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 .
Application Status
Amended claims were filed on 3/30/2026, such that claims 1, and 4-14 are under examination in this Office action. Claims 2-3 and 15 were cancelled. Claim 14 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected group.
In response to the restriction mailed on 6/27/2025, which is still deemed proper, Applicant elected Group I (claims 1-13), and the following species: for claim 4 “within 15 days from immuno-inflammatory attack”, for claim 7, IL10, and for claim 8, “mRNA level”. The elected species will be used for search purposes.
Any rejection or objection not reiterated herein has been overcome by amendment.
Applicant’s amendments and arguments have been thoroughly reviewed but are not persuasive to place the claims in condition for allowance for reasons that follow.
Claim Rejections - 35 USC § 112
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.
Claim 4 is 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.
Claim 4 persists in being unclear and indefinite regarding what the immuno-inflammatory attack references and thus how to establish metes and bounds of the claim. There is no definition in the specification for immuno-inflammatory attack.
Claim 4 is also unclear regarding the risk of “healthcare associated infection”, and whether this is intended to be different from the nosocomial infection acquired in claim 1, or whether it is the same nosocomial infection addressed in claim 1.
Claim Rejections - 35 USC § 112
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 1 and 4-13 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a NEW MATTER rejection.
MPEP 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112a, as lacking adequate written description". According to MPEP § 2163.I.B, "While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure" and "The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117".
In the instantly rejected claims, the new limitation of "according to a predefined decision criterion" in claim 1 appears to represent new matter. No specific basis for this limitation was identified in the specification, nor did a review of the specification by the examiner find any basis for the limitation. Since no basis has been identified, the claims are rejected as incorporating new matter.
Regarding claims 4-13, these claims are additionally rejected for depending from claim 1 and therefore incorporating the new matter recited in claim 1.
Response to Arguments
In Applicant’s Response of 3/30/2026, Remarks indicate that support for amendments is found in [0006],[0007],[0010],[0011], and [0022]-[0024]. Further, In discussion of claim 1, support is said to be found in [0006]-[0011] and [0022]-[0024]. These cited paragraphs were considered, but support was not found for the phrase “according to a predefined decision criterion”.
35 U.S.C. § 112(a): Maintained and modified in view of amendment
Claims 1, 4-13 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 entire scope of the claimed invention.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Nature of the Invention:
The invention is broadly directed to detection of nosocomial infection through gene
expression measurement use.
Claim 1 recites, “An in vitro or ex vivo method for determining the risk of occurrence of a nosocomial, infection in a patient within an emergency unit a resuscitation unit, an intensive care unit or ongoing care unit, comprising (a step of) i) measuring the expression of CX3CR1, in a biological sample from said patient, and ii), determining said risk by comparing the measured expression to at least one reference value according to predefined decision criterion.”
Focusing on the phrases in bold and amendments, it is therefore expected that the instant application will provide sufficient disclosure of a method that determines the risk of occurrence of any type of (e.g. bacterial, fungal, viral) of (any) nosocomial infection in any patient in any unit by measuring CX3CR1 expression.
State of the art:
The state of the art suggests that the regulation of CX3CR1 expression was highly complex and influenced by a wide array of possible causes not related to infections broadly or nosocomial infections specifically. For example, Guglielmotti (WO 2009/109613) teaches that “the pathologies associated with the expression of CX3CR1 are rheumatoid arthritis, lupus nephritis, diabetic nephropathy, Crohn's disease, ulcerative colitis, coronary disorders, restenosis, atherosclerosis, myocardial infarction, angina, and complications following surgical interventions such as, for example, angioplasty, arterectomy and circulation recovery techniques” (see page 14, lines 4-9). Accordingly, it would have been unpredictable for one of ordinary skill in the art to determine the risk of a nosocomial infection, specifically, given the complexity regarding the regulation of CX3CR1 expression.
Kashianath (Kashianath, M., et al., Nosocomial infections in patients admitted in intensive care unit of a tertiary health center, India, 2014, Annals of Medical and Health Sci Research, 4, 738-741) indicated that rate of nosocomial infection varied in the intensive care unit varied by multiple factors which included type of infection acquired (and patient age, sex), with infection most significantly associated with invasive devices (Pg 738, Abstract Table 3). Infection rate varied in ICU by procedure and body system (34% of nosocomial infections were urinary tract infections, 22% pneumonia, 17% surgical site, 13% blood stream) where nosocomial infections result from many infectious agents, here including A. baumannii, E. coli, K. pneumoniae, P. aeruginosa, S. aureus, with A. baumannii being the only singular species indicated as being found in all types of infection (e.g. UTIs, pneumonia, blood stream/meningitis).
Hota (Hota, B., Contamination disinfection and cross colonization: are hospital surfaces reservoirs for nosocomial infections? 2004, Healthcare Epidemiology 39: 1182 -1187) points to unpredictability in our understanding of nosocomial infection transmission, with unknowns related to how common fungal infections are transferred (Pg 1884, right col, para 2; Table 1). Nosocomial infective species also demonstrate different patterns, with Aspergillus and Zygomycetes surface-borne nosocomial infections associated particularly with IV catheters, bandages and post-operative wounds (Pg 1884, right col para 3), but with C. difficile, spores occur near infected patents, on health-care worker hands, and on basic equipment such as blood pressure cuffs, walls, floors, stethoscopes (Pg 1884, right col final para, Pg 1885 left col, para 1).
Friggeri (Friggeri A., et al., Decreased CX3CR1 messenger RNA expression is an independent molecular biomarker of early and late mortality in critically ill patients, 2016, Critical Care 20:204, cited in Restriction) identified CX3CR1 as a biomarker of sepsis-induced immunosuppression (Abstract), noting decreased mRNA expression after septic shock (Pg 2 left col para 4).
Chirkova (Chirkova T., et al., 2015, CX3CR1 is an important surface molecule for respiratory syncytial virus infection in human airway epithelial cells, Jour of General Virol, 96, 2543-2556, cited in restriction) conducted in vitro work addressing interactions with CX3CR1 and its expression level in human epithelial cells as relevant to RSV pathogenicity, indicating a G protein-CX3CR1 interaction affects human immune response to infection likely by expression of high levels of CX3CR1 by immune cells.
What the Specification does and does not teach:
The specification broadly states that the invention concerns methods addressing risk of a (implying any) health-care-associated infection in a patient (Pg 1, line 4-6). The infection may be bacterial fungal or viral (Pg 3 end para 1). However, the teachings do not disclose details regarding infections identified (accurately or inaccurately), or the number of infective species, or whether they are common or rare as nosocomial infections in this (Lyon) unit, making it unclear whether risk for all taxonomic groups (e.g. bacteria, virus, fungi), and all species within each group, would be equally likely to be identified accurately with the method.
The specification points to “no clinical in vitro” diagnostic test for identifying patients at high risk of healthcare-associated infection. Claim 1 considers risk in four types of units.
The specification points out that is it surprising that CX3CR1 gene expression allows risk determination of health-care associated risk in patients (Pg 2 lines 6-9). Not disclosed are the bacteria, virus or fungi that were considered to be identified as nosocomial infections, and whether any of these are surprising.
The working example references a single hospital (in Lyon, Pg 12 line 1-2). The patients evaluated are of a particular nature, namely a subset of possible patients, and a subset of those who are in serious condition, these conditions also being subset of all types of conditions (Pg 12, lines 5-11). The Specification is divided into sections to describe the patients (septic state/shock, severe trauma, major surgery, severe burns; Pg 12-Pg 13). Exclusion criteria are mentioned, also (Pg 13), thus not all patients were included. A fraction of the subset of patients developed HAI before leaving or by 30 days (Pg 13). These, and healthy volunteers are the patients for whom data is presented.
Conclusion regarding possession:
Taking into consideration the factors outlined above, including the nature of the invention, the state of the art and multiple factors that affect predictability, including a significance of infection type and complexity in gene regulation, where increased expression is associated with at least some viral infections and decreased expression known to be associated with immunosuppression, and unknowns regarding nosocomial transmission identified, the guidance provided by the applicant and the singular working example from one hospital, it is the conclusion that Applicant does not possess the invention recited in the claims. There is not sufficient specific written example in the Specification that would lead one with ordinary skill in the art to a different conclusion.
The varied nature of results in the art, e.g. different species as primary nosocomial infectious agents in different units, leads to the question of whether all nosocomial agents would be identified in the expression assays. There is no disclosure of any of the nosocomial species identified in the working example, or how many are identified, or whether all nosocomial agents (e.g. bacteria, virus, fungi) would produce the same expression results, which is particularly relevant since the art discloses, for example that RSV expression results in higher expression of CX3CR1, which may impact interpretation of expression results in this work. The units in different facilities and myriad differences including additional other factors impacting expression as presented above re: RSV, and from the art indicative of CXCR3 as a biomarker of sepsis-induced immunosuppression, result in high expectation of unpredictability in the present claim(s) determinations for all unit patients infected with any nosocomial infection.
While CX3CR1 expression may be a valid marker for particular nosocomial infection acquisition as depicted in the severely compromised individuals in the specification (for whom, even sub-selection was made), the unpredictable nature of gene interaction with HAI, the inventors comment regarding this being a “surprising result”, the lack of assessment in alternate settings with mean risk that may vary, or with alternate patients with different risk or immunocompromise, or viral infection, contributes to an unpredictable outcome when this work is extrapolated to all patients in these units and their risk of any nosocomial infection.
Claim 1 is rejected for the reasons discussed. Claims 4-13 depend from claim 1 and as such suffer from the same language, and therefore are rejected for the same reasons.
Written description (possession) therefore, does not extend beyond human patients in hospital, in serious conditions as disclosed. The human patients in hospital (Pg 12 line 2) include patients in septic state/septic shock, or with severe burns, or severe trauma, in hospitalization in a resuscitation unit or ICU after major surgery (Pg 12-13). Of 377, just 26% (of a subset) had HAI infections, for whom decreased CX3CR1 was associated with higher risk of nosocomial infection (Pg 15, lines 10-12).
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, 5-13 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. The instant claims recite a law of nature, a risk of nosocomial infection occurrence in a patient correlated with gene expression measurement of CX3CR1. Further recitation in claim 1 includes abstract ideas (mental steps or mathematical calculations) in determining risk by comparing measured expression to a reference value according to predefined decision criterion.
Regarding laws of nature, their unpatentability was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., No. 10-1150 (March 20, 2012). “Laws of nature, natural phenomena, and abstract ideas” are not patentable. Diamond v. Diehr, 450 U.S. 175, 185 (1981); see also Bilski v. Kappos, 561 U.S. 593, 604, 95 USPQ2d 1001, 1007 (2010).
101 Analysis:
Re: step 1: Yes, the claims are directed to a valid statutory category, here a process (method).
Re: step 2A, prong 1: Yes, the claims are directed to a law of nature and/or an abstract idea (mathematical calculations) or mental process, and thus recite judicial exceptions, here a natural correlation between gene expression and risk of nosocomial infection, and mental processes to perform math calculations to compare measured expression data to reference value with predefined decision criterion.
Re: step 2A, prong 2: No, the claims do not recite additional elements beyond the judicial exception(s) that integrate them into a practical application (see MPEP 2106.04(d)). The claims are not, for example, integrated into a practical application by reciting an explicit treatment, or other meaningful limitation imposed upon the judicial exception (see MPEP 2106.05(a-h).
Re: step 2B: Additional elements do not amount to significantly more than the judicial exception, and constitute insignificant extra-solution activity, since the claims employ well-understood, conventional methods and data gathering that are used routinely in molecular biology and biomedicine, including measuring gene expression, expression comparison to reference, use of a biological sample that is blood, measuring mRNA, conducting PCR, normalizing data, as shown:
Measuring gene expression is routinely performed, along with comparison of results to reference values and is considered insignificant extra-solution activity and mere data gathering, particularly when the recitation is at a high level of generality. Cazalis (US20120077693 A1; published 3/29/2012) teaches an in vitro method for determining the risk of poor survival in a patient with a health issue (here, SIRS or systemic inflammatory response syndrome), by measuring the expression of the CX3CR1 gene in biological sample from said patient and comparing this to a reference value (here a predetermined threshold) to identify survival prognosis/risk of death (Abstract, [0010]). Using PCR methods and including housekeeping genes for normalization in RT-PCR, is also common (Turabelidze, A. et al. Importance of housekeeping gene selection for accurate RT-qPCR in a wound healing model, 2010, Wound Repair Regen, 18 460-466).
Determining risk of infection by performing correlations was known (Hoover, L. et al., Systemic inflammatory response syndrome and nosocomial infection in trauma, 2006, Jour Trauma injury, infection and critical care 61: 310-317) determined the risk of acquiring healthcare-associated infection (HAI) for patients admitted to a health care facility ICU (Abstract para 2): Hoover teaches a relationship between systemic inflammatory response syndrome (SIRS) and nosocomial infection disclosing that SIRS was more common in these ICU patients who acquired nosocomial infections in the hospital (Pg 310, Abstract, Results; right col para 2; Pg 311, left col, final para).
Comparing measured expression to a reference value according to set criteria is known Friggeri (Friggeri, A. et al, Decreased CX3CR1 messenger RNA expression is an independent molecular biomarker of early and late mortality in critically ill patients, 2016, Critical Care, 20:204) considered differential expression of CX3CR1 in survivors/non-survivors of sept shock (Abstract), invoking housekeeping control genes, where second derivative maximum was used to automatically determine cross point for individual samples, then standard curves were generated (with replicate cDNA standard), and relative standard curves that described PCR efficiency of selected genes were used to perform efficiency corrected quantification (relative quantification) (Pg 3 right col, 2nd para near end). Gene expression was normalized using HPRT1 housekeeping gene, and results were expressed as calibrated normalized relative quantity (Pg 3 right col, 2nd para near end).
The calculation of an expression value compared to a reference is considered a mental process that amounts to an abstract idea since the calculation relies upon the application of a mathematical formula after using routine wet lab techniques and can be “performed within the mind.” (see MPEP 2106.04(a)(2)(III)). Notably, the courts do not distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer MPEP 2106.04(a)III., Mental Processes.
The additional claims further characterize the exception of claim 1 but do not integrate the claim or concept into a practical application (see MPEP 2106.04(d)(2)) or rise above insignificant extra solution activity including Claims 5 and 6, blood and whole blood samples, as well as claims 8 and 9, mRNA, which are sample materials commonly used in biomedical studies, including by Friggeri et al (Fig 2). Claim 10 is a routine method RT-PCR method (Turabelidze, Abstract), claim 11, where expression is measured by sequencing is routine (Cazalis, [0075]), claim 12, where expression is measured by hybridization (Cazalis, [0066]-[0072]), claim 13, where expression is normalized with housekeeping genes is routine (Turabelidze, Abstract).
Thus, claims 1,5-13 constitute judicial exceptions that are not integrated into a practical application, and are considered judicial exception without significantly more (see MPEP 2106.04(d)(2)) and therefore are patent ineligible subject matter under 35 § U.S.C. 101.
Response to Remarks/Arguments
Applicant’s response re: 35 § U.S.C. 112(b): These rejections were withdrawn, except for the rejection of Claim 4, which was rejected for two reasons, antecedent basis and a lack of clarity regarding what the immuno-inflammatory attack references. While the former was adequately addressed, the latter was not adequately addressed, save to indicate paras where the term was used in the specification ([0014],[0015],[0055]), which do not satisfactorily define and delimit the term for clear use in a claim, thus the rejection is maintained:
[0014] does not reference the term at all, but does provide introduction to [0015], where the term is used with a parenthetical: “[0015] within 15 days from the immunoinflammatory attack (i.e. the trauma for patients with trauma, the burn for patients with burns, the surgery for patients having underg[o]ne a surgery, or the diagnosis of sepsis for septic patients)…”, which does not remedy the missing definition issue for immuno-inflammatory attack. [0055] the third reference of applicant, addresses results that predict health-care associated infection(s) within 15 days from the immuno-inflammatory attack, which does not define the term.
Applicant’s response re: 35 § U.S.C. 112(a), (Pg 4-5), claims 1-2, indicates particular amendments related to risk determination of nosocomial infection, and to particular care units, for which there is support. However, Applicant fails to address the entirety of written description issues, which also related to a(ny) patient experiencing a(ny) nosocomial infection, therefore this aspect of the rejection is maintained and modified in view of amendment which, in part now discloses nosocomial infections and ICU and other units.
Applicant’s response re: 35 § U.S.C. 102 and 103: The rejections were withdrawn.
Conclusion
All claims are rejected. 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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/LISA HORTH/Examiner, Art Unit 1681
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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