DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. Applicant’s election of OSM, LAG3, and FGF-23 in the reply filed on 07 May 2026 is acknowledged. 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)).
Applicant's election with traverse of influenza as the viral disease and pneumonia as the bacterial disease in the reply filed on 07 May 2026 is acknowledged. The traversal is on the ground(s) that the claims are not drawn to distinct diseases, but a unified method for classifying an infectious condition as bacterial or viral and determining its severity. In addition, Applicant states that all claims share the same core technical features. This is not found persuasive because the common technical feature does not define a contribution over the prior art, and thus is not a special technical feature. Applicant has not established that the claimed invention would provide a contribution over the cited prior art in the Restriction Requirement mailed 08 January 2026. Additionally, each disease will have different associated biomarkers, and it is not clear that every infectious disease will have a measurable difference in biomarker levels for every protein recited in Tables 3, 4, and 6. Therefore, the requirement is still deemed proper and is therefore made FINAL.
Claims 12-13 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 07 May 2026.
Claim Status
3. Claims 12-13 are withdrawn.
Claims 2-3, 14-16, 18, 21-22, and 25-42 are canceled.
Claims 1, 4-7, 17, 19-20, and 23-24 are under consideration.
Priority
4. The Instant Application is a National Stage (371) of PCT/IL2022/050076, filed 18 January 2022, which claims priority to U.S. provisional applications 63/138,530 and 63/172,135, filed 18 January 2021 and 08 April 2021, respectively. The species election of OSM, LAG3, and FGF-23 are all disclosed in 63/138,530 and thus the instant claims are granted the effective filing date of 18 January 2021.
Information Disclosure Statement
5. The information disclosure statements (IDS) submitted on 04 May 2026, 28 April 2026, 24 March 2026, 25 February 2026, 17 September 2025, 09 September 2025, 24 June 2025, 12 June 2025, 13 March 2025, 11 February 2025, 02 June 2024, 20 February 2024, 04 February 2024, 12 December 2023, 19 September 2023, and 03 September 2023 was filed before the mailing date of the Non-Final Office Action. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
It is noted that the foreign patent document crossed out on the IDS filed 17 September 2025 is due to the lack of a provided copy.
Specification
6. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The tables that refer to UnitProt IDs should also have their equivalent sequence identifiers listed.
7. The abstract is objected to because “A method… are disclosed” is improper grammar. Examiner suggests rewording the abstract to “a method… is disclosed”.
8. The use of the terms “TRIZOL” (Page 47, line 32), “BioArray HighYield” (Page 48, line 4), and many of the fluorescence dyes (Page 56), which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Note that these are merely examples and all improper uses of trademarks in the specification should be identified by Applicant and properly addressed.
Claim Objections
9. Claims 1 and 23 are objected to because of the following informalities: “the infection” should read “the infectious disease” for consistency. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
10. 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.
11. Claim 1, 4-7, 17, 19-20, and 23-24 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.
Regarding claims 1 and 5-7, the tables render the claim indefinite because the claims should be complete in themselves. See MPEP 2173.05(s) “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).”
Claims 4-7, 17, 19-20, and 23-24, which depend on claim 1, are similarly rejected.
Claim 24 recites the limitation "the infection type". There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112(a) – Enablement
12. 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.
13. In making a determination as to whether an application has met the requirements forenablement under 35 U.S.C. 112 ¶ 1, the courts have put forth a series of factors. See, In reWands, 8 USPQ2d 1400, at 1404 (CAFC 1988). The factors considered include: (1) the breadth of the claims, (2) the nature of the invention, (3) the relative skill of those in the art, (4) the presence or absence of working examples, (5) the amount of direction or guidance provided, (6) the state of the prior art, (7) the level of predictability in the art, and (8) the quantity of experimentation necessary.
14. Claims 1, 4-7, 17, 19-20, and 23-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the method of treating a subject having an infectious disease using the recited biomarkers in blood-based samples from human subjects, does not reasonably provide enablement for similar methods using just any sample type or such from just any species. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The claims recite a method of treating a subject having an infectious disease, wherein protein biomarkers are measured to determine the type and severity of disease.
The nature of the invention is methods of treating an infectious disease.
The level of skill of one of ordinary skill in this art is high.
The specification states that the subject can be a mammal or bird (Page 7, lines 23-25). However, the study description of example 1 (Page 64, line 20 to page 66, line 28) appears to only test human subjects. The working examples nor the drawings seem to imply that subjects other than humans were tested. The specification also states that the sample can be whole blood, serum, plasma, saliva, mucus, breath, urine, CSF, sputum, sweat, stool, hair, seminal fluid, biopsy, rhinorrhea, tissue biopsy, cytological sample, platelets, reticulocytes, leukocytes, epithelial cells, or whole blood cells (Page 16, lines 5-9). However, the study description of example 1 states that the patients had serum blood measurements taken (Page 64, line 24). The working examples do not discuss any other sample type.
A search of the art shows that OSM (UniProt ID: P13725), LAG3 (UniProt ID: P18627), and FGF-23 (UniProt ID: Q9GZV9) are all human biomarkers (See the UniProt pages for each biomarker). One of ordinary skill in the art would not assume that even if there were homologous or otherwise similar biomarkers in other species, that the same nexus would exist between species. Furthermore, it is taught that protein biomarkers are often species-specific in both presence and host response. Kawanishi (22 July 2019, PNAS, 116(32): 16036-16045) teaches a human-specific loss of CMP-N-acetylneuraminic acid hydroxylase which relates to an increase in risk for cardiovascular disease when compared to closely-related chimpanzees (Abstract). Nutma (28 August 2023, Nature Communications, 14: 5247) teaches “We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells depends on the transcription factor AP1 and is unique to a subset of rodent species within the Muroidea superfamily. Finally, we identify LCP2 and TFEC as potential markers of microglial activation in humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO-PET signals in humans reflect the density of inflammatory cells rather than activation state.” (Page 1, ¶ 1). Mishra (07 April 2025, Cellular and Molecular Life Sciences, 82: 147) teaches in relation to neurological degenerative diseases (NDDs) “In case of NDDs, animal models show multiple differences, including genetics, with human patients, for example some hereditary disease causing genes are not found in animal models, such as the gene APOE ε4 allele responsible for AD is not found in mice.” (Introduction, ¶ 1) and “Interestingly, in PD, CRISPR/Cas9 mediated disruption of PINK1 and Parkin in monkeys showed degenerative phenotypes, while they did not make significant differences in transgenic pigs.” (Page 10, right column, ¶ 2). In summary, the art shows that not all subjects will have the same biomarkers as many are species-specific, even between closely related species. Furthermore, even if different species have the same biomarkers, they will not necessarily affect both species in the same way.
In addition, it was unpredictable whether or not a biomarker detected in any biological specimen could be used to specifically identify a cancer or a subject suffering from a cancer. Ludwig (2005, Nature Reviews: Cancer, 5: 845-856) teaches that a marker for cancer to be used in screening the general population must have an extremely high specificity to minimize false positives that necessitate costly or invasive follow-up studies (Page 850, column 2, ¶ first full). This specificity refers in part to the cancer's tissue of origin. A tumor’s anatomical location usually indicates its tissue of origin. Thus, molecular markers are generally not required for classification of origin (Page 847, column 2, ¶ first full). By extension, for a biomarker to function as an indicator of cancer in a specimen containing no tumor cells, it is helpful if said marker is tissue-specific. Ludwig further teaches that relevant immunohistochemical markers may have prognostic or therapeutic value as in the case of breast cancer wherein estrogen receptor (ER) and HER2/NEU receptor status can help predict a patient's response to certain therapies (Page 849, column 2, ¶ first full). Taken together, even though some biomarkers allow for prognosis, not all are specific enough for diagnosis in just any type of biological specimen.
Mantovani (1994, European Journal of Cancer, 30A(3): 363-369) teaches that a biomarker that functions in one sample type need not function in another. They teach that folate binding protein levels in serum were significantly different in ovarian cancer patients compared to healthy donors (Abstract). However, the same cannot be said when urine was used as sample type (Figure 5 and page 368, column 2, ¶ 2). This is further supported by Williamson (30 April 2012, Nurs. Res. Pract., 2912: 246178), which teaches “We undertook this comparison of levels of biomarkers (27 specific cytokines) in 3 sample types (plasma, passive drool saliva, and saliva collected on filter paper) […] . Passive drool saliva samples were significantly associated with plasma samples for only 3 biomarkers. No significant associations between filter paper saliva and plasma samples were found.” (Discussion, ¶ 1).
Since the art teaches that biomarker presence and effect are unpredictable across multiple species and sample types, and the specification does not provide ample guidance with respect to
treating a subject having an infectious disease using the recited biomarkers in anything other than blood-based samples from human subjects, one would be burdened with undue experimentation to use the claimed invention to use similar methods with any sample type from any species.
Claim Rejections - 35 USC § 103
15. 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.
16. 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.
20. Claims 1, 5, 7, 17, 19-20, and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Oved (WO 2013117746 A1; 15 August 2013) in view of Jegaskanda (March 2019, J. Virol., 93(5)), Schnedl (2015, Disease Markers), and Stringer (US 20170052192 A1; Published 23 February 2017).
Regarding claims 1, 5, 7, and 23-24, Oved teaches "The present invention, in some embodiments thereof, is based on the identification of signatures and determinants associated with bacterial, viral and mixed (i.e. bacterial and viral coinfections) infections, patients with non-infectious disease, and healthy subjects. The methods of the invention allow for the identification of type of infection a subject is suffering from, which in turn allows for the selection of an appropriate treatment regimen." (¶ [0010]). After identification, Oved further teaches “if a subject is identified as having a viral infection the subject is selected to receive an anti-viral treatment regimen. […] When a subject is identified as having a bacterial or a mixed infection the subject is selected to receive an antibiotic treatment regimen.”
(¶ [00028]). Oved does not teach using LAG3 or FGF-23 as the specific biomarkers for diagnosing influenza and disease severity, respectively.
However, Jegaskanda teaches “Surface markers of activation, such as lymphocyte activating gene 3 (LAG-3) and CD69, were also significantly upregulated at the transcriptional level following NK cell exposure to influenza virus-infected cells.” (Page 6, last ¶). Schnedl teaches “In a small prospective cohort study of 30 hospitalized adults with and 30 without AKI, sepsis severity was positively correlated with FGF23 levels” (Page 4, ¶ 2) and “Fibroblast growth factor 23 is an excellent marker of disease severity and outcomes, particularly in chronic kidney disease. Emerging data suggest a similar role for clinical outcomes in acute illness.” (Conclusion). Stringer teaches that influenza can progress into sepsis: “Sepsis is the body's response to infection. This response is characterized by the cardinal signs of inflammation (e.g., vasodilation, leukocyte accumulation, and increased microvascular permeability) occurring in tissues that are remote from the infection. Even a minor infection, such as strep throat or influenza, can trigger sepsis.” (¶ [0004]). In summary, it is known in the art that an influenza infection is associated with the upregulation of LAG3 and FGF-23 is associated with disease severity, as it is upregulated during sepsis. It is standard in the art to use multiple biomarkers to test for different conditions.
Therefore, it would be obvious to one of ordinary skill before the time of filing to take the method of Oved and further measure LAG3 and FGF-23 to determine if the subject is infected with influenza and if it is severe or not, then prescribe the appropriate medication depending on the identification. The combination of familiar elements is likely to be obvious when it does no more than yield predictable results. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, A.). A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, A. and 2143.02).
Regarding claim 17, Oved further teaches "To facilitate a solution that is generally applicable, the inventors performed a large clinical trial in which they enrolled a heterogeneous cohort of 655 patients including different ages, medical backgrounds, ethnicities, pathogen types, clinical syndromes and time from appearance of symptoms, fever, co-morbidities (see Figures 4-10)." (¶ [00092]). It is standard in the art to test individuals with symptoms for diseases and treat them accordingly.
Regarding claim 19, Oved does not teach such testing and treating a subject with a chronic non-infectious disease. One of ordinary skill would not envision a subject with a chronic non-infectious disease as having the same bacterial and viral disease progression as an otherwise healthy subject.
Regarding claim 20, Oved further teaches “The sample is for example, whole blood or a fraction thereof.” (¶ [0030]). Jegaskanda teaches that the samples taken in their study were PBMC and thus, blood-based (Page 5, ¶ 2) and could have obviously been blood-based since blood contains PBMCs. Schnedl teaches that FGF23 affects peripheral blood monocytes and thus were also blood-based (Page 4, ¶ 2) and FGF23 is found in serum (Pg. 2, Column 2, Paragraphs, third through fifth) which is blood-derived and blood can thus be used as a sample for FGF23 analysis obviously.
17. Claims 4 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Oved (supra), Jegaskanda (supra), Schnedl (supra), and Stringer (supra), as applied to claims 1, 5, 7, 17, 19-20, and 23-24 above, and further in view of Suda (March 2002, Cytokine, 17(6): 335-340), NIH (August 2014, News in Health, Surviving Sepsis), and Bevilacqua (US 20050060101 A1; Published 17 March 2005)
Regarding claims 4 and 6, Oved, Jegaskanda, Schnedl, and Stringer make claim 1 obvious, as discussed supra. All discussions thereon incorporated here. None of these references teach OSM as a biomarker for pneumonia. However, Suda teaches “To clarify this, using human DCs derived from peripheral blood cells, we measured the protein levels of OSM in the supernatants of DC cultures by ELISA and examined the expression of OSM mRNA by RT-PCR after stimulation with lipopolysaccharide (LPS) … Upon stimulation with bacterial products, DCs secreted a large amount of OSM protein in a dose- and time-dependent manner.” (Abstract). Since the DCs were derived from peripheral blood cells, the sample type was thus blood-based. Furthermore, NIH teaches “Sepsis can be triggered by many types of infections. “But the most common cause of sepsis is community–acquired pneumonia,”” (¶ 8).
Therefore, it would have been obvious to one of ordinary skill before the filing date to take the method made obvious by Oved, Jegaskanda, Schnedl, and Stringer, and further add OSM as a biomarker to identify a bacterial pneumonia infection. The connection between pneumonia and sepsis allows the identification of disease severity using FGF-23. It is standard in the art to use multiple biomarkers. The type of disease will be able to be diagnosed faster with more biomarkers measured, so that more potential causes can be ruled in or out. The combination of familiar elements is likely to be obvious when it does no more than yield predictable results. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, A.). A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, A. and 2143.02).
Additionally, Bevilacqua teaches “Furthermore, in embodiments of the present invention, Gene Expression Profiles can also be used for characterization and early identification (including pre-symptomatic states) of infectious disease, such as sepsis. This characterization includes discriminating between infected and uninfected individuals, bacterial and viral infections…” (¶ [0264]). If a patient is septic or otherwise ill, one of ordinary skill would want to test for the cause of the infection so that proper treatment can be administered. The Instant Specification further states that OSM is inherently upregulated in bacterial infections (Table 2) and FGF-23 is inherently upregulated in severe infections (Table 5). One of ordinary skill would want such specificity of each biomarker such that the type and severity of the disease can be properly identified. Since Jegaskanda teaches that LAG3 is upregulated in influenza, Suda teaches OSM is upregulated in bacterial infections, and Schnedl teaches that FGF-23 is upregulated in severe infection/sepsis, the limitation of specificity is met.
Conclusion
18. No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA E LY whose telephone number is (571)272-5169. The examiner can normally be reached Monday - Thursday, 8:00 am - 5:00 pm EST.
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/KRISTINA E. LY/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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