary Examiner, Art Unit 1651