DETAILED ACTION
Disposition of Claims
Claims 1-17 are pending.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US20240069023A1, Published 02/29/2024.
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Optional Authorization to Initiate Electronic Communications
The Applicant’s representative may wish to consider supplying a written authorization in response to this Office action to correspond with the Examiner via electronic mail (e-mail). This authorization is optional on the part of the Applicant’s representative, but it should be noted that the Examiner may not initiate nor respond to communications via electronic mail unless and until Applicant’s representative authorizes such communications in writing within the official record of the patent application. A sample authorization is available at MPEP § 502.03, part II. If Applicant’s representative chooses to provide this authorization, please ensure to include a valid e-mail address along with said authorization.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/02/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Notably, the disclosure statement filed lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. 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. See “https://www.nejm.org/doi/full/10.1056/NEJMc2009787” at ¶[0137].
Specification - Drawings
The drawings are objected to under 37 CFR 1.83(a). The drawings must show every feature of the invention specified in the claims. Therefore, the features of Figure 2-3, 5, and 7 which are noted to be in color (e.g. see specification at ¶[0020-0021][0023][0025] which notes different colored dots and lines) must be shown or the feature(s) canceled from the claim(s) and/or specification. No new matter should be entered.
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.
If it is desired that the referenced drawings show color, it should be noted that there is a specific petition to introduce color into utility applications. Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing referenced as being executed in color (Figures 2-3, 5, 7; see specification at ¶[0020-0021][0023][0025]). Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Claim Objections
Claim 1 is objected to because of the following informalities: the definition of the abbreviations “COVID19”, “SARS-CoV-2”, and “ACE2” are not provided. For clarity, it is requested that the first recitation of an abbreviation within a claim set be preceded by its full-length name (i.e. … coronavirus 2019 disease (COVID19)…severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)…angiotensin converting enzyme 2 (ACE2) ...).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b); Second Paragraph
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 1, 3, 6-7, and 11, and dependent claims 2, 4-5, 8-10, and 12-17 thereof 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.
The term “severe” in claims 1, 3, 6-7, and 11 is a relative term which renders the claim indefinite. The term “severe” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. With respect to claims 1, 3, and 6, “severe” is used in relation to COVID19 disease or symptoms, and while dependent claims may provide what one or more “severe” symptom may encompass, it is unclear if “severe” COVID19 only requires one or more than one of those symptoms, and if said symptom must last a specific period of time. With respect to claim 7, “severe” is used to describe cough, but it is unclear what type of cough is “severe” (e.g. it is unclear if the cough must be productive, and if it is productive, is it mucus of a certain color/consistency and/or blood (hemoptysis), if the cough has lasted for a certain number of days, a paroxysmal cough (persistent cough in uncontrollable fits), etc.) With respect to claim 11, “severe” is used to describe “disease”, and again, it is unclear what the onset of “severe disease” is marked by (e.g. presence of X number of symptoms, etc.)
The term “extended duration” in claim 1 is a relative term which renders the claim indefinite. The term “extended duration” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. While claim 2, which depends upon claim 1, defines “extended duration” as “about 44 days”, the independent claim does not have any range to define whether or not “extended duration” may be longer or shorter than this period of time, and when the time frame is measured (e.g. after clinical confirmation of infection, after initial onset of symptoms, etc.)
As these terms have not been clearly defined in the specification, and are not clearly defined in the art, the claims are rejected for being indefinite. Claims 2, 4-5, 8-10, and 12-17 are also rejected as they depend upon claim 1, 3, 6-7, or 11, but do not clarify the metes and bounds of said claims.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1 is drawn to a method for diagnosing the probability of extended duration of severe COVID19 symptoms in a subject infected with a SARS-CoV2 virus or suspected of being infected with the SARS-CoV2 virus, the method comprising:
(a) providing a biological sample from the subject; and
(b) detecting the presence of an anti-ACE2 IgM antibody in the biological sample, thereby diagnosing the probability of extended duration of severe COVID 19 symptoms in the subject.
Further limitations on the method of claim 1 are wherein the extended duration of severe COVID19 symptoms is about 44 days (claim 2); wherein a severe COVID 19 symptom comprises one of more of: high fever (pyrexia), severe cough, shortness of breath (dyspnea), difficulty breathing, fatigue, muscle aches (myalgia), headache, loss of taste (ageusia) or smell (anosmia), congestion, nausea, persistent pain or pressure in the chest (angina), confusion, inability to wake or stay awake (hypersomnia), delirium, seizures, or stroke (claim 7); wherein the biological sample is a blood sample (claim 10); wherein the presence of the anti-ACE2 IgM antibody is detected at the onset of severe disease in the subject (claim 11)
Claim 3 is drawn to a method for diagnosing the probability of severe COVID19 symptoms in a subject infected with a SARS-CoV2 virus or suspected of being infected with the SARS-CoV2 virus, the method comprising:(a) contacting a biological sample from the subject with an antibody that binds to an anti-ACE2 IgM antibody in the biological sample, producing an antibody-anti- ACE2 IgM antibody complex; and (b) detecting the presence of the antibody-anti-ACE2 IgM antibody complex, thereby diagnosing the probability of severe COVID19 symptoms in the subject.
Further limitations on the method of claim 3 are wherein the method comprises an immunoassay to detect the presence of the antibody-anti-ACE2 IgM antibody complex (claim 4), and wherein the immunoassay is an ELISA assay (claim 5).
Claim 6 is drawn to a method for treating a subject infected with a SARS-CoV2 virus or suspected of being infected with the SARS-CoV2 virus, the method comprising:
(a) providing a biological sample from the subject;
(b) detecting the presence of an anti-ACE2 IgM antibody in the biological sample, wherein the presence of the anti-ACE2 IgM antibody subject indicates the probability of severe COVID 19 symptoms; and
(c) administering to the subject a COVID 19 treatment, thereby treating the subject infected with the SARS-CoV2 virus.
Claim 8 is drawn to a method of screening for a clinically effective therapeutic agent to treat a subject infected with a SARS-CoV2 virus, the method comprising:
(a) providing a biological sample from the subject;
(b) detecting the presence of an anti-ACE2 IgM antibody in the biological sample; and
(c) screening for a clinically effective therapeutic agent to administer to the subject as a COVID19 treatment.
Further limitations on the method of claim 8 are wherein the COVID 19 treatment comprises an immunosuppressing agent, an anti-SARS-CoV2 monoclonal antibody, an antiviral agent, supplemental oxygen, or mechanical ventilatory support (claim 9)
Claim 12 is drawn to a kit comprising:
(a) a lateral flow device comprising a first pad, a second pad, and a membrane, wherein the first pad receives a biological sample from a subject having a SARS- CoV2 infection, the second pad comprises an antibody that binds to an anti-ACE2 IgM antibody, and the membrane that reacts to the antibody bound to the anti- ACE2 IgM antibody; and
(b) instructions to use the kit to detect the anti-ACE2 IgM antibody in the biological sample.
Further limitations on the kit of claim 12 are wherein the biological sample is a blood sample (claim 13).
Claim 14 is a lateral flow device adapted to perform the method of claim 3 for detecting an anti-ACE2-IgM antibody in a biological sample of a subject infected with a SARS-CoV2 virus.
Further limitations on the lateral flow device of claim 14 are wherein the biological sample is a blood sample (claim 15).
Claim 16 is drawn to a dipstick assay to perform the method of claim 3 for detecting an anti- ACE2-IgM antibody in a biological sample of a subject infected with a SARS-CoV2 virus.
Further limitations on the dipstick assay of claim 16 are wherein the biological sample is a blood sample (claim 17).
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 1-16 are rejected under 35 U.S.C. 101 because the claimed invention is directed to natural phenomena, methods of detecting said natural phenomena, and products to detect said natural phenomena, without significantly more. The claims recite a method for diagnosing the probability of extended duration of severe COVID19 symptoms in a subject infected with a SARS-CoV2 virus or suspected of being infected with the SARS-CoV2 virus, the method comprising: (a) providing a biological sample from the subject; and (b) detecting the presence of an anti-ACE2 IgM antibody in the biological sample, thereby diagnosing the probability of extended duration of severe COVID 19 symptoms in the subject. Additional claims are drawn to generically claimed devices used to perform the claimed methods. This judicial exception is not integrated into a practical application because the method is drawn to the diagnosis of a condition or probability without the method claiming a practical application of said natural phenomenon. Autoantibodies against the natural receptor of SARS CoV-2, angiotensin converting enzyme type 2 (ACE2), are known to occur naturally (see e.g. Chappell MC. Arthritis Res Ther. 2010;12(3):128. Epub 2010 Jun 28.) The generation of anti-ACE2 antibodies in a host and the likelihood of suffering from severe COVID-19 disease is a natural correlation, and the method is recited at such a high level of generality and does not include additional elements in the method to go beyond identification of the natural phenomenon. Additional independent claims are also recited at such a high level of generality and include routine or conventional steps that do not add an inventive element to the claims (e.g. “administration of treatment” could be giving the subject a glass of water, “ELISA assays” are routine and conventional tests performed by a skilled artisan and do not comprise specific, tangible elements in the assay which are novel or inventive). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because, under Step 2A Prong one, the claim recites a natural phenomenon (YES) and under the Step 2A prong two, the claim is directed to a judicial exception (YES), and under Step 2B prong, there is no additional inventive element or step to amount to significantly more than the judicial exception (NO). It is suggested that a specific step, such as administration of a specific type of treatment (e.g. specific type of vaccine, antiviral, etc.) and/or the use of an element within the method to identify the natural phenomenon that amounts to something more than what is routine or conventional (e.g. use of a specific ELISA to detect the autoantibodies, wherein the ELISA employs a novel chimeric antibody to detect the autoantibodies or uses a novel fusion protein of ACE2 tagged to a detectable fluorescent marker to detect said antibodies, etc.), be added to the independent claims in order to assist in adding patent eligibility to the claims. Additionally, limitations from claims not included in this rejection could be incorporated into the independent claims to aid in having the claims drawn to patent-eligible subject matter. The devices of claims 14-16 can also be amended to recite specific, inventive elements (e.g. use of a novel chimeric antibody to detect autoantibodies against human ACE2, etc.) to add eligibility to these devices, as these devices are recited at such a high level of generality to perform non-patent eligible methods, and such devices are routinely used and found in the field of clinical virology that they do not add an inventive element that amounts to significantly more than the judicial exception.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-17 are rejected under 35 U.S.C. 103 as being unpatentable over Shaw et. al. (Shaw B, et. al. Radiol Med. 2021 Jan;126(1):40-46. Epub 2020 Oct 1.; hereafter “Shaw”); in view of
Townsend (Townsend A. Med Hypotheses. 2020 Nov;144:110043. Epub 2020 Jul 25.; CITED ART OF RECORD; hereafter “Townsend”);
McMillan et. al. (McMillan P, et. al. MOJ Immunol. 2020;7(1):17-19. Epub 2020 May 27.; CITED ART OF RECORD; hereafter “McMillan”);
Amiral et. al. (Amiral J et. al. Transfus Apher Sci. 2020 Jun;59(3):102804. Epub 2020 May 3; CITED ART OF RECORD; hereafter “Amiral”); and
in further view of The Native Antigen Company (The Native Antigen Company. “ELISA Formats for Infectious Disease Diagnostics.” https://thenativeantigencompany.com/elisa-kits/. Pub. 2019/07/17. Wayback Machine capture 05/24/2020; hereafter “Native Antigen”); and
Lu et. al. (Lu H, et. al. J Med Virol. 2020 Oct;92(10):1812-1817. Epub 2020 Jul 28.; hereafter “Lu”.)
The Prior Art
Shaw teaches long-term Coronavirus disease 2019 (COVID19) disease was under investigation, and discusses clinical manifestations of severe COVID-19 disease (entire document; see abstract.) Shaw teaches Severe Acute Respiratory Syndrome—Coronavirus—2 (SARS-CoV-2) infection can, in severe cases, cause severe acute respiratory syndrome, respiratory failure, and death (“Introduction”, p. 40), and relapsing cases show such symptoms as fever, cough, fatigue, dyspnea, and shortness of breath (p. 41, rt. Col., ¶1; instant claim 7). Shaw teaches that one of the treatments for COVID-19 was supplemental oxygen (p. 41, left col., ¶2; instant claim 9). Shaw teaches that it was common for signs of improvement to begin about 14 days after the onset of symptoms, but that chest CTs still show abnormalities at 28 days or greater post-onset (p. 42, rt. Col., ¶4). Shaw teaches that there is evidence that COVID-19 symptoms and pathologies may last for more than a month (p. 44, rt. Col., ¶2).
Townsend teaches that autoimmunity to ACE2 is a potential cause of tissue inflammation in COVID-19 disease (entire document; see abstract.) Townsend teaches inflammatory pneumonia happens in about 14% of SARS CoV-2 infections, with the pathological basis of this inflammatory pneumonia being unknown (p. 1, “Background”). Townsend notes that in SARS CoV vaccination with the spike (S) protein, there was a damaging immune response initiated in a subset of individuals, again with an unknown etiology (p. 1, “Background”). Townsend notes the interaction between ACE2 and the Receptor Binding Domain of the Spike protein is high affinity (~10 nM), equivalent to many monoclonal antibodies, meaning that the association of S and ACE2 is likely long lived, long enough to elicit an immune response in certain hosts that is enough to break self-tolerance to ACE2 (p. 1, “The hypothesis”). This autoimmune response would lead to an inflammatory response in lungs, heart, kidney, and other sites of increased activity of angiotensin II. Townsend teaches that autoantibodies to ACE2 have been described in vasculopathies, with thrombotic tendencies prominent in severe COVID-19 disease (p. 1, “The hypothesis”). Townsend teaches that this hypothesis is easily testable by looking for antibodies and T cell responses to ACE2 in patients with severe disease, and was supported by others in the field (pp. 1-2, “Last word”.)
McMillan teaches that the primary cause of mortality in COVID-19 is respiratory failure secondary to severe pneumonia5 and an atypical form of Adult Respiratory Distress Syndrome (ARDS), with severe inflammatory responses in the lungs, liver, and kidneys (p. 1, ¶2). McMillan notes that ACE2 exists in soluble and membrane-bound forms (p. 1, ¶3-4), and that if the soluble ACE2 receptor combines with SARS CoV-2 virions, this complex itself could become an antigen (p. 2, ¶1). If the ACE2 receptor is attacked by antibodies and is also attached to SARS CoV-2 virions, this means angiotensin 2 in the body would cause dysregulation of the renin-angiotensin axis, along with those cells that naturally express ACE2 on the surface becoming targets for the autoantibodies (p. 2, ¶2). McMillan also suggests these autoantibodies may cross-react with ACE, and could further target the lungs, causing severe pulmonary edema as seen in ARDS (p. 2, ¶3). McMillan notes that elevated autoantibodies against ACE2 are seen with pulmonary hypertension secondary to scleroderma (p. 2, ¶4), and a similar degree of lung inflammation was seen with SARS CoV in 2003 (p. 2, ¶5). McMillan suggests measurement of serum ACE2 antibody titers would identify which patients would progress into ARDS (p. 2, ¶5).
Amiral teaches that they believe an auto-immune reaction may be contributing to the severe complications seen in certain SARS CoV-2 patients (entire document; see abstract), and that a sudden worsening of symptoms starting 7 to 14 days after preliminary symptoms indicates a strong inflammatory response (p. 1, left col.) Amiral notes that SARS-CoV-2 has a major impact on the Renin Angiotensin Aldosterone System (RAAS), through its binding to the membrane cellular glycoprotein, Angiotensin Converting Enzyme-2 (ACE-2), then infecting cells for replication, and they hypothesize the possible implication of an autoimmune response, induced by generation of allo- or autoantibodies to ACE-2, or to its complexes with viral spike protein (entire document; see abstract.) Amiral notes that a person infected with SARS CoV-2 develops IgM and IgG antibodies after infection, yet surprisingly those with the highest antibody concentration were most critical (p. 3, “”5. Immune response”). Amiral notes the formation of a strong complex between ACE-2, a self-component, and viral S1 (or S Protein), constitutes the basic context for developing allo-antibodies and generating a delayed autoimmune response, with antibodies first targeted to viral antigens, but which can extend to the associated self-component through epitope spreading. Then, antibodies to ACE-2 could develop, or eventually to another cell protein close to or complexed with ACE-2. Amiral then hypothesizes that an allo-immune response can follow the initial immune reaction to the viral infection, and that epitope spreading can induce antibodies to ACE-2, or to proteins with which it is complexed, thus targeting the immune system to cells exposing ACE-2 (abundant in lungs and some other organs) (p. 3, “6. Hypothesis on the induction of an auto-immune complication”). Amiral states that this hypothesis could be easily explored by testing allo-antibodies to ACE-2, or to its complexes with SARS-CoV-2 S Protein or its cleaved subunits, S1, and eventually associated with S2 or nucleoprotein. Amiral teaches that recombinant ACE-2 and recombinant SARS-CoV-2 proteins or peptide sequences, including S Protein and S1, are available from various suppliers, and a capture ELISA, designed by coating recombinant ACE-2, or its complexes with S-Protein or its S1 subunit, or eventually the viral nucleoprotein, onto the plate could be designed for capturing possible antibodies present in Covid-19 patients, especially those with delayed severe complications (p. 3, “7. Strategy for investigating allo/autoantibodies”).
Shaw teaches about the clinical manifestations of COVID-19, and provides insight on severe disease and how it manifests in patients. Townsend, McMillan, and Amiral all teach that it was likely the severe disease seen in certain SARS CoV-2 infections was likely due to ACE2 autoantibodies, and teach ways that this could have been tested to determine if anti-ACE2 antibodies were elevated in patients with SARS CoV-2 infection. While Amiral teaches this could be measured by developing an ELISA assay, and Townsend, McMillan, and Amiral all teach that these antibodies could be measured in patient sera, neither specifically teach measuring IgM antibodies against ACE2. However, such methods would be obvious to a skilled artisan, as evidenced by the teachings of Native Antigen and Lu.
Native Antigen teaches the diagnosis of infection is aided by diagnostic antibody tests which can determine the phase of infection or antibody production against the foreign material. Native Antigen teaches that a variety of ELISA tests can be generated to distinguish between IgG and IgM antibodies against a specific antigen, such as “antigen down ELISAs”, “capture assays”, and “Double Antigen Bridging (DABA) assays”. Native Antigen notes a variety of detection methods may be employed in their assays, such as horseradish peroxidase (HRP) or Biotin/Streptavidin (“Detection methods”; instant claims 4-5.) Native Antigen teaches that the Lateral Flow Assay (LFA) is a more compact and robust immunoassay that is becoming widely adopted in point of care (PoC) diagnostic tests (“PCR or ELISA?”, instant claims 14, 16).
Lu teaches the difference between performing molecular and serology tests on a patient with COVID-19, in that detection of antibodies in a patient can indicate the stage of infection. For instance, if only IgM antibodies against a viral antigen are detected, that indicates the patient is in early stages of infection. If IgM antibodies are detected, the presence of IgG and/or viral RNA can further indicate at what stage of infection or disease progression the patient is within (Table 2). Lu teaches that ELISAs and lateral flow assays (LFAs) which test serum, plasma, or whole blood had been used in the COVID-19 setting (Sect. 1.4.2, p. 1815; instant claims 4-5, 10, 12-17). 4-5, 7, 9-10, 12-17
Given the teachings of Shaw, one of skill in the art would be aware of the severity and long-term potential of COVID-19 disease. Given the teachings of Townsend, McMillan, and Amiral, one of skill in the art would be motivated to test for the presence of anti-ACE2 antibodies in a patient with COVID-19. Given the teachings of Townsend, McMillan, and Amiral, one of skill in the art would hypothesize that if anti-ACE2 antibodies were present, that the patient is likely going to have severe disease compared to other patients. Given the teachings from Lu, a skilled artisan would be apprised as to the difference between IgM and IgG antibodies in a patient sample and what stage of infection this indicates, and would be able to develop a specific ELISA method to detect IgM antibodies against ACE2, given the knowledge in the art as provided by Native Antigen. One of skill in the art would be motivated to determine the difference between anti-ACE2 IgM vs. IgG antibodies, as IgM against ACE2 likely indicate an initial, new antibody response against ACE2 and therefore a more likely disruption of the Renin/Angiotensin pathway, potentially leading to more severe COVID-19 disease. Therefore, given what was known in the art at the time of filing, arriving at the limitations of instant claims 1-17 would be obvious to a skilled artisan, as the motivation to test for anti-ACE2 antibodies in COVID-19 patients was present, the tools, kits, and reagents for performing such an analysis were readily available to a skilled artisan, and symptoms of disease and treatment options were known at the time of filing, as evidenced by the combined teachings of Shaw, Townsend, McMillan, Amiral, Lu, and Native Antigen.
It would have been obvious to one of ordinary skill in the art to test the hypotheses and methods taught by Townsend, McMillan, and Amiral in order to determine if anti-ACE2 antibodies were present in patients with severe COVID-19, thereby identifying a susceptible population of patients that may have more severe or long-term effects from SARS CoV-2 infection, like those effects identified by Shaw. One would have been motivated to do so, given the suggestion by Lu and Native Antigen that immunological methods and compositions for testing for antibodies, such as isotype-specific antibodies against a known target, were known in the art. There would have been a reasonable expectation of success, given the knowledge that IgM and IgG levels would correlate to a specific phase of SARS CoV-2 mediated disease, and that IgM levels would be the first to show in SARS CoV-2 primary infection, as taught by Lu, and also given the knowledge that ELISAs and LFAs could be developed to test for IgM antibodies against a known protein target, as taught by Native Antigen. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL B GILL whose telephone number is (571)272-3129. The examiner can normally be reached on M to F 8:00 AM to 5:00 PM Eastern.
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/RACHEL B GILL/
Primary Examiner, Art Unit 1671