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’s election without traverse of Group 1, claims 1-22 and species election A. Assay type: ELISpot (claim 1), B. Cell Type: both, T cell and monocyte (claim 1), C. Patient Group: Sepsis (claim 20), D Innate cell type: Monocyte (claim 4), E. Parameter determined: Cell function, F. Cytokine: Combination of IFNγ and TNFα (claim 7), G. Immune status: Effect of immune therapy to restore innate immunity in an immunosuppressed patient (claim 13), and H. Endotype: Subject has sepsis and immunosuppressive endotype (claim 17), in the reply filed on 09/04/2025 is acknowledged.
Claims 23-40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Priority
The present application was filed 09/20/2021 and claims benefit under 35 U.S.C. 119(e) to provisional applications No. 63/232,273, filed 08/12/2021 and 63/080,774, filed 09/20/2020.
Information Disclosure Statement
The information disclosure statement (IDS), filed 11/14/2022, has been considered, initialed and is attached hereto.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Objections
Claims 2, 9, and 16 are objected to because of the following informalities:
There appear to be a typographical errors.
Regarding claim 2, lines 2 and 5 both start with the letter “d.”. It is suggested to replace “d.” and “d.” with ---d.--- and ---e.---, respectively.
Regarding claim 9, the claim recites “an amount of cytokine produced on a cell”. This appears to be a typographical error.
The instant specification recites “an amount of proinflammatory cytokine produced per cell” (page 5, lines 29-30), “the amount of cytokine produced on a per cell basis” (page 64, lines 4-5 and page 87, lines 17-18), language which aligns with the method of the ELISpot assay of detecting cytokines secreted by a cell into the supernatant and captured by antibodies bound to the ELISpot assay plate (see rejection under 35 U.S.C. 102 below). There is only one instance of “detecting an amount of cytokine produced on a cell” (page 5, line 7 of the instant specification).
It is suggested to amend the claim to ---an amount of cytokine produced per cell---.
Regarding claim 16, the claim recites “an amount of proinflammatory cytokine produced per cell […] are decreased” (in lines 5-6). It is suggested to replace “are” with ---is---.
Appropriate correction is required.
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 1-22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a law of nature/natural phenomena and to abstract ideas without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to”, we
look to whether the claim recites:
any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (2) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “’inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent -eligible application of the judicial exception. Alice, 573, U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
adds a specific limitation beyond the judicial exception that is no “well-understood, routine, conventional: in the field (see MPEP § 2106.05(d)); or
simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, prong 1
Regarding claim 1, the claim is directed to the natural correlation between an immune phenotype of a subject and the quantity of cytokines associated with cellular immunity. Claim 2 recites “determining that a subject has an immunosuppressive endotype if […] cytokine production or secretion is decreased compared to a control; or […] determining that a subject has a hyper-inflammatory endotype if […] the proinflammatory cytokine production or secretion is increased”; claim 3 recites “determining if the subject has immunosuppressive endotype if immune cells amount is reduced”; claim 4 recites “detecting a level of innate immunity comprising detecting a level of blood monocytes”; claim 5 recites “detecting a level of adaptive cellular immunity comprising detecting a level of blood lymphocytes”; claim 6 recites “wherein the subject has an immunosuppressive endotype if an amount of CD4+ and CD8+ cells is reduced compared to a control, has reduced responsiveness of the T cells”; claim 13 recites “evaluating an effect of an immune therapy” and “identifying optimal immune therapy”; claim 16 recites “the subject is septic and is determined to be at risk for premature death if: an amount of proinflammatory cytokine producing immune effector cells are decreased” and “proinflammatory cytokine produced per cell […] are decreased”; claim 19 recites “administering a drug to a subject in need thereof and determining immune function […] during a course of immune therapy”.
The natural relationship to which the claims are directed, i.e. between an immune phenotype, immune endotype, or sepsis and cytokine production or number of immune cells, is a law of nature. Similar concepts have been held by the courts to constitute law of nature/ natural phenomena, as in the identification of a correlation between the presence of MPO in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those as in Cleveland Clinic Foundation, as they involve a relationship itself [which] exists in principle apart from any human action, namely the relationship between the release of cytokines or number of immune cells and the immune phenotype.
Furthermore, the claimed steps of determining the immunological endotype of a subject based on the comparison to a control (such as “determining” in claims 2 and 3; “compared to” in claim 6; “evaluating” and “identifying” in claim 13) may also be categorized as an abstract idea, namely a mental process/concept performed in the human mind (such as a practitioner simply observing the results and thinking about the quantified amount relative to the control value, and making an evaluation, judgement, or opinion (See MPEP 2106). The claims, under broadest reasonable interpretation, cover performance of these steps solely within the human mind.
Step 2A Prong2
The above discussed steps of determining, comparing, evaluating, and identifying are steps insufficient to constitute a practical application. In this case, detecting the endotype and comparing it to a control represent judicial exceptions and not a practical application thereof.
The limitations that are recited in addition to the judicial exceptions include the steps of “providing or having been provided a biological sample […], stimulating a T cell or monocyte cell or both to secrete a cytokine […] and quantitating at least one cytokine […] using ELISpot assay” (claim 1), “detecting a level of blood monocytes […] or detecting a level of monocyte function” (claim 4), “detecting a level of blood lymphocytes or blood lymphocytes function” (claim 5), “detecting an amount of cytokine-producing immune effector cells; or detecting an amount of cytokine produced on a cell” (claim 9), “measuring ex vivo cytokine production” (claim 15), “administering a drug to a subject in need thereof and determining immune function or leukocyte function of the subject in response to the drug” (claim 18), “the biological sample is placed in fluid contact with a test therapeutic agent” (claim 21), and “the assay comprises a well pre-coated with a treatment directed at detecting one or more cytokines or chemokines” (claim 22). Such steps of providing a sample, stimulating cells, and measuring a cytokine or cell function or number, administering a drug and determining the immune function in response are insufficient to integrate the judicial exception(s) because the purpose is merely to obtain data. This does not go beyond insignificant presolution activity, i.e. mere data gathering steps necessary for the judicial exception, similar to the fact pattern in In re Grams, 888 F.2d 835 (Ded.Cir. 1989) and Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015). Furthermore, the steps directed at measuring enzymatic activity and/or platelet levels are recited at a high level of generality and not tied to any particular machine or apparatus. See also MPEP 2106.4(a)(2). The limitations of claims 7 and 8 do not add an active step but rather merely limit the type of cytokine measured and claims 11 and 12 limit the sample type. Claim 10 describes the units measured which is also not an active step of the method.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN “INVENTIVE CONCEPT”
Regarding the additional elements of the claims, including the “quantitating at least one cytokine associated with cellular immunity using ELISpot assay […] in the biological sample”, these limitations also do not add significantly more to the judicial exception(s). The step of quantitating the cytokine is well known, routine and conventional. See applicant’s originally filed specification at page 56, where Applicant acknowledges the routine and conventional nature of the methods, reciting that ELISpot quantitation of IFNγ and TNFα was performed by “ELISpot analysis, as per the manufacturer’s instruction […] and as previously described (38, 39)”. The references number 38 and 39 refer to Mazer et al. IL-10 has differential effects on the innate and adaptive immune systems of septic patients. Journal of Immunology. 2019 Oct 15;203(8):2088-99; epub 09/09/2020; of record: IDS 11/14/2022; as cited in more detail below under 35 U.S.C. 102 and 103) and Thampy et al. (Restoration of T Cell function in multi-drug resistant bacterial sepsis after interleukin-7, anti-PD-L1, and OX-40 administration. PLoS One. 2018 Jun 26;13(6):e0199497; of record: IDS 11/14/2022). Mazer teaches ELISpot quantitation of T cell IFNγ and monocyte TNFα producing cells (Mazer, page 2089, ‘Materials and Methods’, see title ‘Mazer teaches ELISpot quantitation of T cell IFNγ and monocyte TNFα producing cells’). Mazer further teaches placing a sample into ELISpot culture plates and culturing the sample with the cytokine human rIL-10 (Mazer, page 2089, ‘PBMC culture conditions’, lines 12-14) and Thampy similarly teaches ELISpot quantitation of T cell IFNγ function (Thampy, page 4 of 19, line 4). Thampy further teaches culturing the cells with IL-7, anti-PD-L1, and OX-40 ligand (Thampy, page 4 of 19, ‘ELISpot quantitation of T cell IFN-γ production’, 2nd paragraph, lines 1-3). Jones et al. (Prolonged disturbances of in vitro cytokine production in patients with severe acute respiratory syndrome (SARS) treated with ribavirin and steroids. Clinical & Experimental Immunology. 2004 Mar;135(3):467-73) also teaches detecting cytokines such as IFNγ and TNFα in patient samples by ELISpot (Jones, page 468, ‘Cytokine ELISPOTS’, lines 1-10). As such, the method of quantitating cytokine secretion by immune cells by ELISpot was well known, routine and conventional activity previously performed by those of skill in the art. It is not the case that the active steps recited, which are performed in order to gather the data or perform the assay, are steps recited or performed in an unconventional or non-routine way, such as to provide an inventive concept under step 2B.
The claimed limitations as currently presented fail to recite limitations that add a feature that is more than well understood, conventional or routine in the field of diagnostics and biochemical assay methodologies.
For all of these reasons, the claims fail to include additional elements that are sufficient to either integrate the judicial exception(s) into practical application(s) thereof, or amount to significantly more than judicial exceptions(s).
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-9, 11, 13-15 and 18-22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by to Mazer et al. IL-10 has differential effects on the innate and adaptive immune systems of septic patients. Journal of Immunology. 2019 Oct 15;203(8):2088-99; epub 09/09/2020; of record: IDS 11/14/2022.
Regarding claim 1, Mazer teaches using serial ELISpot assays as a measure of immune phenotype (Mazer, page 2098, 3rd paragraph, lines 25-26). Mazer further teaches using samples from septic patients (Mazer, page 2089, 2nd paragraph, line 11), stimulating cells for IFNγ analysis with anti-CD3 and anti-CD28 antibody, as well as cells for TNFα analysis with LPS, whereas anti-CD3 with anti-CD28 and LPS were used as positive controls to evaluate the function of T cells and monocytes, respectively (Mazer, page 2089, ‘PBMC culture conditions’, lines 4-8). Mazer further teaches quantitating the number of IFNγ producing T cells and TNFα producing monocytes, as well as the amount of cytokine produced by each cell by enzyme by ELISpot assay. Mazer teaches that the number of spots in a well indicate individual cells that are producing and secreting a cytokine and the spot size indicates the magnitude of the secretory response (Mazer, page 2089, ‘ELISpot quantitation of T cell IFNγ- and monocyte TNFα producing cells’, lines 1-3 and page 2090, lines 2-5).
Regarding claims 2 and 3, Mazer teaches that sepsis manifests by an initial hyperinflammatory phase comprising systemic circulation of proinflammatory cytokines and chemokines such as TNFα, IL-1β, IL-6, IL-8, and CXCL1 and if sepsis persist, patients develop a phase of immunosuppression characterized by lymphocyte apoptosis and immune cell anergy (Mazer, page 2088, lines 5-12). As such, Mazer teaches that a patient has a hyper-inflammatory endotype (subtype of a health condition) defined by increased expression of, for example, TNFα. Mazer further teaches comparing septic patients with nonseptic critically ill patients and healthy volunteers (Mazer, page 2089, ‘Study design’, lines 1-3) and compares IFNγ and TNFα baseline function by ELISpot in the three patient groups (Mazer, page 2092,see figure 1). Put another way, Mazer teaches a method of determining immune cell associated inflammatory cytokine levels which can be used to determine a hyperinflammatory endotype in sepsis.
Regarding claim 4, Mazer teaches the use of the ELISpot method to show decreased monocyte function by decreasing the number of TNFα producing cells by ex vivo addition of IL-10 (Mazer, page 2092, lines 4-6). Mazer teaches measuring the monocyte function with and without the ex vivo addition of IL-10 (Mazer, page 2096, see Figure 5 A). Mazer further teaches that an immunosuppressive effect on innate immunity is shown via decreased TNFα expression by monocytes (Mazer, page 2093, ‘Discussion’, lines 1-3). Mazer teaches collecting blood samples for immune functional testing (Mazer, page 2089, ‘Study design’, 2nd paragraph, lines 3-4). As such Mazer teaches detecting a level of blood monocyte function.
Regarding claim 5, Mazer teaches examining adaptive immunity in effector cells from patients with sepsis and determined IFNγ production by T cells (Mazer, page 2089, 2nd paragraph, lines 7-13). Mazer teaches collecting blood samples for immune functional testing (Mazer, page 2089, ‘Study design’, 2nd paragraph, lines 3-4). Mazer teaches collecting blood samples for immune functional testing (Mazer, page 2089, ‘Study design’, 2nd paragraph, lines 3-4). As such Mazer teaches detecting a level of blood lymphocyte function.
Regarding claim 6, Mazer teaches that sepsis frequently manifests by an initial hyperinflammatory phase typified by fever, shock and respiratory failure which is mediated by specific proinflammatory cytokines such as TNFα, IL-1β, IL-6, IL-8, and CXCL1 and that if sepsis persists, patients develop a phase of immunosuppression characterized by lymphocyte apoptosis and immune cell anergy (immunosuppressive endotype; Mazer, page 2088, lines 6-12). Mazer further teaches stimulating cells for IFNγ analysis with anti-CD3 and anti-CD28 antibody, to evaluate the function of T cells (Mazer, page 2089, ‘PBMC culture conditions’, lines 4-8). Mazer further teaches that the number of IFNγ producing cells was 3-fold greater in healthy controls compared with septic patients after overnight stimulation with αCD3/αCD28 to activate T cells (Mazer, page 2090, ‘IFNγ production is reduced in septic and CINS patients compared with healthy controls’, lines 1-6). Put another way, Mazer teaches that subjects in an immunosuppressive phenotype, are characterized by a reduction in the amount of responsive T cells (both CD4 and CD8) compared to healthy controls.
Regarding claims 7-9, Mazer teaches quantitating the number of IFNγ producing T cells and TNFα producing monocytes, as well as the amount of cytokine produced by each cell by enzyme by ELISpot assay. Mazer teaches that the number of spots in a well indicate individual cells that are producing and secreting a cytokine and the spot size indicates the magnitude of the secretory response (Mazer, page 2089, ‘ELISpot quantitation of T cell IFNγ- and monocyte TNFα producing cells’, lines 1-3 and page 2090, lines 2-5). As such, Mazer teaches quantitating proinflammatory cytokines, including IFNγ and TNFα, that are associated with cellular immunity by detecting the amount cytokine producing cells and the amount of cytokines produced by a cell.
Regarding claim 11, Mazer teaches plating peripheral blood mononuclear cells (Mazer, page 2089, ‘PBMC culture conditions’, line 1) and further teaches quantitating the number of IFNγ producing T cells and TNFα producing monocytes in the sample (Mazer, page 2089, ‘ELISpot quantitation of T cell IFNγ- and monocyte TNFα producing cells’, lines 1-3 and page 2090, lines 1-2). As such Mazer teaches a sample comprising T cells or monocytes or both.
Regarding claim 13, Mazer teaches that IL-10 inhibition has a positive effect on the stimulation of both the innate and adaptive immune systems in patients with sepsis and that addition of IL-10 in patients with sepsis also has a positive effect on the activation of the adaptive immune system and that addition of IL-10 to patients with sepsis diminishes the activity of the innate immune system. Mazer further teaches that in the future IL-10 could be applied to divergent sepsis hyper- and hypoinflammatory states, which could be assessed and evaluated through serial ELISpot assays to measure the immune phenotype and response to therapy (Mazer, page 2098, see entire 3rd paragraph).
Regarding claim 14, Mazer teaches using samples from septic patients (Mazer, page 2089, 2nd paragraph, line 11).
Regarding claim 15, Mazer teaches stimulating cells for IFNγ analysis with anti-CD3 and anti-CD28 antibody, as well as cells for TNFα analysis with LPS, whereas anti-CD3 with anti-CD28 and LPS were used as positive controls for external stimuli in order to evaluate the function of T cells and monocytes, respectively (Mazer, page 2089, ‘PBMC culture conditions’, lines 4-8).
Regarding claims 18-19, Mazer teaches that in the future IL-10 could be applied to divergent sepsis hyper- and hypoinflammatory states, which could be assessed and evaluated through serial ELISpot assays to measure the immune phenotype and response to therapy (Mazer, page 2098, see entire 3rd paragraph).
Regarding claim 20, Mazer teaches using samples from septic patients (Mazer, page 2089, 2nd paragraph, line 11).
Regarding claim 21, Mazer teaches measuring the monocyte function with and without the ex vivo addition of IL-10 (Mazer, page 2096, see Figure 5 A).
Regarding claim 22, Mazer teaches that capture antibody recoated 96-well strip plates were used for single-color enzymatic assay (Mazer, page 2089, ‘ELISpot quantitation of T cell IFNγ- and monocyte TNFα producing cells’, lines 4-6).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or 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.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Mazer et al. as applied to claim 1 above.
Regarding claim 10, Mazer teaches a method of immune phenotyping a subject by quantitating at least one cytokine associated with cellular immunity using ELISpot assay substantially as claimed.
Mazer fails to teach quantitating cytokines in units of response per volume of blood.
Mazer teaches that sepsis manifests by an initial hyperinflammatory phase comprising systemic circulation of proinflammatory cytokines and chemokines such as TNFα, IL-1β, IL-6, IL-8, and CXCL1 and if sepsis persist, patients develop a phase of immunosuppression characterized by lymphocyte apoptosis and immune cell anergy. Mazer further teaches that during the immunosuppressive phase, patients are particularly vulnerable to hospital-acquired secondary infections (Mazer, page 2088, lines 5-14). Mazer further teaches that in the future IL-10 could be applied to divergent sepsis hyper- and hypoinflammatory states, which could be assessed and evaluated through serial ELISpot assays to measure the immune phenotype and response to therapy (Mazer, page 2098, see entire 3rd paragraph).
It would have been prima facie obvious to one having ordinary skill in the art at the time of the effective filing date of the claimed invention to have measured the quantitated cytokines associated with cellular immunity in units of response per volume blood because of the teaching of Mazer that the later phase of sepsis results in lymphocyte apoptosis and immune cell anergy and reporting total cell number per unit blood allows to measure loss of cell number due to sepsis induced apoptosis and loss of lymphocyte activity due to anergy per unit blood in a patient. One of ordinary skill in the art would be motivated to do so because in order to observe cell loss and anergy in a patient over time or in response to therapy.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Mazer et al. as applied to claim 1 above and further in view of Ghobrial et al., WO2016191289A2.
Regarding claim 12, Mazer teaches a method of immune phenotyping a subject by quantitating at least one cytokine associated with cellular immunity using ELISpot assay substantially as claimed.
Mazer fails to teach quantitating cytokines in a sample, wherein the biological sample does not comprise isolated peripheral blood mononuclear cells.
Ghobrial teaches a method of treatment of a subject having an inflammatory disorder comprising determining the level of one or more biomarkers in a biological sample from the subject, the biomarkers comprising TNFα (Ghobrial, page 4, paragraph [0008], lines 1-6). Ghobrial further teaches that the level of biomarkers in a sample may be measured and the level determined by a variety of techniques including ELISPOT (Ghobrial, page 4-5, see entire paragraph [0009]). Ghobrial further teaches that in some aspects the biological sample is whole blood or serum (Ghobrial, page 5, paragraph [0010], lines 8-9). Ghobrial teaches that in one embodiment the fluid sample obtained from the patient may be whole blood or components thereof, including plasma, serum, and blood cells, such as red blood cells, white blood cells, and platelets (Ghobrial, page 37, paragraph [0087], lines 5-8).
It would have been prima facie obvious to one having ordinary skill in the art before of the effective filing date of the claimed invention, to have modified the method of Mazer to evaluate TNFα by ELISpot in a sample that does not comprise isolated peripheral blood lymphocytes, such as whole blood as taught by Ghobrial as a matter of a simple substitution of one art recognized sample over another. Both Mazer and Ghobrial teach the detection of biomarkers such as TNFα by ELISpot. Further, at the time the prior art recognized the ability of detecting TNFα by ELISpot in various sample types such as whole blood or components thereof, including blood cells such as red blood cells, white blood cells, and platelets (see Ghobrial). As such it would have been obvious to apply the ELISpot method of Mazer to detect biomarkers such as TNFα in whole blood as taught by Ghobrial as one of ordinary skill in the art would appreciate that one sample type is usable in place of the other. The results would have been predictable, namely in that both sample types would be expected to be suitable for detecting biomarkers. One having ordinary skill in the art would have recognized that applying the known sample type (whole blood) of Ghobrial would have predictably resulted in the detection of biomarkers by ELISpot and as a result, one would have had a reasonable expectation of success.
Claims 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Mazer et al. as applied to claims 1 and 2 and further in view of Yende et al. Long-term host immune response trajectories among hospitalized patients with sepsis. JAMA network open. 2019 Aug 7;2(8):e198686, 15 pages.
Regarding claims 16 and 17, Mazer teaches a method of immune phenotyping a subject by quantitating at least one cytokine associated with cellular immunity using ELISpot assay substantially as claimed.
As discussed previously in detail in the rejection of claim 2 above, Mazer teaches that sepsis manifests by an initial hyperinflammatory phase comprising systemic circulation of proinflammatory cytokines and chemokines and if sepsis persist, patients develop a phase of immunosuppression (Mazer, page 2088, lines 5-12).
Yende teaches that compared to normal phenotype, those sepsis patients with hyperinflammation and immunosuppression phenotype had a higher mortality rate (Yende, page 1 of 15, ‘Results’, lines 13-14). Yende further teaches that persistent elevation of inflammation and immunosuppression biomarkers occurred in two-thirds of patients who survived a hospitalization for sepsis and was associated with worse long-term outcomes (Yende, page 2 of 15, see ‘Conclusions and Relevance’).
It would have been prima facie obvious to one having ordinary skills in the art before of the effective filing date of the claimed invention, to have applied the method of Mazer of determining an amount of proinflammatory cytokine producing effector cells or an amount of cytokine produced per effector cells that are decreased and are therefore considered immunosuppressed (see Mazer) in order to identify patients with a higher mortality rate. The ordinary artisan would be motivated to do so because of the teaching of Yende that persistent elevation of inflammation and immunosuppression biomarkers occurred in two-thirds of patients who survived a hospitalization for sepsis and is associated with worse long term outcomes.
One of ordinary skill in the art would have a reasonable expectation of success using the method of Mazer to predict if a subject is at risk for death because Yende teaches that persistent change in biomarkers identify sepsis patients at higher risk for death and Mazer teaches measuring biomarkers in sepsis patients.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEFANIE J KIRWIN whose telephone number is (571)272-6574. The examiner can normally be reached Monday - Friday 7.30 - 4 pm.
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/STEFANIE J. KIRWIN/Examiner, Art Unit 1677
/ELLEN J MARCSISIN/Primary Examiner, Art Unit 1677