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 .
Detailed Action
Summary
This is a Final Office action based on the 17/766155 application response filed 02/03/2026.
Claims 1-6 & 8-24 have been elected and fully considered.
Claim 7 is cancelled.
Claims 25-28 are withdrawn.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
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 non-obviousness.
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(s) 1-5, 8-10, 12, 21-23 is/are rejected under 35 U.S.C. 103 as obvious by MUHIE in US 20150051094 in view of ROGGE in US 20180267058.
With respect to Claim 1, MUHIE teaches of a method of detecting immune suppression/dysfunction. The diagnostic biomarkers are genes and/or transcripts that are up or down regulated compared to normal expression when a subject has been stressed either mentally and/or physically (this reads on the claimed, “stimulus,” through broadest reasonable interpretation). The invention also relates to a method of detecting compromised or suppressed immune response in a subject by comparing certain diagnostic biomarkers in the subject to a control set of diagnostic biomarkers (abstract).
More specifically, MUHIE teaches of taking a blood sample and incubating it with Enterotoxin B (SEB) (which is the stimulus) (paragraph 0109, 0004); and
Measuring expression of at least two biomarkers which are from at least two different lists of the claimed lists S1, S2, and S3. Specifically, MUHIE teaches of determining cDNA microarray expression (paragraph 0109), which includes determining the levels of CCL20 (Table 5, paragraph 0058)--- this is on instant “List S1”, CCL8(Table 4)--- this is one instant “List S2,” IL2 (Tables 4 & 5, paragraph 0078)--- this is on instant “List S3,” and CD44 (Table A, 2A and 3A, & 4, paragraph 0061).
Further, in Claim 2 MUHIE teaches of the biomarkers comprising at least 5 or more of the genes: CCR7, IGHG1, CSPG2, LAPTM5, CSF1R, ALB, HLA-C, HLA-DRA (which is in instant lists S 2 & S3), HLA-DPA1, CD14, LOC652128, MGAT1, HCLS1, ANPEP, IL1B, IL1B, SATB1, LCP1, AQP9, HLA-DRB1, NP, AFP, DUSP6, B2M, SCYB5, FCN1, FTH1, HLA-DRB1(which is in instant lists S1, S2, and S3), PPBP, FCGR3A, IGHG1, IGFBP1, WIPF1, MAGEA6, LPXN, CXCL1, GAGE2, CDKN1A, FCGR3A, TTC9, FYN, SERPINB2, CENPF, LIMS1, MDK, AX025098, A2M, CD74, IER3, HLA-B, ACTB, ANXA1, LAIR1, CD44 (which is in instant lists S1, S2, and S3), COL6A1, PRKCH, MAFB, EVI2A, LAT. Therefor this reads on measuring the expression of “at least two different biomarkers selected respectively from at least two different lists from the following lists,” (Claims 1 & 2 of MUHIE indicate expression of these biomarkers are detected).
MUHIE teaches of the sample is a whole blood sample (paragraph 0067, 0098). However, MUHIE does not teach of incubating a whole blood sample before any other processing with a stimulus as instantly amended 02/03/2026.
ROGGE is used to remedy this. ROGGE teaches of methods of predicting and measuring immune responses when exposed to stimuli (abstract). ROGGE more specifically teaches of taking whole blood and putting it in a TruCulture tube in batches with a stimulus and then incubating (paragraph 0089). The stimulus can be and agent that stimulates the innate or adaptive immune response (paragraph 0009, 0013-0015, 0036-0042).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to incubated a whole blood sample with a stimulus as is done in ROGGE in the method of MUHIE due to the advantage the TruCulture assay used by MUHIE has shown as being a highly standardized ex vivo assay that preserves physiological cellular interactions in whole blood and allows for precise measurements of immune parameters, with and without stimulation (ROGGE, paragraph 0008).
With respect to Claims 2-3, MUHIE teaches of measuring expression of at least two biomarkers which are from at least two different lists of the claimed lists S1, S2, and S3. Specifically, MUHIE teaches of determining cDNA microarray expression (paragraph 0109), which includes determining the levels of CCL20 (Table 5, paragraph 0058), CCL8(Table 4), HLA-DMB, HLA-DPA1, and CXCL10 (Claim 2 of MUHIE), and CCL2 (Table 4). This reads on “at least two different biomarkers from at least two different lists,” of the lists S1-1, S1-2, and S3-1, and list S1-2, S2-2, or S3-2.
With respect to Claim 4, MUHIE teaches of measuring expression of at least two biomarkers which are from at least two different lists of the claimed lists S1, S2, and S3. Specifically, MUHIE teaches of determining cDNA microarray expression (paragraph 0109), which includes determining the levels of HLA-DMB, HLA-DPA1, and CXCL10 (Claim 2 of MUHIE), and CCL2 (Table 4). MUHIE also teaches of measuring the levels of INFGR2 and INFGR1(which reads on INFG )(Tables 4 & 5), PTGS2(Table 2), SRC (Table 3B), and TNFA (Table 5). This reads on “at least two different biomarkers from at least two different lists,” of the lists S1-3, S2-3, or S3-3.
With respect to Claim 5, MUHIE teaches of measuring expression of at least three different biomarkers which are from at least three different lists of the claimed lists S1, S2, and S3. Specifically, MUHIE teaches of determining cDNA microarray expression (paragraph 0109), which includes determining the levels of CCL20 (Table 5, paragraph 0058), CCL8(Table 4), IL2 (Tables 4 & 5, paragraph 0078), CD44 (Table A, 2A and 3A, & 4, paragraph 0061).
Further, in Claim 2 of MUHIE they teach of detecting the biomarkers comprising at least 5 or more of the genes: CCR7, IGHG1, CSPG2, LAPTM5, CSF1R, ALB, HLA-C, HLA-DRA (which is in instant lists S 2 & S3), HLA-DPA1, CD14, LOC652128, MGAT1, HCLS1, ANPEP, IL1B, IL1B, SATB1, LCP1, AQP9, HLA-DRB1, NP, AFP, DUSP6, B2M, SCYB5, FCN1, FTH1, HLA-DRB1(which is in instant lists S1, S2, and S3), PPBP, FCGR3A, IGHG1, IGFBP1, WIPF1, MAGEA6, LPXN, CXCL1, GAGE2, CDKN1A, FCGR3A, TTC9, FYN, SERPINB2, CENPF, LIMS1, MDK, AX025098, A2M, CD74, IER3, HLA-B, ACTB, ANXA1, LAIR1, CD44 (which is in instant lists S1, S2, and S3), COL6A1, PRKCH, MAFB, EVI2A, LAT. Therefor this reads on measuring the expression of “at least three different biomarkers selected respectively from at least three different lists from the following lists,” (Claims 1 & 2 of MUHIE indicate expression of these biomarkers are detected).
With respect to Claim 8, MUHIE teaches of the stimulus being Staphylococcal Enterotoxin B (SEB) (which is the stimulus) (paragraph 0109, 0004), which is “a molecule capable of binding at least one type of antigen presenting cells and at least one type of adaptive immunity cell”, which is a T cell (T cell activator) (paragraph 0066).
With respect to Claim 9, MUHIE teaches of the stimulus being Staphylococcal Enterotoxin B (SEB) (which is the stimulus) (paragraph 0109, 0004).
With respect to Claim 10, MUHIE teaches of the stimulus being Staphylococcal Enterotoxin B (SEB) (which is the stimulus) (paragraph 0109, 0004).
With respect to Claim 12, MUHIE teaches of the stimulus being Staphylococcal Enterotoxin B (SEB) (which is the stimulus) (paragraph 0109, 0004), which is a potent T cell activator (T cells are lymphocytes) (paragraph 0066, 0089, 0113).
With respect to Claim 21, MUHIE teaches of measuring by hybridization (paragraph 0099, 0100).
With respect to Claim 22, MUHIE teaches of measuring in respect or comparison to a housekeeping gene (paragraph 0104) and of normalization (paragraph 0046,0049, 0051, 0068, 0106 Table 3 A).
With respect to Claim 23, MUHIE teaches of measuring the same biomarkers in a control sample (abstract, paragraph 0005, 0029). MUHIE specifically teaches of samples exposed to SEB (the stimulus) and the control samples not being exposed to SEB (paragraph 0067).
Claim(s) 6,18-19 & 24 is/are rejected under 35 U.S.C. 103 as obvious over MUHIE in US 20150051094 in view of ROGGE in US 20180267058 in view of RUSSWURM in US 20110098195.
With respect to Claim 6, MUHIE teaches of the claims as shown above for Claim 1. MUHIE teaches of the person being a patient (paragraph 0039, 0094). MUHIE teaches of the sample is a whole blood sample (paragraph 0067, 0098). However, MUHIE does not teach of incubating a whole blood sample before any other processing with a stimulus as instantly amended 02/03/2026.
ROGGE more specifically teaches of taking whole blood and putting it in a TruCulture tube in batches with a stimulus and then incubating (paragraph 0089).
MUHIE and ROGGE do not teach of the patient being a patient being a patient in intensive care or having had surgery or sepsis.
RUSSWURM is used to remedy this and more specifically teaches of a method for the in vitro detection and/or differentiation and/or progress observation of pathophysiological conditions with the aid of sample nucleic acids, including determination of gene activities by means of a plurality of polynucleotides, determination of gene activities of at least one internal reference gene, and formation of an index value from the single determined normalized gene activities of a multigene biomarker indicating the pathophysiological condition (abstract).
Even more specifically, RUSSWURM teaches of the patient having sepsis (paragraphs 0012-0022), and of detecting specific gene biomarkers for the sepsis (Figure 11, Table 7, 10, 11, 15, 20).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to detect markers in a patient who has sepsis as is done in RUSSWURM in the method of MUHIE and ROGGE due to the need in the art to detect biomarkers of sepsis early as successfully fighting a casual infection likelihood of survival (RUSSWURM, paragraph 0004).
With respect to Claim 18, MUHIE teaches of measuring the biomarkers at the mRNA level (paragraph 0018, 0108, Table 3 A & 3B). However, if this is not clear, RUSSWURM is used to remedy this and teaches that when measuring gene expression, the quantity of mRNA is measured (paragraph 0036, 0057, 0066, 0069, 0071, 0109). It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to measure mRNA for the gene expression as is done in RUSSWURM in the method of MUHIE and ROGGE due to the advantage that measuring/quantifying mRNA allows for, in the search for new active agents, to analyze the effects of particular factors on cells, observe the differentiation of precursor cells in various cell types, or track the gene expression in host cells as a response to infections. (RUSSWURM, paragraph 0141).
With respect to Claim 19, MUHIE teaches of measuring the biomarkers at the mRNA level (paragraph 0021, 0044, 0071) and also of measuring through real time PCR (paragraphs 0011-0012, 0036, 0052, 0054). However, if this is not clear, RUSSWURM is used to remedy this.
RUSSWURM further teaches of measuring through real time PCR (RT-PCR) (paragraph 0141, 0224-0227, 0338, 0405, Example 5). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to use real-time PCR as is done in RUSSWURM in the method of MUHIE and ROGGE due to the advantage real-time PCR offers with returning results on the same day (RUSSWURM, paragraph 0141).
With respect to Claim 24, MUHIE teaches of comparing ratios (paragraph 0095), but does not teach of comparison of ratios of expression.
RUSSWURM is used to remedy this and teaches that the expression data includes ratios of the expression values (paragraph 0382). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to calculate ratio of expression values as is done in RUSSWURM in the method of MUHIE and ROGGE due to the advantage that this ratio value gives for indicating fold change and by what factor the transcript in one sample was expressed differently than in the other sample (RUSSWURM, paragraph 0382).
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as obvious over MUHIE in US 20150051094 in view of ROGGE in US 20180267058 in view of SCHETTINI in US 20150301058.
With respect to Claim 11, MUHIE teaches of the stimulus being Staphylococcal Enterotoxin B (SEB) (which is the stimulus) (paragraph 0109, 0004). Staphylococcal Enterotoxin B (SEB) is a superantigen, so reads on “analogous to a superantigen.” Staphylococcal Enterotoxin B (SEB) however is not a bispecific antibody.
MUHIE teaches of the sample is a whole blood sample (paragraph 0067, 0098). However, MUHIE does not teach of incubating a whole blood sample before any other processing with a stimulus as instantly amended 02/03/2026.
ROGGE teaches of methods of predicting and measuring immune responses when exposed to stimuli (abstract). ROGGE more specifically teaches of taking whole blood and putting it in a TruCulture tube in batches with a stimulus and then incubating (paragraph 0089).
MUHIE and ROGGE do not teach of using a bispecific antibody.
SCHETTINI is used to remedy this. SCHETTINI teaches of a method in which biomarkers are assessed for candidate treatments (abstract) and further teaches that one of the candidate treatments or stimulus can be bispecific antibodies (paragraph 0212, 0211).
It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to use bispecific antibodies as is done in SCHETTINI in the method of MUHIE and ROGGE due to the advantage these bispecific antibodies have for binding preferentially to two (bi) parts instead of one (SCHETTINI, paragraph 0212).
Claim(s) 13-17, & 20, is/are rejected under 35 U.S.C. 103 as obvious over MUHIE in US 20150051094 in view of ROGGE in US 20180267058 in view of BORGLUM in US 20090297563.
With respect to Claim 13, MUHIE teaches of the claims as shown above but it does not teach of the antibodies activating the T-cells.
MUHIE teaches of the sample is a whole blood sample (paragraph 0067, 0098).
ROGGE teaches of methods of predicting and measuring immune responses when exposed to stimuli (abstract). ROGGE more specifically teaches of taking whole blood and putting it in a TruCulture tube in batches with a stimulus and then incubating (paragraph 0089). The stimulus can be and agent that stimulates the innate or adaptive immune response (paragraph 0009, 0013-0015, 0036-0042).
However, MUHIE and ROGGE do not teach of incubating a whole blood sample before any other processing with a stimulus as instantly amended 02/03/2026.
BORGLUM is used to reedy this and teaches of binding antibodies to activate T cells (paragraph 0007, 0022, 0054). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant invention to activate the T cells as is done in BORGLUM in the method of MUHIE and ROGGE due to the advantage this offers in triggering signals (BORGLUM, paragraph 0022).
With respect to Claim 14, MUHIE teaches of the claims as shown above but do not teach of the stimulus being anti-CD3 antibody.
BORGLUM is used to remedy this and teaches of stimulating with anti-CD3 and measuring responses (paragraph 0027). It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to stimulate with anti-CD3 as is done in BORGLUM in the method of MUHIE and ROGGE due to the advantage this has in further investigating TH1, HRH1 and HRH2 cells activation (BORGLUM, paragraph 0027).
With respect to Claim 15, MUHIE teaches of the claims as shown above but do not teach of the stimulus being imidazoquinoline. BORGLUM is used to remedy this and more specifically teach of using imidazoquinoline as an activator/stimulator of immune cells (paragraph 0035). It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to stimulate with imidazoquinoline as is done in BORGLUM in the method of MUHIE and ROGGE due to the advantage is has a being a potent activator/stimulator of immune cells (BORGLUM, paragraph 0035).
With respect to Claim 16, MUHIE teaches of the claims as shown above but do not teach of the stimulus being resquimod. BORGLUM is used to remedy this and more specifically teach of using resquimod as an activator/stimulator of immune cells (paragraph 0035). It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to stimulate with resquimod as is done in BORGLUM in the method of MUHIE and ROGGE due to the advantage is has a being a potent activator/stimulator of immune cells (BORGLUM, paragraph 0035).
With respect to Claim 17, MUHIE teaches of the stimulus being Staphylococcal Enterotoxin B (SEB) (which is the stimulus) (paragraph 0109, 0004). MUHIE does not teach that the stimulator is for therapeutic purposes.
BORGLUM is used to remedy this and more specifically teach of using resquimod and imidazoquinoline as an activator/stimulator of immune cells (paragraph 0035). It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to stimulate with resquimod as is done in BORGLUM in the method of MUHIE and ROGGE due to the advantage is has a being a potent activator/stimulator of immune cells (BORGLUM, paragraph 0035).
With respect to Claim 20, MUHIE teaches of the claims as shown above, but do not teach of measuring the biomarkers by sequencing.
BORGLUM is used to remedy this and more specifically teach of measuring biomarkers by sequencing (paragraph 0261). It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the instant invention to measure the biomarkers by sequencing as is done in BORGLUM in the method of MUHIE and ROGGE due to the advantages this offers for identifying polymorphism or mutated residues (BORGLUM, paragraph 0261).
Response to Arguments
Applicant's arguments filed 02/03/2026 have been fully considered but they are not persuasive.
It is noted that the inserted of information in prior instant Claim 7 into instant Claim 1 in amendments dated 02/02/2026, changes the scope of the instant claims to something which was not required in the previous set of claims. Notably, in the prior Claim set, in Claim 7, it was only required that the blood sample was, at some point a whole blood sample and not that, as instantly claimed--- the whole blood sample itself is incubated with a stimulus.
Therefore, a new reference, ROGGE in US 20180267058 is used to teach of the new claim limitation. Applicant argues that the other references used, do not teach of the claimed incubation with a stimulus and whole blood sample. Again, this is why the new reference ROGGE is used.
Applicant argues that the MUHIE reference teaches away from using whole blood samples and incubation of stimulus with it, simply because MUHIE does not teach of this limitation. The examiner disagrees with this and notes that the ROGGE reference teaches why one would want to use a whole blood sample in that it maintains normal physiological conditions (ROGGE, paragraph 0008). This IS an advantage for analysis and would be an improvement on MUHIE as are the teachings of RUSSWURM, SCHETTINI, and BORGLUM, in contrast to what applicant argues to the opposite effect.
Applicant argues that the RUSSWURM, SCHETTINI, and BORGLUM references, since they drawn towards a slight different purpose that MUHIE, would require “altering the principle of operation of both MUHIE,” and the other references. Applicant gives no further detail or support of this other than making this statement. The examiner disagrees with applicant.
In response to applicant's argument, the examiner notes that, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
As shown above, from the combination of the references used--- the references would have suggested the instantly claimed invention as obvious to one of ordinary skill.
In response to applicant's argument that that RUSSWURM, SCHETTINI, and BORGLUM are nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, RUSSWURM, SCHETTINI, and BORGLUM are reasonably pertinent to the problem which the inventor was concerned, even if they are not directed to exactly the same purpose as one another. This is further especially true with as broad the instant claims are written in that the method is “for determining individual ability to respond to a stimulus,” wherein both the claimed stimulus and individual can be practically anything.
All claims remain rejected.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to REBECCA M FRITCHMAN whose telephone number is (303)297-4344. The examiner can normally be reached 9:30-4:30 MT Monday-Friday.
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/REBECCA M FRITCHMAN/Primary Examiner, Art Unit 1758