DETAILED ACTION
Applicant’s response filed 01/26/2026 has been fully considered. The following rejections and/or objections are either reiterated or newly applied.
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 163-171 are newly added by Applicant.
Claims 3, 8-12, 14, 16-20, 22-34, 36-38, 42-74, 76-78, 81-158 and 162 are cancelled by Applicant.
Claims 1-2, 4-7, 13, 15, 21, 35, 39-41, 75, 79-80, 159-161 and 163-171 are currently pending and are herein under examination.
Claims 1-2, 4-7, 13, 15, 21, 35, 39-41, 75, 79-80, 159-161 and 163-171 are rejected.
Claims 159, 164 and 170 are objected.
Priority
The instant application claims domestic benefit to Application PCT/US2019/055821 filed 10/11/2019, which claims domestic benefit to U.S. Provisional Application No. 62/744,760 filed 10/12/2018. The claim to domestic benefit is acknowledged. As such, the effective filing date for claims 1-2, 4-7, 13, 15, 21, 35, 39-41, 75, 79-80, 159-161 and 163-171 is 10/12/2018.
Withdrawn Rejections
35 USC 112(b)
The rejection of claims 1-7, 13-15, 21, 35, 39-41, 75, 79-80, 137-139 and 156-162 are withdrawn in view of claim amendment, excepted for the rejection of claim 41 discussed below in section Response to Arguments under 35 USC 112(b).
35 USC 112(d)
The rejection of claims 4 and 79 under 35 USC 112(d) is withdrawn in view of claim amendments.
35 USC 103
The rejection of claims 3, 137-139, 156-162 under 35 U.S.C. 103 as being unpatentable over Blanchard et al. in view of Shafer is withdrawn in view of claim amendment.
The rejection of claims 1-2, 4-7, 13-15, 21 and 40 under 35 U.S.C. 103 as being unpatentable over Blanchard et al. in view of Shafer and in further view of Koehrsen is withdrawn in view of claim amendment.
The rejection of claims 35 and 39 under 35 U.S.C. 103 as being unpatentable over Blanchard et al. in view of Shafer and Koehrsen and in further view of Krutzik et al. is withdrawn in view of claim amendment.
The rejection of claims 41 and 80 under 35 U.S.C. 103 as being unpatentable over Blanchard et al. in view of Shafer and Koehrsen is withdrawn in view of claim amendment.
The rejection of claims 75 and 79 under 35 U.S.C. 103 as being unpatentable over Blanchard et al. in view of Shafer and Koehrsen and in further view of Krutzik et al. is withdrawn in view of claim amendment.
Claim Objections
The objection to claim 1 is withdrawn in view of claim amendment.
Claims 159, 164 and 170 are objected to because of the following informalities:
Claim 159, pg. 9, line 15, recites “the an immune cell” which should be “the immune cell”.
Claim 164, line 1, should have a comma after “163”.
Claim 170 recites “combination” which should be “combinations”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
35 USC 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 163-164 and 166-171 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
This rejection is newly recited as necessitated by claim amendment.
Claim 163 is rejected because it does not adequately describe a sufficient number of species for a claimed genus (MPEP 2163.II.A.3(a).ii). Claim 163, lines 9, 11 and 17, recites “black box engineering model”. Applicant claims the genus of all black box engineering models whereas there is only disclosure for species of black box engineering models. The specification provides non-limiting species of black box engineering models (pg. 18, lines 1-6; pg. 22, lines 1-6; pg. 27, lines 14-19). However, these species are not a sufficient representative number of species for the claimed genus of all black box engineering models. MPEP 2163.II.A.3(a).ii states that in order for a claimed genus to have a sufficient description of a representative number of species, wherein the genus has substantial variation of species within it (i.e., all types of black box engineering models), the disclosure must adequately describe a sufficient variety of species to reflect the variation within the genus. Therefore, the disclosure does not provide written description for all types of black box engineering model.
Furthermore, claims 164 and 166-171 are also rejected because they depend on rejected claim 163. However, claim 165 is not rejected because it resolves the issue by limiting the model to be a species of black box engineering model.
35 USC 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-2, 4-7, 13, 15, 21, 35, 39-41, 75, 79-80, 159-161 and 163-171 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
This rejection is either newly recited as necessitated by claim amendment or is maintained from the previous Office action.
Claims dependent from a rejected claims are also rejected, unless otherwise noted.
Claim 1, pg. 2, lines 4 and 9, recite “the subsequent cycle” which renders the claim indefinite. It is unclear which subsequent cycle is being referenced because pg. 1, line 12, recites “at least one subsequent cycle”. Clarify which cycle is being referenced.
Claim 35, lines 4-5, recites “the change in the inflammatory state of the immune cell” which renders the claim indefinite. It is unclear which change is being referenced because both claims 1 and 2 detecting difference changes in inflammatory state. Clarify which change is being referenced.
Claim 41, pg. 6, lines 18-21, recites “predict the predicted change”, which renders the claim indefinite. It is unclear if this recitation requires the same predicting steps recited in claim 1, or if it is a product by process where the method of predicting the previously predicted change may be different than the method recited in claim 1. This ambiguity is reinforced by the fact that claim 41, pg. 6, line 1 recites “a system for performing the method of claim 1”, which indicates an intended use of the system rather than requiring the system to perform the exact method of claim 1. For examination purposes, claim 41 means that the predicting steps recited in claim 1 are required in claim 41 to perform “predict the predicted change.” Clarify whether this recitation is a product by process or requires the steps of claim 1.
Claim 41, pg. 6, line 18-21, recites “the predicted change” which renders the claim indefinite. It is unclear which predicted change is being referenced because claim 1, pg. 1, lines 12-16 and pg. 2, lines 4-6, recite repeating subsequent cycles which necessitates more than one predicted change. Clarify which predicted change is being referenced.
Claim 41, pg. 7, line 6, recites “the change in inflammatory state” which renders the claim indefinite because claim 41, pg. 6, line 14, recites “detect, in real-time, each of the changes in inflammatory state”. Clarify which change is being referenced.
Claim 41 (pg. 7, line 10) and claim 75 (pg. 8, line 4) recite “the change in the inflammatory state of the immune cell” which renders the claims indefinite. It is unclear which change is being referenced because both claim 1 pg. 1, line 5, and pg. 1, line 23, recite “a change in the inflammatory state of the immune cell”. Clarify which change is being referenced.
Claim 41, pg. 7, lines 10-13, the following that renders the claim indefinite: “the change in inflammatory state of the immune cell is accounted for by the controller and adjusted in real-time as the immune response proceeds; the detector detects change in the inflammatory state of the immune cell by measuring a marker characteristic of the inflammatory state.” MPEP 2173.05(p) discusses a product and process in the same claim and recites “A single claim which claims both an apparatus and the method steps of using the apparatus is indefinite under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.” See In re Katz Interactive Call Processing Patent Litigation, 639 F.3d 1303, 1318, 97 USPQ2d 1737, 1748-49 (Fed. Cir. 2011). In the instant case, claim 41 recites a system and the limitations recited above equate to method steps of using the system. For purpose of examination, these limitations recite an intended use of the system.
Claim 161, lines 7-8, recites “the modulating” which renders the claim indefinite. It is unclear which modulating step is being referenced because claim 159 recites modulating with a first and second modulating stimulus. It is also unclear if “the modulating” refers to claim 161, line 4, “stimuli”. Clarify which modulating step is referenced.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Claim 163 line 9 recites a broad recitation of “input and/or output data” while lines 10, 12 and 17-18 recite a narrower limitation of “input and output data” of the broader recitation. The claim is indefinite because there is a question as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 163, line 13, recites “the delivering, detecting, generating, fitting and selecting” which renders the claim indefinite. It is unclear which step of delivering, detecting, generating, fitting, and selecting is being referenced because these steps are repeated as indicated by “sequentially delivering … modulating stimuli” and “respective”. Clarify which steps are being referenced.
Claim 163, line 17, recites “the best fitting black box engineering model” which renders the claim indefinite. Claim 163 requires after each “respective fitting” that a best fitting black box model is selected, indicating that each iteration selects a model. Thus, it is unclear which best fitting model is being referenced. Clarify which model is being referenced.
Claim 163, lines 17-18, recites “is predicted by applying” which renders the claim indefinite. It is unclear if this requires an active step of predicting, or if it is a product by process that defines how the product of “the inflammatory response of the immune cell” was acquired. See MPEP 2113.I regarding product by process limitations. This interpretation is reinforced by the fact that the limitation is embedded in a wherein clause and there is no prior active step of predicting. For examination purposes, this is being interpreted as a product by process limitation.
Claim 164 recites “wherein the method at least one of: provides exogenous control …; enables predictive monitoring …; or enables predictive modeling …” which renders the claim indefinite. Because of the grammar of this recitation it is unclear if it recites active steps or intended uses. For examination purposes, it is being interpreted as intended uses. Clarify how this should be interpreted.
Claim 164, line 6, recites “the immune system’s” which lacks antecedent basis. Provide antecedent basis.
Claim 164, line 7, recites “these activities” which lacks antecedent basis. Provide antecedent basis.
Response to Arguments under 35 USC 112 (b)
Applicant's arguments filed 01/26/2026 have been fully considered but they are not persuasive.
Applicant’s remarks regarding the rejection of claim 41 under 35 USC 112(b) for reciting a product and process in the same claim is not persuasive because the amendments have not fixed the issue and no arguments have been provided (pg. 1, para. 5 of remarks).
35 USC 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 41, 75 and 79-80 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims depend from a rejected claims are also rejected, unless otherwise noted.
Claim 41 fails to include all the limitations of claim 1 to which it depends as indicated by “for performing the method of claim 1”. Claim 41 at least does not require claim 1 limitations of “repeating the subsequent cycle.”
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 163-170 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
This rejection is newly recited as necessitated by claim amendment.
Step 1:
Step 1 asks whether the claims recite statutory subject matter. In the instant application, claims 163-170 recite a method. As such, these claims recite statutory subject matter (Step 1: YES).
Step 2A, Prong 1:
Claims that recite statutory subject matter are analyzed under Step 2A, Prong 1 to determine if they recite any concepts that equate to an abstract idea, law of nature or natural phenomena. The instant claims recite the following limitations that equate to one or more categories of judicial exception:
Claim 163 recites “after generating a respective input and/or output data, fitting a black box engineering model to the respective input and output data; after a respective fitting, selecting a best fitting black box engineering model based on the respective input and output data; and determining from the delivering, detecting, generating, fitting and selecting, a sequence of modulating stimuli that produces a trajectory of immune cell response that matches within a tolerance of a desired trajectory of immune cell response; wherein the inflammatory response of the immune cell to the respective delivered modulating stimuli is predicted by … to the respective input and output data.”
Claim 164 recites “determining the desired trajectory of immune cell response; wherein the method at least one of: provides exogenous control of the immune cell in order to dynamically and predictively drive the immune response through pro-inflammatory activity to anti-inflammatory activity, mimicking the immune system's natural progress10n through these activities during health and restoring proper regulation; enables predictive monitoring and control of immune cell polarization, leading to predictive control and regulation of inflammation and the immune response; or enables predictive modeling and control of the inflammatory response of the immune cell via temporally regulated immune-modulating stimuli.”
Claim 165 recites “wherein the black box engineering model comprises an autoregressive exogenous (ARX) model.”
Limitations reciting a mental process.
Claims 163-164 contain limitations recited at such a high level of generality that they equate to a mental process because they are similar to the concepts of collecting information, analyzing it, and displaying certain results of the collection and analysis in Electric Power Group, LLC, v. Alstom (830 F.3d 1350, 119 USPQ2d 1739 (Fed. Cir. 2016)), which the courts have identified as concepts that can be practically performed in the human mind. The BRI in claim 163 of selecting a model and determining a sequence include a mental determination. The BRI in claim 164 of determining a desired trajectory includes selecting a proinflammatory response. The limitations in claim 164 of “provides exogenous control … enables predictive monitoring … and enables predictive modeling” are intended uses and are not required by the claim.
Limitations reciting a mathematical concept.
Claim 163 and 165 recite limitations that equate to a mathematical concept because they are similar to the concepts of organizing and manipulating information through mathematical correlations in Digitech Image Techs., LLC v Electronics for Imaging, Inc. (758 F.3d 1344, 111 U.S.P.Q.2d 1717 (Fed. Cir. 2014)), which the courts have identified as mathematical concepts. The BRI of fitting an autoregressive exogenous ARX model includes mathematical calculations to update model parameters.
As such, claims 163-170 recite an abstract idea (Step 2A, Prong 1: YES).
Additional Elements:
Once limitations have been identified that recite a judicial exception, the claims are evaluated for additional elements. The additional elements are then analyzed under Step 2A, Prong 2 then Step 2B. The instant claims recite the following additional elements:
Claim 163 recites “sequentially delivering, through an inlet of a fluid chamber via a controller, modulating stimuli to an immune cell; after a respective delivered modulating stimuli, detecting in real-time with a detector in fluid communication with the fluid chamber, an inflammatory response of the immune cell to the respective delivered modulating stimuli; after a respective detected inflammatory response, generating with the detector input and/or output data indicative of the respective detected inflammatory response; applying the best fitting black box engineering model.”
Claim 166 recites “wherein the fluid chamber is a cell culture chamber, a cell culture well, or a microfluidic chamber.”
Claim 167 recites “wherein the immune cell is a cell selected from a group consisting of a microglial cell, an astrocyte, a macrophage, a B cell, a T cell, a natural killer cell, and a leukocyte.”
Claim 168 recites “wherein each modulating stimuli comprise at least one immune-modulating molecule selected from a group consisting of an antigen, a cytokine, a growth factor, a sphingolipid, a complement factor, an immunomodulatory small molecule, an intracellular signaling inhibitor, an activator of pro-inflammatory or anti-inflammatory pathways, a cytokine inhibitor, and combinations thereof.”
Claim 169 recites “wherein a first of the modulating stimuli causes the immune cell to change from a quiescent state or homeostatic state to a pro-inflammatory state.”
Claim 170 recites “wherein the inflammatory response of the immune cell is detected by measuring a marker characteristic selected from a group consisting of iNOS, SOCS3, TLR4, TLR2, IL-IR, MHCII, CD68, CD80, CD86, and combination thereof.”
These above recited additional elements are analyzed below under both Step 2A, Prong 2 and Step 2B:
Step 2A, Prong 2:
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). The judicial exception is not integrated into a practical application because the claims do not recite additional elements that reflect an improvement to a computer, technology, or technical field (MPEP § 2106.04(d)(1) and 2106.5(a)), require a particular treatment or prophylaxis for a disease or medical condition (MPEP § 2106.04(d)(2)), implement the recited judicial exception with a particular machine that is integral to the claim (MPEP § 2106.05(b)), effect a transformation or reduction of a particular article to a different state or thing (MPEP § 2106.05(c)), nor provide some other meaningful limitation (MPEP § 2106.05(e)). Rather, the claims include limitations that equate to an equivalent of the words “apply it” and/or to instructions to implement an abstract idea on a computer (MPEP § 2106.05(f)), insignificant extra-solution activity (MPEP § 2106.05(g)), and field of use limitations (MPEP § 2106.05(h)). The paragraphs below discuss the additional elements recited above in the instant claims.
The additional elements in claims 163 and 166-170 equate to insignificant extra-solution activity of necessary data gathering because they gather data necessary to perform the abstract ideas in claim 163 of fitting/selecting a model and determining a sequence of modulating stimuli.
The BRI of “applying the best fitting black box engineering model” in claim 163 includes it being mere instructions to implement an abstract idea on a generic computer. MPEP 2106.05(f) provides the following considerations for determining whether a claim simply recites a judicial exception with the words “apply it” (or an equivalent), such as mere instructions to implement an abstract idea on a computer: (1) whether the claim recites only the idea of a solution or outcome i.e., the claim fails to recite details of how a solution to a problem is accomplished; (2) whether the claim invokes computers or other machinery merely as a tool to perform an existing process; and (3) the particularity or generality of the application of the judicial exception. The following paragraph provides analysis under these considerations.
The model performs the abstract idea predicting inflammatory immune response based on input/output data. The model is used to generally apply the abstract idea without placing any limits on how the model functions. Rather, this limitation only recites the outcome of the abstract idea and does not include any details about how the prediction is accomplished. See MPEP 2106.05(f). This limitation also merely indicates a field of use or technological environment in which the judicial exception is performed. Although this limitation limits the abstract idea, it merely confines the use of the abstract idea to a particular technological environment (i.e., black box engineering models) and thus fails to add an inventive concept to the claims. See MPEP 2106.05(h).
As such, claims 163-170 are directed to an abstract idea (Step 2A, Prong 2: NO).
Step 2B:
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). These claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because these claims recite additional elements that equate to instructions to apply the recited exception in a generic way and/or in a generic computing environment (MPEP § 2106.05(f)) and to well-understood, routine and conventional (WURC) limitations (MPEP § 2106.05(d)). The paragraphs below discuss the additional elements recited above in the instant claims.
The additional limitations in claims 163 and 166-170, when considered individually and in combination, are WURC as taught by Blanchard et al. (“Blanchard”; FOR ref. 1 on IDS filed 04/09/2021; WO-2018/063914-A1; previously cited) Zhang et al. (“Zhang”; US 2022/0041966 A1; effective filing date 05/17/2017; previously cited on PTO892 mailed 10/08/2024), and Ammer et al. (“Ammer”; WO 2009/024595 A2; published 02/26/2009; previously cited on PTO892 mailed 10/08/2024).
Blanchard discloses a device for measuring an inflammatory response in a subject that involves monitoring changes of biophysical properties of immune cells (abstract) [4]. The interior portion of the device includes a sample reservoir configured to receive a sample, an elongate channel, and a processing chamber [4]. The elongate channel contains an inlet and an outlet [4]. Immune cells are deposited into the sample reservoir, wherein the elongated channel connects via fluid communication the sample reservoir and processing chamber [5]. Blanchard discloses exposing the cells to a chemoattractant [9] [13] [53], wherein the chemoattractant is housed in the processing chamber [5]. The processing chamber is in fluid communication with the sample reservoir through the elongate channel [4]. The induced cellular response via doping may be with proinflammatory cytokines [71]. A controller may be used to perform various functions of the device [153]. Blanchard states that any step may be repeated [68], thus doping via proinflammatory cytokine may occur more than once. Blanchard discloses in vitro evaluation of biophysical properties of immune cells by measuring immune response [1]. Upon initiation of a desired cellular response, a program is run on an analyzer to capture dynamic biophysical behavior by using onboard optical equipment, which may include a phase-contrast at 400x total magnification and a camera attachment [74]. The result is a time-lapsed video of cellular movement [74] and analysis of the images is performed in real-time [97]. The captures images are acquired output data [33].
Zhang discloses a high-throughput automated microfluidic system for cell culture, differentiation and analysis of cells in precisely defined dynamic microenvironments, mimicking signaling in vivo [6]. The device contains an inlet, an outlet, a recess defining chamber with a first portion and second portion with a first channel extending between the inlet and the first port (claim 1). The ports and channels are in fluid communication (claim 1). The device stimulates immune cells in culture while tracking single cells with video microscopy [6]. Figure 1C-2A depicts stimulation of the culture chambers. Figure 3A depicts single-cell response to TNF-alpha stimulation, wherein cell response is marked by triangles in cell images. Figure 10A depicts real-time fluorescent images of 3T3 cells during stimulation with 0.1 and 0.5 ng/ml TNF-alpha 2-hour pulse, wherein red arrows indicate responsive cells [64]. Zang discloses using PDGF media [45]. Pulses were repeated every 24 hours [27].
Ammer discloses a culture device comprising a plurality of culture units, wherein each unit comprises a culture chamber, an inlet port for liquid supply of the culture and an outlet port for discharging liquid from the unit, wherein the inlet port is in fluid communication with the culture chamber and the culture chamber is in fluid communication with the outlet port (abstract). The device is suitable for testing immune cells and immunofunction in vitro (abstract). The device allows for cultivating immune cells and an analyzing the effect of a test compound on immune cells (abstract). The test compound is added to the culture unit through the inlet port (claim 39). A sample of the culture media after adding the compound is then analyzed for an effect of the test compound on the immune cells, which may be quantifying the presence of cytokines or chemokines or other soluble factors that may be Il-2 and TNF-alpha (claim 42; pg. 20, para. 3). The test includes immune fluorescence, light microscopy, flow cytometry, fluorescence activated cell sorting, histology, and enzyme linked immuno-spot methods (ELISPOT) and others after the culture process (pg. 21, para. 3). Proinflammatory cytokines may be TNF-alpha and IFN-gamma (pg. 26, para. 3). Ammer discloses putting growth factors in the cell culture media (pg. 9, in bold Supplements). Test substances/compounds can be continuously supplied to the cells or at time intervals (pg. 12, para. 5).
The limitation in claim 163 of applying the best fitting black box engineering model equates to instructions to “apply” the abstract ideas, which cannot provide an inventive concept (MPEP 2106.05(f)). See above in section Step 2A, Prong 2 for further discussion.
When these additional elements are considered individually and in combination, they do not provide an inventive concept because they equate to mere instructions to apply the abstract idea and are WURC limitations in view of Blanchard, Zhang and Ammer. Therefore, these additional elements do not transform the claimed judicial exception into a patent-eligible application of the judicial exception and do not amount to significantly more than the judicial exception itself (Step 2B: No).
As such, claims 163-170 are not patent eligible.
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.
Claims 163-171 are rejected under 35 U.S.C. 103 as being unpatentable over Blanchard et al. (“Blanchard”; FOR ref. 1 on IDS filed 04/09/2021; WO-2018/063914-A1; previously cited) in view of Nounou et al. (“Nounou”; Applied Soft Computing 7, no. 3 (2007): 711-721; newly cited) and Shafer (US Patent Application ref. 1 on IDS filed 04/09/2021; US-2006/0287678-A1; previously cited).
This rejection is newly recited as necessitated by claim amendment.
The bold and italicized text below are the limitations of the instant claims, and the italicized text serves to map the prior art onto the instant claims.
Claim 163:
sequentially delivering, through an inlet of a fluid chamber via a controller, modulating stimuli to an immune cell;
Blanchard assesses systemic immune response by monitoring changes of biophysical properties of immune cells in response to a gradient of chemoattractant (abstract). A device monitors changes of biophysical properties of immune cells (abstract) [4]. The device comprises a sample reservoir, an elongate channel, and a processing chamber, wherein the elongate channel contains an inlet and outlet [4]. Immune cells are deposited into the sample reservoir, wherein the elongated channel connects via fluid communication the sample reservoir and processing chamber [5]. Immune cells are exposed to a chemoattract housed in the processing chamber [5] [9] [13] [53]. The induced cellular response via doping may be with proinflammatory cytokines [71]. A controller may be used to perform various functions of the device [153]. Any step may be repeated [68], thus doping via proinflammatory cytokine may occur more than once.
after a respective delivered modulating stimuli, detecting in real-time with a detector in fluid communication with the fluid chamber, an inflammatory response of the immune cell to the respective delivered modulating stimuli; after a respective detected inflammatory response, generating with the detector input and/or output data indicative of the respective detected inflammatory response;
Blanchard evaluates in vitro biophysical properties of immune cells by measuring immune response [1]. Upon initiation of a desired cellular response, a program is run on an analyzer to capture dynamic biophysical behavior by using onboard optical equipment, which may include a phase-contrast at 400x total magnification and a camera attachment [74]. The result is a time-lapsed video of cellular movement [74] and analysis of the images is performed in real-time [97]. The captures images are acquired output data [33].
after generating a respective input and/or output data, fitting a black box engineering model to the respective input and output data; after a respective fitting, selecting a best fitting black box engineering model based on the respective input and output data; and
Blanchard shows in Figure 9 a classification model 940 that uses metrics derived during cell imagining 935, such as the biophysical characteristics of each cell, to classify the cell with an inflammatory index [94] [143]. The models are trained/fitted [130] [144].
However, Blanchard does fit a black box engineering model or select a best fitting model.
Nounou improves prediction accuracy and parsimony of auto-regressive with exogenous variable model which decomposes input-output data at multiple scales, constructs an ARX model at each scale, uses cross-validation, and selects among all models a best predicting model (abstract).
It would have been prima facie obvious to have used the ARX model of Nounou for the classification step of Blanchard that produces an inflammatory response. Motivation for doing so is that ARX provides an optimum prediction and maximum noise-feature separation (pg. 712, col. 1, para. 3). There would have been a reasonable expectation of success because the ARX model can use multi-scale time data to make predictions, wherein Blanchard uses multi-scale data of temporal and spatial image tracking of cells [118] [124].
determining from the delivering, detecting, generating, fitting and selecting, a sequence of modulating stimuli that produces a trajectory of immune cell response that matches within a tolerance of a desired trajectory of immune cell response;
Blanchard shows in Figure 9 inducing an immune response, monitoring biophysical characteristics, and classifying an immune cell response using a classification model to produce an inflammatory index, which is indicative of the desired immune cell response that was initiated (delivering, generating, fitting … a trajectory of immune cell response that matches within a tolerance of a desired immune cell response) [72-74] [144].
However, Blanchard does not select a best fitting ARX model. As discussed above, Nounou selects a best fitting ARX model (selecting).
However, Blanchard and Nounou do not determine a sequence of modulating stimuli.
Shafer uses a system to modulate an immune response by stimulating the parasympathetic and/or sympathetic nervous system (abstract) [12]. The system detects whether an immune response has been attenuated or enhanced [9]. After initial stimulation 210 a determination is made as to whether the stimulation resulted in an improvement 220, wherein one or more criterion is used to determine whether am improvement is me, and if not met, then additional stimuli is applied [102] (Figure 11).
It would have been prima facie obvious to have modified the method of Blanchard for inducing a desired immune cell response [74] and generating an inflammatory index indicative of the immune cell response by modulating the immune cell until it reaches the desired immune cell response as taught by Shafer. This would result in a sequence (or number of modulations) needed to achieve the desired immune cell response. Motivation for doing so is taught by Shafer who states that an initial modulation, intended to achieve a desired immune response (i.e. attenuation or enhancement), may not be sufficient, which is why additional stimuli may be needed [102] (Figure 11). One of ordinary skill in the art would have recognized that the same concept applies to Blanchard who also modulates immune cells to achieve a desired immune response and allows for repeated dosing [68] [71].
There would have been a reasonable expectation of success to repeat the steps in Blanchard until reaching a desired immune cell response because Blanchard states that any step in the method can be repeated [68].
wherein the inflammatory response of the immune cell to the respective delivered modulating stimuli is predicted by applying the best fitting black box engineering model to the respective input and output data.
As discussed above in 35 USC 112(b), this limitation is a product by process. Thus, the product of the inflammatory immune response achieved by using chemoattractants in Blanchard reads on this limitation, even though it is not predicted using the process of the instant claim.
Claim 164:
Blanchard determines a desired trajectory [72] [74]. As discussed above in section 35 USC 112(b), the limitations of “provides exogenous … enables predictive … and enables predictive” recites an intended use and is thus not required by the claim.
Claim 165:
As discussed above in claim 163, Nounou discloses the ARX model.
Claim 166:
Blanchard states that the biomimetic cassette includes an onboard container to house cell-suitable media [32].
Claim 167:
Blanchard states that the one or more cells is selected from the group of cells relevant to macroscopic inflammatory behavior, including, natural killer cells, macrophages, B cells, T cells and dendritic cells [23].
Claim 168:
Blanchard discloses cytokines [71].
Claim 169:
Blanchard adheres immune cells to the surface of a chamber via protein-mediated arrest (quiescent state) then chemoattractants are used initiate an immune response [53] [72]. The chemoattractants may be pro-inflammatories (pro-inflammatory state) [71] [79].
Claim 170:
Blanchard monitors changes in biophysical properties of immune cells in response to a chemoattractant (abstract), but does not measure any of the claimed markers.
Shafer determines an attenuation of an inflammatory immune response by measuring a decrease in one or more proinflammatory cytokines such as CD86 (anti-inflammatory) [43].
It would have been prima facie obvious to have modified Blanchard for measuring biophysical characteristics of immune cells during an immune response to track the immune response by measuring mediators of immune response such as CD86 as taught by Shafer. Motivation for doing so is that CD86 indicates immune response attenuation as taught by Shafer [43], which aligns with Blanchard’s motivation for assessing immune response (abstract). There would have been a reasonable expectation of success because the cellular markers of immune response taught in Shafer could be identified with the FACS of Blanchard [164].
Claim 171:
Blanchard monitors changes of biophysical properties of immune cells in response to a chemoattractant (abstract) and an embodiment that uses a fluorescence-activated cell sorter (FACS) [164]. However, Blanchard does not detect fluorescence indicative of inflammatory response and does not increase a stimulus based on output or input data.
Shafer monitors fluorescence of immune response mediators [47]. Shafer recites “Inflammation may be measured in vitro or in vivo by analysis of inflammatory markers in the blood and fluorescence and histological evidence” [47]. Figure 11 shows that if an improvement is not detected that stimulation may be increased [102]. The improvement is determined “by one or more changes in levels of immune mediators, objective changes in symptoms related to the deleterious characteristic, disorder, and/or disease state of an immune response” [102].
It would have been prima facie obvious to have modified Blanchard by measuring fluorescence markers of inflammatory response to then administer a second increased dosage of a chemoattractant/anti-inflammatory if the desired immune response is not achieved with a first dose, as taught by Shafer. Shafer states that this technique enhances an immune response such as an inflammatory response [9] [12], wherein Blanchard is directed toward achieving a proinflammatory state in immune cells [71]. There would have been a reasonable expectation of success because Blanchard discloses that any step of their method may be repeated [68], which includes dosing, and because the modification requires increasing/decreasing a dose of a chemoattractant/anti-inflammatory.
Response to Arguments under 35 USC 103
Applicant's arguments filed 01/26/2026 have been fully considered but they are not persuasive.
Applicant argues Blanchard and Shafer not teach a black box engineering model for predictive control of immune cell inflammatory states (pg. 2, last para. – pg. 3, para. 7). Applicant’s arguments are not persuasive for the following reasons:
Claim 163 does not require delivering a second stimulus based upon a prediction for how an immune cell will respond to the second stimulus. Blanchard in view of Nounou teach fitting and selecting a black box model with inflammatory change input/output data. Blanchard in view of Shafer disclose matching within a tolerance of a desired trajectory as taught in the rejection above.
Applicant’s argument regarding Blanchard and Shafer not disclosing active updating of modulating stimulus, determining a future sequence of immune stimuli, or an engineering-model based feedback control are not persuasive because claim 163 does not recite these limitations (pg. 4, para. 2 – pg. 5, para. 4 of remarks). Additionally, Applicant’s argument regarding hindsight reasoning is noted but is not persuasive because it pertains to the withdrawn rejections of claims 41 and 159 (pg. 5, last para. of remarks).
Applicant’s argument regarding insufficient motivation to combine Blanchard and Shafer are not persuasive because it pertains to an obviousness rational that has been withdrawn in view of claim amendment (pg. 6, para. 1 of remarks).
Applicant’s remarks regarding Koehrsen are acknowledged but are not persuasive because Koehrsen is no longer applied (pg. 6, para. 2 of remarks).
Conclusion
No claims are allowed.
Claims 1-2, 4-7, 13, 15, 21, 35, 39-41, 75, 79-80 and 159-161 are free from the prior art because the prior art does not fairly teach or suggest the following limitations: Claim 1 recites “predicting, using an engineering model, a predicted change in the inflammatory state of the immune cell based on how the immune cell is expected to respond to a subsequent modulating stimulus … each subsequent set of input and/or output data is re-classified as the current set of input and/or output data upon repeating the subsequent cycles.” Claim 41 recites “predict the predicted change”, referring to the claim 1 prediction, as discussed in section 35 USC 112(b). Claim 159 recites “predicting, using an engineering model fitted to the first input and/or output data, a predicted change in the inflammatory state of the immune cell based on how the immune cell is expected to respond to a second modulating stimulus; delivering the second modulating stimulus to the immune cell, wherein the second modulating stimulus is delivered based on the predicted change in the inflammatory sate of the immune cell to produce a trajectory of immune cell response that matches within a tolerance of a desired trajectory of immune cell response.” The closest prior art is Blanchard et al. (FOR ref. 1 on IDS filed 04/09/2021; WO-2018/063914-A1; previously cited).
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/N.A.A./Examiner, Art Unit 1687
/KAITLYN L MINCHELLA/Primary Examiner, Art Unit 1685
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