DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 6 April 2026 has been entered.
Applicant's response has been fully considered. Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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 Status
Claims 88, 90, 92-95 and 98-119 are currently pending.
Claims 88, 90, 92-95, 98-115, and 118-119 are examined herein.
Claims 116 and 117 are withdrawn.
Claims 1-87, 89, 91 and 96-97 have been cancelled.
Specification
Note: All references to the Specification herein pertain to the PG publication: US20210319279.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
A. Claims 88, 90, 92-95, 98-99, 107-109, and 111-115 are rejected under 35 U.S.C. 103 as being unpatentable over Blagovic et al. (Current Opinion in Biotechnology (2013) Vol. 24:940-947) in view of Garg et al. (Antonie van Leeuwenhoek (2014) 105:289–305).
This rejection is newly recited and necessitated by claim amendment herein.
Claim 88, as now amended is directed to:
A system for biological computing, comprising:
(a) a first computing unit[[s]] (CU[[s]]) and a second CU, wherein the first and second CUs comprise[[s]] one or more genetically engineered microbial cells and
(b) one or more sample objects derived from an input sample, wherein the one or more sample objects comprise one or more cells or clusters of cells;
wherein the
(i) the first CU[[s]] interacts with the one or more sample objects through a first surface-bound entity (SBE[[s]]) associated with the first CU[[s]] to form a computational cluster and releases one or more within the computational cluster; and
(ii) the second CU interacts with the one or more SOs in the computational cluster through a second SBE associated with the second CU and attenuates or enhances production or degradation of the one or more SOs
The prior art to Blagovic et al. disclose engineered cell-cell interactions modeling juxtacrine signaling. Blagovic et al. disclose, “an approach to directly tune cell–cell signals utilizes material scaffolds that are normally used to present adhesive matrix cues, such as the short peptide RGD. Proteins or peptides involved in juxtacrine signaling are immobilized on the scaffold to mimic cues that would otherwise be presented by adjacent cells (p. 940, col. 2; Figure 1). Figure 1 includes (a)-a cell; (b) cell sample object and surface bound entities associated with (a) cells. And transfer of signal objects inside of the cell. Blagovic et al. further disclose independent cells which meet the definition of a computational cluster as being “one or more CUs and one or more sample objects” (see p. 940, Figure 1) and an SBE comprising an SO at Figure 1 (p. 940).
With respect to a first and second CU that is a microbial cell, Blagovic et al. do not disclose said aspects. Blagovic et al. further do not disclose the second CU interacting with one or more SOs (signal objects).
However, the prior art to Garg et al. disclose the mechanisms of quorum sensing cell-cell communication in bacteria, wherein communication is mediated via self-generated signaling molecules (autoinducers) to change gene expression profiles. Signaling molecules, such as AHLs in gram-negative bacteria operate via the LuxIR circuit. Said signaling operates to regulate expression of virulence and regulate other accessory genes, for example. (page 290, col. 1). The RI-sensory system includes I-genes that encode synthase protein and R-genes that encode LuxR-like protein that interact with its specific signal molecule. AHL is the most common class of AI and LuxI-type AHL synthase catalyze the formation of a specific AHL from the substrate SAM (intermediate of methione/homocysteine pathway) and acyl-ACP. AHLs traverse the lipid bilayer of the cell membrane and navigate intracellular and extracellular environments. Eventually when AHL reaches a max level, DNA binding TFs (R proteins) bind specific AHL signaling autoinducers and the complex activates or represses multiple target genes (p. 290, col. 2).
With respect to Garg et al. in combination with Blagovic et al., it would have been prima facie obvious to one of skill in the art before the effective filing date of the claimed invention to have used the principals of quorum sensing as disclosed by Garg et al. in the genetic engineering of cells to replicate the same functions as quorum sensing in bacteria, as Blagovic et al. disclose the principals of engineered cell-cell interactions that could be adapted to mimic that of bacterial quorum sensing as described in Garg et al. and one of skill in the art would have had a reasonable expectation of success in so doing, as Garg et al. motivate the use of said mechanism in synthetic biology systems (p.292, col. 2-p.293). Garg et al. specifically disclose that cell-cell communication represents valuable mechanism to engineer novel constructs in bacteria (p. 293).
With respect to claim 90, Blagovic et al. disclose cells capable of recognition of a signal object (p. 940, Figure 1).
With respect to claim 92, Blagovic et al. disclose attachment at the surface of the cell (Figure 1, p. 940; p. 943, col. 1- A non-genetic approach is to induce interactions between T cells and their target cells by exogenously introducing cell–cell bridging molecules, such as antibodies or its fragments).
With respect to claim 93, the prior art to Garg et al. disclose that a CU in the system is capable of producing an SO that is released into the medium (AHLs traverse the lipid bilayer of the cell membrane and navigate intracellular and extracellular environments [p. 290, col. 2]).
With respect to claim 94, Garg et al. disclose AHLs that traverse the lipid bilayer of the cell membrane and navigate intracellular and extracellular environments. Eventually when AHL reaches a max level, DNA binding TFs (R proteins) bind specific AHL signaling autoinducers and the complex activates or represses multiple target genes (p. 290, col. 2).
With respect to claim 95, Garg et al. disclose AHLs that traverse the lipid bilayer of the cell membrane and navigate intracellular and extracellular environments. Eventually when AHL reaches a max level, DNA binding TFs (R proteins) bind specific AHL signaling autoinducers and the complex activates or represses multiple target genes (p. 290, col. 2).
With respect to claim 98, Blagovic et al. disclose a sample object (cell) that is associated with an SBE, for example (Figure 1).
With respect to claim 99, Blagovic et al. disclose recognition of SO to induce another SO (see eph/ephrin interaction in Figure 1).
With respect to claims 107-109 and 111-115 which each include desired results of a cell to produce a first signaling object as being enhanced and/or attenuated or of a generation to include presence or absence of features, the desired programming for either attenuation or enhancement would have been prima facie obvious as a mere design choice of said system and the “capability” of the cell in the system to do so is not claimed beyond said wishful operation. Further, desired results of the particular “generation” of the output are also a design feature wherein there are no components of a system as to said particular embodiments. As such, the “wherein” clause is not limiting to the system as claimed and is obvious herein over the art to Blagovic et al. in combination with Garg et al., as signals in cellular interactions operate to either enhance or degrade. It is suggested that said components be claimed as those of the system components only.
B. Claim 100 is rejected under 35 U.S.C. 103 as being unpatentable over Blagovic et al. (Current Opinion in Biotechnology (2013) Vol. 24:940-947) in view of Garg et al. (Antonie van Leeuwenhoek (2014) 105:289–305), as applied to claim 88 and in view of Brownlee (CIS Technical Report 070427A (April 2007): 5 pages).
Claim 88, as now amended is directed to:
A system for biological computing, comprising:
(a) a first computing unit[[s]] (CU[[s]]) and a second CU, wherein the first and second CUs comprise[[s]] one or more genetically engineered microbial cells and
(b) one or more sample objects derived from an input sample, wherein the one or more sample objects comprise one or more cells or clusters of cells;
wherein the
(i) the first CU[[s]] interacts with the one or more sample objects through a first surface-bound entity (SBE[[s]]) associated with the first CU[[s]] to form a computational cluster and releases one or more within the computational cluster; and
(ii) the second CU interacts with the one or more SOs in the computational cluster through a second SBE associated with the second CU and attenuates or enhances production or degradation of the one or more SOs
The prior art to Blagovic et al. disclose engineered cell-cell interactions modeling juxtacrine signaling. Blagovic et al. disclose, “an approach to directly tune cell–cell signals utilizes material scaffolds that are normally used to present adhesive matrix cues, such as the short peptide RGD. Proteins or peptides involved in juxtacrine signaling are immobilized on the scaffold to mimic cues that would otherwise be presented by adjacent cells (p. 940, col. 2; Figure 1). Figure 1 includes (a)-a cell; (b) cell sample object and surface bound entities associated with (a) cells. And transfer of signal objects inside of the cell. Blagovic et al. further disclose independent cells which meet the definition of a computational cluster as being “one or more CUs and one or more sample objects” (see p. 940, Figure 1) and an SBE comprising an SO at Figure 1 (p. 940).
With respect to a first and second CU that is a microbial cell, Blagovic et al. do not disclose said aspects. Blagovic et al. further do not disclose the second CU interacting with one or more SOs (signal objects).
However, the prior art to Garg et al. disclose the mechanisms of quorum sensing cell-cell communication in bacteria, wherein communication is mediated via self-generated signaling molecules (autoinducers) to change gene expression profiles. Signaling molecules, such as AHLs in gram-negative bacteria operate via the LuxIR circuit. Said signaling operates to regulate expression of virulence and regulate other accessory genes, for example. (page 290, col. 1). The RI-sensory system includes I-genes that encode synthase protein and R-genes that encode LuxR-like protein that interact with its specific signal molecule. AHL is the most common class of AI and LuxI-type AHL synthase catalyze the formation of a specific AHL from the substrate SAM (intermediate of methione/homocysteine pathway) and acyl-ACP. AHLs traverse the lipid bilayer of the cell membrane and navigate intracellular and extracellular environments. Eventually when AHL reaches a max level, DNA binding TFs (R proteins) bind specific AHL signaling autoinducers and the complex activates or represses multiple target genes (p. 290, col. 2).
With respect to Garg et al. in combination with Blagovic et al., it would have been prima facie obvious to one of skill in the art before the effective filing date of the claimed invention to have used the principals of quorum sensing as disclosed by Garg et al. in the genetic engineering of cells to replicate the same functions as quorum sensing in bacteria, as Blagovic et al. disclose the principals of engineered cell-cell interactions that could be adapted to mimic that of bacterial quorum sensing as described in Garg et al. and one of skill in the art would have had a reasonable expectation of success in so doing, as Garg et al. motivate the use of said mechanism in synthetic biology systems (p.292, col. 2-p.293). Garg et al. specifically disclose that cell-cell communication represents valuable mechanism to engineer novel constructs in bacteria (p. 293).
Neither Blagovic et al. nor Garg et al. specifically disclose the elements of claim 100. However, with respect to the sample object being a cell and the SBE associated with the cell comprising an antigen, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to engineer said design, as it is well-known in the art of immunology, as disclosed, for example, in a review of Brownlee that antigens interact with antibodies on cell surfaces (Figure 1). One would have been motivated to provide such in cell-cell interaction systems such as those in Blagovic et al. in combination with the mechanisms disclosed in Garg et al., wherein Blagovic et al. motivate that strategies from immune system regulation are integral to understanding cell-cell interaction signaling in the context, for example, of cell surface manipulations (page 943, col. 1). As such a reasonable success would be expected as each of said technologies are in the same endeavor of cellular signaling
C. Claims 101-106 and 118-119 are rejected under 35 U.S.C. 103 as being unpatentable over Blagovic et al. (Current Opinion in Biotechnology (2013) Vol. 24:940-947) in view of Garg et al. (Antonie van Leeuwenhoek (2014) 105:289–305), as applied to claim 88 and in view of Weiss et al. (Natural Computing (2003) Vol. 2:47-84).
This rejection is newly recited and necessitated by claim amendment herein.
Claim 88, as now amended is directed to:
A system for biological computing, comprising:
(a) a first computing unit[[s]] (CU[[s]]) and a second CU, wherein the first and second CUs comprise[[s]] one or more genetically engineered microbial cells and
(b) one or more sample objects derived from an input sample, wherein the one or more sample objects comprise one or more cells or clusters of cells;
wherein the
(i) the first CU[[s]] interacts with the one or more sample objects through a first surface-bound entity (SBE[[s]]) associated with the first CU[[s]] to form a computational cluster and releases one or more within the computational cluster; and
(ii) the second CU interacts with the one or more SOs in the computational cluster through a second SBE associated with the second CU and attenuates or enhances production or degradation of the one or more SOs
The prior art to Blagovic et al. disclose engineered cell-cell interactions modeling juxtacrine signaling. Blagovic et al. disclose, “an approach to directly tune cell–cell signals utilizes material scaffolds that are normally used to present adhesive matrix cues, such as the short peptide RGD. Proteins or peptides involved in juxtacrine signaling are immobilized on the scaffold to mimic cues that would otherwise be presented by adjacent cells (p. 940, col. 2; Figure 1). Figure 1 includes (a)-a cell; (b) cell sample object and surface bound entities associated with (a) cells. And transfer of signal objects inside of the cell. Blagovic et al. further disclose independent cells which meet the definition of a computational cluster as being “one or more CUs and one or more sample objects” (see p. 940, Figure 1) and an SBE comprising an SO at Figure 1 (p. 940).
With respect to a first and second CU that is a microbial cell, Blagovic et al. do not disclose said aspects. Blagovic et al. further do not disclose the second CU interacting with one or more SOs (signal objects).
However, the prior art to Garg et al. disclose the mechanisms of quorum sensing cell-cell communication in bacteria, wherein communication is mediated via self-generated signaling molecules (autoinducers) to change gene expression profiles. Signaling molecules, such as AHLs in gram-negative bacteria operate via the LuxIR circuit. Said signaling operates to regulate expression of virulence and regulate other accessory genes, for example. (page 290, col. 1). The RI-sensory system includes I-genes that encode synthase protein and R-genes that encode LuxR-like protein that interact with its specific signal molecule. AHL is the most common class of AI and LuxI-type AHL synthase catalyze the formation of a specific AHL from the substrate SAM (intermediate of methione/homocysteine pathway) and acyl-ACP. AHLs traverse the lipid bilayer of the cell membrane and navigate intracellular and extracellular environments. Eventually when AHL reaches a max level, DNA binding TFs (R proteins) bind specific AHL signaling autoinducers and the complex activates or represses multiple target genes (p. 290, col. 2).
With respect to Garg et al. in combination with Blagovic et al., it would have been prima facie obvious to one of skill in the art before the effective filing date of the claimed invention to have used the principals of quorum sensing as disclosed by Garg et al. in the genetic engineering of cells to replicate the same functions as quorum sensing in bacteria, as Blagovic et al. disclose the principals of engineered cell-cell interactions that could be adapted to mimic that of bacterial quorum sensing as described in Garg et al. and one of skill in the art would have had a reasonable expectation of success in so doing, as Garg et al. motivate the use of said mechanism in synthetic biology systems (p.292, col. 2-p.293). Garg et al. specifically disclose that cell-cell communication represents valuable mechanism to engineer novel constructs in bacteria (p. 293).
Neither Blagovic et al. nor Garg et al. specifically disclose the AND, OR and/or NOT gates as in claims 101-106. However, the prior art to Weiss et al. disclose programmed cellular behaviors that are operational in computations, communication and signal processing (abstract). The processes as disclosed include those in circuit design and are applied to biological computing (abstract). Specifically, operational design includes those based in logic gate operation, which include, for example AND, OR and NOT gating (pp. 48-55).
With respect to claims 118-119, Weiss et al. disclose that cell-cell communication is important in both eukaryotic and prokaryotic cell systems, thus making obvious the inclusion of said logic gate operation in the context of E. coli (prokaryote that is specifically disclosed in Weiss et al., for example at p. 71-74) and as would also be obvious in yeast systems (which are eukaryotes).
As such, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized the cell-cell communication units as in Blagovic et al. in combination with the quorum sensing mechanism as disclosed in Garg et al. and discussed above further with the detailed gate operations as disclosed in Weiss et al., as Weiss et al. describe specific operations for cell-cell and multi-cell signal procedures (starting p. 71) and wherein each of said references are in the same field of endeavor thus lending a reasonable expectation of success.
D. Claim 110 is rejected under 35 U.S.C. 103 as being unpatentable over Blagovic et al. (Current Opinion in Biotechnology (2013) Vol. 24:940-947) in view of Garg et al. (Antonie van Leeuwenhoek (2014) 105:289–305), as applied to claim 88 and in view of Khorshid (Proc. 2nd Saudi Sci. Conl, Fac. Sci., KAU; 15-17 March 2004, Part I. pp.67-98 (2005).
Claim 88, as now amended is directed to:
A system for biological computing, comprising:
(a) a first computing unit[[s]] (CU[[s]]) and a second CU, wherein the first and second CUs comprise[[s]] one or more genetically engineered microbial cells and
(b) one or more sample objects derived from an input sample, wherein the one or more sample objects comprise one or more cells or clusters of cells;
wherein the
(i) the first CU[[s]] interacts with the one or more sample objects through a first surface-bound entity (SBE[[s]]) associated with the first CU[[s]] to form a computational cluster and releases one or more within the computational cluster; and
(ii) the second CU interacts with the one or more SOs in the computational cluster through a second SBE associated with the second CU and attenuates or enhances production or degradation of the one or more SOs
The prior art to Blagovic et al. disclose engineered cell-cell interactions modeling juxtacrine signaling. Blagovic et al. disclose, “an approach to directly tune cell–cell signals utilizes material scaffolds that are normally used to present adhesive matrix cues, such as the short peptide RGD. Proteins or peptides involved in juxtacrine signaling are immobilized on the scaffold to mimic cues that would otherwise be presented by adjacent cells (p. 940, col. 2; Figure 1). Figure 1 includes (a)-a cell; (b) cell sample object and surface bound entities associated with (a) cells. And transfer of signal objects inside of the cell. Blagovic et al. further disclose independent cells which meet the definition of a computational cluster as being “one or more CUs and one or more sample objects” (see p. 940, Figure 1) and an SBE comprising an SO at Figure 1 (p. 940).
With respect to a first and second CU that is a microbial cell, Blagovic et al. do not disclose said aspects. Blagovic et al. further do not disclose the second CU interacting with one or more SOs (signal objects).
However, the prior art to Garg et al. disclose the mechanisms of quorum sensing cell-cell communication in bacteria, wherein communication is mediated via self-generated signaling molecules (autoinducers) to change gene expression profiles. Signaling molecules, such as AHLs in gram-negative bacteria operate via the LuxIR circuit. Said signaling operates to regulate expression of virulence and regulate other accessory genes, for example. (page 290, col. 1). The RI-sensory system includes I-genes that encode synthase protein and R-genes that encode LuxR-like protein that interact with its specific signal molecule. AHL is the most common class of AI and LuxI-type AHL synthase catalyze the formation of a specific AHL from the substrate SAM (intermediate of methione/homocysteine pathway) and acyl-ACP. AHLs traverse the lipid bilayer of the cell membrane and navigate intracellular and extracellular environments. Eventually when AHL reaches a max level, DNA binding TFs (R proteins) bind specific AHL signaling autoinducers and the complex activates or represses multiple target genes (p. 290, col. 2).
With respect to Garg et al. in combination with Blagovic et al., it would have been prima facie obvious to one of skill in the art before the effective filing date of the claimed invention to have used the principals of quorum sensing as disclosed by Garg et al. in the genetic engineering of cells to replicate the same functions as quorum sensing in bacteria, as Blagovic et al. disclose the principals of engineered cell-cell interactions that could be adapted to mimic that of bacterial quorum sensing as described in Garg et al. and one of skill in the art would have had a reasonable expectation of success in so doing, as Garg et al. motivate the use of said mechanism in synthetic biology systems (p.292, col. 2-p.293). Garg et al. specifically disclose that cell-cell communication represents valuable mechanism to engineer novel constructs in bacteria (p. 293).
Neither Blagovic et al. nor Garg et al. specifically include viscosity discussions, as in claim 110.
However, with respect to disclosure of a system that has an agent to increase viscosity of a medium, the prior art to Khorshid discloses that a cellular medium viscosity can alter the cellular reactions to topography and can affect cellular interactions and growth as demonstrated by cells in the presence of a variety of concentrations of macromolecules (p. 67 at abstract).
As such it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized the cell-cell communication units as in Blagovic et al. combined with the quorum sensing mechanisms as disclosed in Garg et al., as discussed above, with the ideal medium conditions that include viscosity agents as described in Khorshid. One would have been motivated to do so because Khorshid discloses that an elevated medium viscosity is pertinent to biochemical and cellular functions (abstract).
Conclusion
No claims are allowed.
It is suggested that the inventive features as discussed in the Interview conducted on 7 October 2025, be more specifically claimed herein, such as those directed to the aspects that would distinguish the recitations from cell-cell mechanisms over those as disclosed in the prior art. This might include, for example, the yeast strains and binders as scaffolded to said strains that also include pheromone signal objects that act to activate cells/reporters.
Inquiries
Papers related to this application may be submitted to Technical Center 1600 by facsimile transmission. Papers should be faxed to Technical Center 1600 via the PTO Fax Center. The faxing of such papers must conform to the notices published in the Official Gazette, 1096 OG 30 (November 15, 1988), 1156 OG 61 (November 16, 1993), and 1157 OG 94 (December 28, 1993) (See 37 CFR § 1.6(d)). The Central Fax Center Number is (571) 273-8300.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lori A. Clow, whose telephone number is (571) 272-0715. The examiner can normally be reached on Monday-Thursday from 11:00AM to 9:00PM ET.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Karlheinz Skowronek can be reached on (571) 272-9047.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/Lori A. Clow/ Primary Examiner, Art Unit 1687
Prosecution Insights