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
Election/Restrictions
Applicant’s election without traverse of species in Claims 1, 8, and 10 in the reply filed on 02/17/26 is acknowledged.
In response to the Species Election requirement of Claim 1, Applicant elects B) and 1) without traverse, drawn to a combination of ribavirin with etanercept and with methylprednisolone.
Regarding the Species Election requirement of Claim 8, Applicant elects IL6, IL1RL1, SMOC1, KRT19, PTX3, TNC, AREG, HGF, TNFRSF10B, IL18R1, MSTN and CLEC4C, without traverse.
Applicant amends Claim 10 to recite Table 5, for more direct reference to the described proteins. Applicant elects AHCY, ALCAM, AZU1, BAG6, CDH1, CDSN, DFFA, F11R, FCGR2A, FCGR3B, HMOX2, IL22RA1, ITGB6, LCN2, LTBP2, PLAU, PLXNB3, PVALB, RNASE3, SELE, SELP, SLITRK2, CD93, LYVEI, NMNATI, NPMI, FETUS, and GPC5, without traverse.
The applicant notes that the species elections herein are encompassed in Claims 1-4, and 7-16.
Claims 5 and 6 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/17/26.
Claim Status
Claims 1-16 pending.
Claim 10 amended.
Claims 5 and 6 withdrawn.
Claims 1-4 and 7-16 are considered.
Examiner Note
Regarding claim 8 election/restrictions response from applicant, the Applicant elects IL6, IL1RL1, SMOC1, KRT19, PTX3, TNC, AREG, HGF, TNFRSF10B, IL18R1, MSTN and CLEC4C, without traverse. However, only IL6, KRT19, HGF, and AREG are options in claim 8 submitted 02/17/2026. Consequently, the claim is interpreted as “at least 1.5-fold upregulation of IL6, KRT19, HGF, and AREG”.
Information Disclosure Statement
05/24/2023
The information disclosure statement (IDS) submitted on 05/24/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings are objected to because the drawings are indicated by “Figure” rather than “FIG.” as required by 37 C.F.R § 1.84 (u)(1) (see also MPEP § 608.02 (V)). The different views must be numbered in consecutive Arabic numerals, starting with 1, independent of the numbering of the sheets and, if possible, in the order in which they appear on the drawing sheet(s). Partial views intended to form one complete view, on one or several sheets, must be identified by the same number followed by a capital letter. View numbers must be preceded by the abbreviation “FIG.” Where only a single view is used in an application to illustrate the claimed invention, it must not be numbered and the abbreviation “FIG.” must not appear.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
The drawings are indicated by “Figure” rather than “FIG.” See objection to the drawings, above. Appropriate correction is required.
The disclosure is also objected to because it contains an embedded hyperlink and/or other form of browser-executable code. See paragraph [0003]. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
In [00028], change “WHO ordinal scale for COVID-19 severity” to “WHO Ordinal Scale for Clinical Improvement” as evidenced by WHO R&D Blueprint Novel Coronavirus COVID-19 Therapeutic Trial Synopsis” (p.6)(See PTO-892: Notice of References Cited).
Claim Objections
Claims 14 and 15 objected to because of the following informalities:
Claims 14: Spell out the acronym for “CRP”. For examination purposes, CRP is being interpreted as C-reactive protein as noted in the specification. Change “Neutrophil” and “Creatinine” to “neutrophil” and “creatinine” for consistency with the other markers in other claims. Change “7-marker nomogram” to 7-marker scoring nomogram” for consistency with Figure 15.
Claim 15: Change “Lymphocyte”, “Neutrophil” and “Creatinine” to “lymphocyte”, “neutrophil” and “creatinine” for consistency with the other markers in other claims.
Appropriate correction is required.
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 12-13 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 12 recites: The method of claim 1, wherein the subject comprises a molecular severity score of at least 20 wherein the molecular severity score is calculated by the average expression of the set of 10 proteins IL6, IL1RL1, SMOC1, KRT19, PTX3, TNC, AREG, HGF, TNFRSF10B, and IL18R1, divided by the average expression of the set of 2 proteins MSTN and CLEC4C.
Claim 13 recites: The method of claim 1, wherein the subject comprises a molecular severity score of at least 15 wherein the molecular severity score is calculated by the average expression of the set of 35 proteins ACE2, ADM, ANGPTL1, AREG, CCL7, CDH2, CEACAM8, CTSL, GFRA1, HAVCR1, HGF, HS3ST3B1, IGFBP2, IL15, IL17RB, IL18R1, IL1R2, IL1RL1,IL6, IL6R, KRT19, LRIG1, MATN3, NECTIN2, PDGFRA, PRTN3, PTN, PTS, PTX3, PVR, SIGLEC10, SMOC1, TINAGL1, TNC, and TNFRSF10B, divided by the average expression of the set of 11 proteins BANK1, BMP4, CLEC4C, COMP, CRTAC1, KIT, KITLG, MSTN, NTRK2, RGMA, and SKAP1.
In making a determination as to whether an application has met the requirements forenablement under 35 U.S.C. 112 P 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 quantityof experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. Id. While it is not essential that every factor be examined in detail, those factors deemed most relevant should be considered. In the present case, the factors deemed relevant are those of: breadth of the claims, the amount of direction and the working examples provided.
The nature of the invention/the breadth of the claims: Claims 12 and 13 are both drawn to molecular severity score value (at least of amount) that are calculated by the average expression of the set of plasma proteins provided divided by the average expression of another set of proteins. However, Claims 12 and 13 lack sufficient detail with respect to calculation procedures for one skilled in the art to determine the molecular severity score in a hospitalized subject to determine eligibility for receiving a drug, e.g., ribavirin with etanercept with methylprednisolone, as a method of treating a SARS-CoV-2 infection (See also the 35 U.S.C. 112(b) rejection below). It appears, based on the specification [00028], protein expression in plasma from subjects can be detected with values reported and analyzed in various different outputs with the aid of the Olink platform/limma package such as was done with the exemplary Massachusetts General Hospital Cohort. However, the claims contain unclear language about “average expression” (see below U.S.C. § 112(b)) values for both the numerator and denominator required in the calculation. It does appear that the equation involves upregulated proteins in the numerator and downregulated proteins in the denominator ([00070], Table 1). The invention centers on “treating a SARS-CoV-2 infection in a subject” but as defined in the claims and in the disclosure, a subject with a couple of different molecular severity scores, e.g., of at least 15 or of at least 20 based on the proteins included in the analysis.
State of the art: Early in the SARS-CoV-2 pandemic and once patient data was available, proteomic exploration of different biomarkers and prognosis prediction using different types of equipment and software were in effect as evidenced by, for example Wendt et al. (See PTO-892: Notice of References Cited) who examined urinary peptides (p. 1, Abstract) and Ruan et al. (See PTO-892: Notice of References Cited) who examined data from 150 patients from Wuhan, China and who suggested “that COVID-19 mortality might be due to virus-activated “cytokine storm syndrome” or fulminant myocarditis” (p. 847) but that more research was needed. Likewise, different clinical scoring systems were being developed to for predicting mortality for severe patients with COVID-19 as evidenced by Shang et al. (See PTO-892: Notice of References Cited) early on.
The amount of direction provided by the inventor: As mentioned above, the disclosure provides examples of different plasma proteins of interest and the technology used to determine the levels of the proteins in the plasma as well as tools available for comparative studies. However, the phrasing in claims 12 and 13 of “average expression of the set” is difficult to decipher and one skilled in the art would need to know by consulting the specification what that means to make the calculation whether by hand or by using sophisticated software as part of the platform used to analyze the plasma. The disclosure does not appear to provide that.
The existence of working examples: As mentioned previously, examples of data analysis are provided in the disclosure. However, more details are needed to understand “the average expression of the set” and how it is used in the calculations for determining a molecular severity score.
In view of the nature of the invention and the lack of sufficient guidance in the specification, and the breadth of the claims, the disclosure as written is not enabling.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 8-16 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.
Claims 8 and 10 both recite “independently” in relation to either an upregulation or a downregulation protein marker. It is unclear what “independently” means in this context. For examination purposes, the claim is being interpreted as a protein’s upregulation or downregulation is not affected by the upregulation or downregulation of another protein listed in its respective grouping within the claims or by another etiology. Claims 9 and 11 are dependent on the rejected claims.
Claim 10 recites “proteins selected from those described in Table 5”. Claim 10 is indefinite due to recitation of Table 5. 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)(See MPEP 2173.05(s), Reference to Figures or Tables). To remedy, amend the claim to recite the elected proteins from Table 5, e.g., AHCY, ALCAM, AZU1, BAG6, CDH1, CDSN, DFFA, F11R, FCGR2A, FCGR3B, HMOX2, IL22RA1, ITGB6, LCN2, LTBP2, PLAU, PLXNB3, PVALB, RNASE3, SELE, SELP, SLITRK2, CD93, LYVEI, NMNATI, NPMI, FETUS, and GPC5.
Claims 12 and 13 recites “wherein the molecular severity score is calculated by the average expression of the set of X proteins…divided by the average expression of the set of X proteins…”. It is unclear how the calculations are being done or if additional software, e.g., OLINK platform [00028] is needed to carry out the calculations. For the numerator (for example, regarding the 10 proteins as recited in claim 12 ), it is not clear if an average expression value is determined for each protein and then each of those values are added together to arrive at the numerator or something else. Neither the drawings nor the specification provide sufficient clarity on the calculations.
Claim 14 recites “whole blood cells count”. Figure 15 includes “WBC”, however, in the specification, “WBC” is defined as white blood cells [00030] not whole blood cells count. It is unclear what the desired parameter is. Additionally, “sum of scores” and references to Figure 15 does not provide sufficient detail. 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)(See MPEP 2173.05(s), Reference to Figures or Tables). The claim language can be improved by using the specification language in [00032].
Claim 15 is unclear. It recites “as detailed in the 7-marker nomogram according to Figure 16”. However, Figure 16 features a “4-marker scoring nomogram” that includes lymphocytes, neutrophils, CRP, and creatinine levels, which is consistent with what is recited in the claim. Additionally, “sum of scores” and references to Figure 16 does not provide sufficient calculation details. 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)(See MPEP 2173.05(s), Reference to Figures or Tables). The claim language can be improved by using the specification language in [00033].
Claim 16 recites “not more than about three days prior to administering”; the term “about” as used here is a relative term and renders the claim indefinite (See MPEP 2173.059(b) Relative Terminology, III A. “About”). To remedy, amend the claim to recite “not more than three days”.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, 7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shah et al. (Shah)(See PTO-892 Notice of References Cited).
See claims 1-4, 7 as submitted 02/17/2026.
Shah teaches various autoimmune and rheumatic manifestations that are associated with COVID-19 and the drugs used in its treatment (p. 1541). Shah also teaches different stages of clinical manifestations and different stages of therapeutic drug use as when they write “clinical outcome of the patients relies on the fate of interaction between the SARS-CoV-2 virus and immune cells of the host…Modulation of this virus-host cell interaction and its aftereffects can be possibly achieved with immunomodulatory therapies repurposed from drugs used in autoimmune diseases…In the early asymptomatic or mild symptomatic stage, antiviral therapy is likely to have maximum efficacy, and the addition of interferon therapy at this stage may theoretically benefit from augmenting the innate antiviral response. In the next stage of pulmonary and systemic hyper-inflammation, early initiation of immunosuppressant, including IVIg, corticosteroids, IL-6, or IL-1 inhibitors may help to halt the immune-mediated damage” (p. 1545). Shah teaches ribavirin as an anti-viral against SARS-CoV-2 but also as an example of an antiviral that can potentially then cause arthralgia, back pain, myositis, and exacerbation of sarcoidosis (p. 1544) which needs to be therapeutically addressed. In addition to the aforementioned use of corticosteroids, Shah also teaches intravenous methylprednisolone, a corticosteroid, as a treatment option for SARS-CoV-2 related myocarditis alongside, for example, other antivirals ritonavir/lopinavir. Additionally, Shah teaches Figure 4 which shows targeted immunosuppressive therapy for COVID-19 on different immune-pathways and includes in (5) TNF inhibitors infliximab, adalimumab, and etanercept (p. 1550).
Accordingly, Shah teaches every aspect of claims 1-4, and 7.
Claim Rejections - 35 USC § 103
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.
Claims 1-4, 7, 16 are rejected under 35 U.S.C. 103 as being unpatentable over Shah et al. (Shah)(See PTO-892 Notice of References Cited) in view of Hung et al. (Hung)( (See PTO-892 Notice of References Cited).
See claims 1-4, 7, 16 as submitted 02/17/2026.
Shah teaches various autoimmune and rheumatic manifestations that are associated with COVID-19 and the drugs used in its treatment (p. 1541). Shah also teaches different stages of clinical manifestations and different stages of therapeutic drug use as when they write “clinical outcome of the patients relies on the fate of interaction between the SARS-CoV-2 virus and immune cells of the host…Modulation of this virus-host cell interaction and its aftereffects can be possibly achieved with immunomodulatory therapies repurposed from drugs used in autoimmune diseases…In the early asymptomatic or mild symptomatic stage, antiviral therapy is likely to have maximum efficacy, and the addition of interferon therapy at this stage may theoretically benefit from augmenting the innate antiviral response. In the next stage of pulmonary and systemic hyper-inflammation, early initiation of immunosuppressant, including IVIg, corticosteroids, IL-6, or IL-1 inhibitors may help to halt the immune-mediated damage” (p. 1545). Shah teaches ribavirin as an anti-viral against SARS-CoV-2 but also as an example of an antiviral that can potentially then cause arthralgia, back pain, myositis, and exacerbation of sarcoidosis (p. 1544) which needs to be therapeutically addressed. In addition to the aforementioned use of corticosteroids, Shah also teaches intravenous methylprednisolone, a corticosteroid, as a treatment option for SARS-CoV-2 related myocarditis alongside, for example, other antivirals ritonavir/lopinavir. Additionally, Shah teaches Figure 4 which shows targeted immunosuppressive therapy for COVID-19 on different immune-pathways and includes in (5) TNF inhibitors infliximab, adalimumab, and etanercept (p. 1550).
Shah does not teach wherein the subject has been admitted to a hospital not more than about three days prior to administering the drug.
Hung, however, teaches “[m]any repurposed drugs have been shown to have in-vitro activity against the close relatives of SARS-CoV-2, which are all beta-coronaviruses. Lopinavir and many interferons, particularly interferon beta, have been shown to have modest activity in vitro against SARS-CoV and Middle East respiratory syndrome (MERS)-CoV, and can be used synergistically with ribavirin…The viral load of COVID-19 peaks at the time of presentation, similar to influenza. Experience from the treatment of patients with influenza who are admitted to hospital suggested that a combination of multiple antiviral drugs is more effective than single drug treatments in this setting of patients with a high viral load at presentation. (p. 1695-1696). Hung conducted a “phase 2 randomised trial to establish whether a combination of three modestly active drugs against SARS-CoV-2 can improve the viral load profile and clinical parameters in adults with COVID-19 requiring hospital admission” (p. 1696) and the “intervention of the treatment had to be started within 48 h after hospitalization admission”(p. 1697)(as recited in claim 16). Patients were randomly assigned (2:1) to a 14-day combination of lopinavir 400 mg and ritonavir 100 mg every 12 h, ribavirin 400 mg every 12 h, and three doses of 8 million international units of interferon beta-1b on alternate days (combination group) or to 14 days of lopinavir 400 mg and ritonavir 100 mg every 12 h (control group)(p. 1695, Summary, Method).
One of ordinary skill in the art would have been motivated to start antiviral therapy such as ribavirin (with or without other drugs) within 48 hours after hospitalization as taught by Hung as it closely coincides with the time when COVID-19 viral load is thought to peak in SARS-CoV-2 infected patient (See MPEP 2143 Rationale A. Combining prior art elements according to known methods to yield predictable results).
One of ordinary skill in the art would have had a reasonable expectation of success for starting at least the antiviral component of the drug during the acute phase, or more specifically, within 48 hours after hospitalization, because the administration timing coincided with the time COVID-19 viral load is thought to peek as taught by Hung. There would have been a reasonable expectation of success given the underlying materials and methods are known, successfully demonstrated in the context of other viral infections in hospitalized patients, and commonly used as evidenced by the applied prior art.
Therefore, the invention as a while would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Claire Cornelius whose telephone number is (571)272-0860. The examiner can normally be reached M-F, 0930-1700.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas J. Visone can be reached at (571) 270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/C.C./Examiner, Art Unit 1672
/M FRANCO G SALVOZA/Primary Examiner, Art Unit 1672