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 .
Status of the Claims
Claims 1-7 are pending and examined herein.
Priority
This application, filed 11/07/2022, is a 371 of PCT/US2021/031591, filed 05/10/2021, which claims benefit of U.S. Provisional Patent Applications 63/023,079 and 63/088,316, filed 05/11/2020 and 10/06/2020 respectively. The benefit is acknowledged and the claims examined herein are treated as having an effective filing date of 05/11/2020.
Information Disclosure Statement
The Information Disclosure Statement(s) filed 06/23/2023 are acknowledged and have been considered.
Specification
Applicant is reminded of the proper content of an abstract of the disclosure. A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Applicant is reminded of the proper language and format for an abstract of the disclosure. The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because the phrase “for identifying patients that are at risk” describes an intended use, as opposed to the technical steps and/or features of the invention. The abstract reads as a research goal or clinical objective, rather than a technical disclosure. Additionally, the abstract is objected to because it does not comply with the word length requirements of 50 to 150 words, as it is fewer than 50 words. Lastly, the abstract is objected to for stating “the present disclosure provides.” Using non-technical, narrative phrasing instead of directly summarizing the claimed invention. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The disclosure is objected to because of the following informalities:
It contains a typographical error. In paragraph [0005], line 3, the word “sad” should read “said.” Appropriate correction is required.
In paragraph [0005], line 8, the phrase “symptomatic or prone to present one or more symptoms of COVD-19 and/or (b) prone to progress to severe COVID-19 disease.” The phrase should read “(a) symptomatic or prone to present one or more symptoms of COVID-19 and/or (b) prone to progress to severe COVID-19 disease.” Appropriate correction is required.
It contains inconsistent terminology. The specification uses multiple phrases (e.g., “clinically significant COVID-19 infection,” and “severe COVID-19 disease”) without clearly defining whether these terms are equivalent. Appropriate correction is required.
The specification does not clearly correspond in scope to the claims. The claims broadly recite “immunoglobulin fucosylation, galactosylation and/or bisection,” while the specification predominantly discusses afucosylation/fucosylation. Appropriate correction is required.
Claim Objections
Claims 1are objected to because of the following informalities:
Claim 1, line 3, recites “sad method comprising.” The word “sad” should read “said.” Appropriate correction is required.
Claims 1, lines 9-12, and 7, lines 4-6 recite “symptomatic or prone to present one or more symptoms of COVD-19 and/or (b) prone to progress to severe COVID-19 disease.” The phrase should read “(a) symptomatic or prone to present one or more symptoms of COVID-19 and/or (b) prone to progress to severe COVID-19 disease.” Appropriate correction is required.
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 1-7 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception, specifically a law of nature (a natural correlation between immunoglobulin glycosylation levels and COVID-19 disease severity) and an abstract idea (mental processes of comparison and diagnosis). The claims do not integrate the judicial exception into a practical application and do not include additional elements sufficient to amount to significantly more than the judicial exception itself.
This rejection is made in accordance with Patent Subject Matter Eligibility as set forth in MPEP §2106. Analysis of subject-matter eligibility under 35 U.S.C. §101 requires consideration under these steps as followed:
Step 1: Are the claims to a statutory category (process, machine, manufacture, or composition of matter)?
Step 2A (Prong 1): Are the claims directed to a judicial exception (law of nature, natural phenomenon, or an abstract idea)?
Step 2A (Prong 2): Do the claims recite additional elements that integrate the judicial exception into a practical application?
Step 2B: Do the claims recite additional elements that amount to significantly more than the judicial exception (inventive concept)?
Step 1 – Statutory Category (Refer to MPEP §2106.03): Claims 1-7 are drawn to a process, which fall within a statutory category under 35 U.S.C. §101.
Step 2A, Prong One – Recitation of a Judicial Exception (Refer to MPEP §2106.04): According to MPEP §2106.04(b), a concept that have been held by the courts to constitute law of nature/natural phenomena, wherein the correlation between the presence of myeloperoxidase in a bodily sample (such as blood or plasma) and cardiovascular disease risk based on Cleveland Clinic Foundation v. True Health Diagnostics, LLC.
Claim 1 states “comparing the fucosylation, galactosylation, and/or bisection from a blood sample from a healthy adult donor” and “wherein a reduced level of fucosylation, galactosylation, and/or bisection when compared with the healthy adult donor is indicative of a subject that is symptomatic or prone to present one or more symptoms of COVID-19 and/or prone to progress to severe COVID-19 disease.” Here, claim 1 recites a natural biological correlation between immunoglobulin glycosylation levels and COVID-19 disease severity or progression. This relationship exists in nature independent of human action and therefore constitutes a law of nature. Furthermore, in MPEP §2106.04(a), the courts consider mental processes (thinking) that can be performed in the human mind to be an abstract idea. Examples of mental processes include observations, evaluations, judgments, and opinions. Hence, Claim 1 recites mental processes, including comparing measured values and drawing a diagnostic conclusion. These actions can be performed in the human mind or by a human using a pen and paper, constituting an abstract idea.
Claims 2-6 are dependent of Claim 1 and add limitations specifying: “the immunoglobulin is IgG” (Claim 2), “the amount of fucosylation is determined” (Claim 3), “the level of afucosylated Fc glycans” (Claim 4), “the subject is a human” (Claim 5), and “the biological sample is blood or a blood fraction” (Claim 6). These claims retain the same natural correlation and mental evaluation steps recited in Claim 1. Narrowing the biomarker, specifying numerical thresholds, or isolating the subject or sample type does not remove the claims from the recited judicial exceptions. Accordingly, claims 2-6 each recite a law of nature and an abstract idea.
Claim 7 states “a method of treating a subject acutely infected with SARS-CoV-2 and at risk of progression to clinically significant COVD-19 infection or disease, the method comprising administering to the subject a therapeutic agent or vaccine.” Here Claim 7 incorporates the same diagnostic determination based on the natural correlation and mental processes recited in Claims 1-6. The treatment step is conditional upon the diagnostic conclusion and does not recite a specific or non-conventional therapeutic technique. Thus, claim 7 also recites a law of nature and an abstract idea.
Step 2A, Prong Two – Integration into a Practical Application (Refer to MPEP §2106.04 (d)): Claims 1-6 constitute mere data gathering and analysis of a natural phenomenon. The claims do not recite a technological improvement, a specific assay technique or a non-conventional laboratory process. Therefore, claims 1-6 do not integrate the judicial exception into a practical application. On the other hand, MPEP §2106.04(d)(2) indicates that one way to demonstrate such integration is when the additional elements apply or use the recited judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. Although Claim 7 recites “administering to the subject a therapeutic agent or vaccine,” the claim does not specify a particular therapeutic agent or vaccine, does not recite a dosing regimen or administration protocol, and does not modify treatment based on the measured values. According to MPEP §2106.04(d)(2), when considering a claim that recites administering a suitable medication to a patient – this administration step is not particular, and is instead merely instructions to “apply” the exception in a generic way. The administration step does not integrate the mental analysis step into a practical application. Therefore, claim 7 does not integrate the judicial exception into a practical application.
Step 2B, Inventive Concept (Refer to MPEP §2106.05): According to MPEP §2106.05(d), one consideration when determining whether a claim recites significantly more than a judicial exception is whether the additional element(s) are well-understood, routine, conventional actional activities previously known to the industry. If, however, the additional element (or combination of elements) is no more than well-understood, routine, conventional activities previously known to the industry, which is recited at a high level of generality, then this consideration does not favor eligibility. For example, the additional elements in Claim 1 consist of “obtaining a biological sample from a subject” and “determining the amount of one or more of immunoglobulin fucosylation, galactosylation and/or bisection in the sample.” These additional steps recited in Claim 1 were previously taken by those in the field as demonstrated by Singh et al. (Association of the IgG N-glycome with the course of kidney function in type 2 diabetes. BMJ Open Diabetes Research & Care. Vol. 8, No. 1, April 2020) and Irvine et al. (Understanding the Role of Antibody Glycosylation through the Lens of Severe Viral and Bacterial Diseases. Glycobiology. Vol. 30, No. 4, March 2020 - IDS entered 06/23/2023). Singh et al. provides direct factual evidence that biological samples were obtained and analyzed for immunoglobulin glycosylation, disclosing that “plasma for IgG N-glycosylation analysis was available” (page 3) from human participants and that “24 IgG glycan peaks were measured by Waters Acquity UPLC instrument,” (page 3) with “the amount of glycans in each peak was expressed as percentage of total integrated area” (page 3). These disclosures demonstrate that obtaining biological samples and quantitatively determining IgG glycosylation traits were routinely performed laboratory activities. Also, Irvine et al. establishes that such IgG Fc glycosylation analysis was well-understood and conventional in the diagnostics field, explaining that “the majority of infection-associated immune profiling has focused on deconvoluting IgG Fc glycosylation changes,” (page 242) and further identifying fucosylation, galactosylation, and bisection as standard Fc-glycan features subject to routine analysis. Taken together, Singh et al. demonstrate that the claimed steps were actually performed using routine laboratory techniques, and Irvine et al. demonstrate that such techniques were widely used and well-understood in the art prior to the effective filing date of the claimed invention. Accordingly, the additional elements of Claim 1 represent well-understood, routine, and conventional activities and therefore fail to add a feature that amounts to significantly more than the judicial exception.
In addition, Claims 2-6 further indicate the following: specifying IgG is a conventional biological choice and does not add significantly more (Claim 2), determining fucosylation is a routine laboratory measurement (Claim 3), threshold selection reflects routine optimization and does not add an inventive concept (Claim 4), specifying a subject type indicates no additional technical or introduces inventive concept (Claim 5), and specifying a sample type provides no inventive concept (Claim 6). Based on Claims 2-6, the steps of biological sampling, biomarker measurement, comparison, and evaluation are well-understood, routine, and conventional activities in the field of diagnostics.
Moreover, the MPEP §2106.05(f), highlights whether the claim recites only the idea of a solution or outcome i.e., the claim fails to recite details of how a solution to a problem is accomplished. The recitation of claim limitations that attempt to cover any solution to an identified problem with no restriction on how the result is accomplished and no description of the mechanism for accomplishing the result, does not integrate a judicial exception into a practical application or provide significantly more because this type of recitation is equivalent to the words “apply it.” This indicates that the treatment step in Claim 7 is generic, conventional, reads on routine administration decisions, and merely applies the diagnostic result.
Ultimately, claims 1-7, when considered individually and as an ordered combination are directed to a law of nature and an abstract idea, are not integrated into a practical application, and do not recite additional elements sufficient to amount to significantly more than the judicial exception.
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.
Claims 1-7 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 "reduced level" in Claim 1 is a relative term which renders the claim indefinite. Also, the terms "prone to present one or more symptoms," "prone to progress to severe COVID-19 disease," and “clinically significant COVID-19 infection or disease” in Claims 1 and 7 are subjective terms which further renders the claims indefinite. These terms are not defined by the claims, 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. In particular, a “reduced level” is a relative term of a degree. It lacks a claim-specified threshold except where claim 4 adds a threshold for afucosylation, but claim 1 covers fucosylation, galactosylation, and/or bisection broadly. According to §MPEP 2173.05(b), even if the specification uses the same term of degree as in the claim, a rejection is proper if the scope of the term is not understood when read in light of the specification. Regarding the term a “reduced level,” the specification does not define an objective standard or boundary for determining the following: how much reduction constitutes a “reduced level”, whether reduction is absolute or relative, whether reduction must be statistically significant, or whether reduction has a clinically meaningful threshold. For purposes of compact prosecution, this claim will be interpreted to mean - a level that is lower than a corresponding level measured in a biological sample from a healthy adult donor. Appropriate correction is required.
In addition, the terms "prone to present," "prone to progress," and “clinically significant” are subjective terms. Regarding the terms "prone to present" and "prone to progress," the specification does not define the following: the relevant timeframe for progression; what probability threshold constitutes being “prone”; whether “prone” means: greater than baseline risk, a statistically significant increase, or a clinician judgment. One of ordinary skill in the art could reasonably interpret “prone” differently, leading to inconsistent claim scope. For purposes of compact prosecution, this claim will be interpreted to mean-prone to present one or more symptoms of COVID-19, as determined by the subject meeting a predetermined biomarker threshold based on the comparing step. Appropriate correction is required.
Furthermore, the term “clinically significant,” is inherently a subjective term. “Clinically significant” can depend on clinical judgment, medical context, practitioner perspective, or evolving standards of care. Although paragraph [0034] of the specifications states the “term clinically significant refers to infection or disease requiring direct observation and/or treatment by a medical professional,” §MPEP 2173.05(b) further highlights that the claim scope cannot depend solely on the unrestrained, subjective opinion of a particular individual purported to be practicing the invention. The definition for “clinically significant” still relies on subjective clinical judgement. Even with the definition, the boundary turns on the following: what a particular medical professional considers requiring observation, differences in clinical practices and/or health-care systems, evolving standards of care (especially for COVD-19). For example, one medical practitioner may observe a patient via telemedicine, while another practitioner may not consider observation necessary at all. This means the definition does not fix a single, objective threshold. Additionally, “direct observation” when defining “clinically significant” in the specifications is itself undefined and expansive. The specification does not define the following: duration of observation, type of observation (in-person vs remote), whether routine check-ins qualify, or whether observation must change clinical management. Therefore, appropriate correction is required.
Claims 2-6 are rejected under 35 U.S.C. 112(b) as being indefinite because they depend from Claim 1 and incorporate by reference the same indefinite limitations, including “reduced level,” “prone to present,” “prone to progress,” and “clinically significant.” The additional limitations recited in Claims 2-6 do not further define or clarify these terms, nor do they provide objective boundaries for determining when the claimed conditions are met. Appropriate correction is required.
Claim 4 recites the limitation "the level of afucosylated Fc glycans" in Claims 1 and 3. There is insufficient antecedent basis for this limitation in the claim. Claim 4 is indefinite because it introduces: “the level” – but there is no antecedent introduction of a “level” in Claims 1-3; and “afucosylated Fc glycans” – is a structurally specific subset not previously defined. Claim 1 refers only to “immunoglobulin fucosylation” generally and does not specify: IgG subclass, Fc glycans, or what is used to calculate a percentage. For purposes of compact prosecution, this claim will be interpreted to mean the amount of immunoglobulin fucosylation comprises a percentage of afucosylated Fc glycans relative to total Fc glycans of IgG antibodies in the biological sample. However, appropriate correction is required.
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.
Claims 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over Irvine et al. (Understanding the Role of Antibody Glycosylation through the Lens of Severe Viral and Bacterial Diseases. Glycobiology. Vol. 30, No. 4, March 2020 - IDS entered 06/23/2023) in view of Singh et al. (Association of the IgG N-glycome with the course of kidney function in type 2 diabetes. BMJ Open Diabetes Research & Care. Vol. 8, No. 1, April 2020), Thulin et al. (Afucosylated Maternal Anti-Dengue IgGs Are a Biomarker for Susceptibility to Dengue Disease in Their Infants. bioRxiv. Preprint. March 2019 - IDS entered 06/23/2023), and Zhou et al. (Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan China: a retrospective cohort study. The Lancet. Vol. 395, No. 10229, March 2020).
Regarding Claim 1, Irvine et al. teaches a conceptual framework indicating that IgG Fc glycosylation patterns are altered during infection and correlate with disease severity. In particular, the “variation in fucosylation, galactosylation, bisection, and sialylation” (page 242) acts “as both markers of disease state but additionally may functionally contribute to control or exacerbation of disease” (page 243). Irvine et al. further discloses that such changes are evaluated by comparison to healthy controls, specifically in “a study that compared IgG Fc glycosylation profiles between healthy individuals, individuals with Hepatitis B Virus (HBV)-related cirrhosis and individuals with chronic HBV infection found that the two HBV-exposed populations exhibited decreased IgG Fc galactosylation when compared to healthy controls” (page 244). Although Irvine et al. teaches the biological relevance of IgG Fc glycosylation, the comparison-to-healthy-donor paradigm, and the specific glycan features claimed – Irvine does not mention COVID-19 or SARS-CoV-2. However, Irvine et al. is explicitly pathogenic-agnostic and surveys immune responses across multiple viral infections. It therefore provides the starting diagnostic framework that a person having ordinary skill in the art (PHOSITA) would naturally apply to a newly emerged viral disease.
On the other hand, Singh et al. teaches how a PHOSITA would practically implement Irvine’s framework, identifying that “key properties of IgG glycosylation are galactosylation, sialylation, fucosylation, and bisection GlcNAc” (page 5) and expressing these properties as derived traits suitable for numerical comparison. Singh et al. supplies the measurement step in Claim 1 (“determining the amount”) indicating that “plasma for IgG N-glycosylation was available in 1837 cases” and “in total, 24 IgG glycan peaks were measured by Walters Acquity UPLC instrument. All chromatograms were separated into 24 peaks and the amount of glycans in each peak was expressed as percentage of total integrated area. From these direct traits, and additional 34 derived IgG glycan traits were calculated based on their structural similarities. As a result, characteristics of the 24 direct glycan peaks are reflected in the derived traits” (page 3). Although Singh et al. provides quantitative measurement methodology and routine analytical workflows, Singh et al. does not apply the glycosylation traits to viral prognosis or COVID-19.
However, Thulin et al. demonstrates that reduced IgG Fc fucosylation (afucosylation) is clinically meaningful in viral disease, affecting disease susceptibility and severity. Specifically, it was revealed that “disease severity during acute secondary dengue infections is impacted by elevations in afucosylated anti-dengue IgGs” (page 16). Thulin et al. further teaches that afucosylation can be used predictively indicating that “this pro-inflammatory Fc glycoform can be utilized to predict susceptibility to dengue disease prior to infection” (page 16). Although Thulin et al. establishes that afucosylation is a result-effective variable in viral disease severity, Thulin does not mention COVID-19.
But, Zhou et al. establishes that COVID-19 presents a wide spectrum of severity. In particular, Zhou et al. discloses “the clinical spectrum of SARS-CoV-2 infection appears to be wide, encompassing asymptomatic infection, mild upper respiratory tract illness, and severe viral pneumonia with respiratory failure and even death” (page 1054). Zhou et al. further emphasizes the clinical importance of early risk identification by disclosing that is its essential to “identify patients with poor prognosis at an early stage” (page 1054). Hence, it would have been obvious to a PHOSITA before the effective filing date of the claimed invention to combine Zhou et al.’s urgent prognostic need to stratify COVID-19 patients (via risk of progression) with Irvine’s et al. infectious disease IgG glycosylation biomarker framework, implement it using Singh et al.’s established quantitative glycoprofiling analytical methods, and interpret reduced fucosylation consistent with Thulin et al.’s viral severity/susceptibility teachings with a reasonable expectation of success. Applying known glycosylation marker-logic to COVID-19 would be expected to produce some measurable stratification, not an un unpredictable new mechanism.
Regarding Claim 2, the cited glycosylation variables are Fc-glycan traits commonly quantified on IgG; Singh et al. frames the glycoprofiling analysis explicitly as IgG, stating that “glycosylation of immunoglobulin G (IgG) is an important post-translation process affecting the inflammatory potential of IgG” (page 1) and the study investigated “the association between 58 IgG N-glycan profiles” (page 1). Accordingly, a PHOSITA implementing Irvine’s antibody glycosylation biomarker framework would use IgG because it is the principal antibody isotype for Fc glycosylation profiling. Using IgG instead of another immunoglobulin is expected to yield measurable Fc glycosylation traits; it is the standard substrate for this type of analysis.
Regarding Claim 3, Irvine et al. identifies fucosylation as a key IgG Fc glycosylation variable, disclosing that “over 90% of IgG in the serum of healthy individuals is core fucosylated in the Fc region” (page 243) and that “decades of work in the monoclonal therapeutics community has clearly demonstrated the critical role of a loss of fucosylation as a key determinant of Fc affinity for FcyRIIIa” (page 243). Once a PHOSITA chooses Fc glycosylation as the biomarker family, fucosylation is one of the primary traits to measure. Singh et al. teaches the measurement as a derived trait (quantified fucose). A PHOSITA would be motivated to include fucosylation because it is explicitly listed among key IgG glycosylation properties. Also, Thulin et al. teaches that afucosylation impacts viral disease severity, making it predictable that fucosylation is a relevant marker to check when looking for immune-based risk stratification tools.
Regarding Claim 4, Thulin et al. explicitly discloses “≥10% afucosylated glycans on maternal anti-E IgGs is a biomarker for susceptibility of their infants to clinically significant primary dengue infections” (page 7). A PHOSITA applying afucosylation as a prognostic marker would naturally consider the same class of thresholds when operationalizing the biomarker in COVID-19. Since afucosylation is recognized as correlated with susceptibility/severity, the cutoff value becomes a parameter adjusted to tune sensitivity/specificity – which is exemplary of routine optimization. Claim 4’s “5% and 10% cutoffs” fall squarely within expected calibration practices.
Regarding Claim 5, Irvine et al.’s biomarker comparisons are made between healthy individuals and patients, as Irvine et al. reveals that “in healthy adults, agalactosylated, monogalactosylated and digalactosylated glycan structures account for approximately 35, 35 and 15% of circulating IgG Fc-glycan, respectively. However, patients with active autoimmune and inflammatory diseases shift the balance of these glycan species largely toward an accumulation of agalactosylated IgG” (page 243). Zhou et al.’s COVID-19 cohort is human hospitalized patients. A PHOSITA would apply the diagnostic stratification to humans because COVID-19 is an infectious disease that spreads between individuals in close contact and the art uses human cohorts for immune-based biomarker comparison and risk stratification.
Moreover, for Claim 6, IgG is routinely obtained from blood-derived samples, including serum or plasma. Each of the cited references utilizes blood-based biological samples. Zhou et al. indicates that blood sampling is standard and expected in COVID-19 evaluation, stating “routine blood examinations were complete blood count, coagulation profile, serum biochemical tests (including renal and liver function, creatine kinase, lactate dehydrogenase, and electrolytes), myocardial enzymes, interleukin-6 (IL-6), serum ferritin, and procalcitonin” (page 1055). This explicit disclosure demonstrates that routine blood examination is a conventional and expected practice in COVID-19 patient assessment. Accordingly, a PHOSITA combining Irvine et al. with Zhou et al. would predictably obtain IgG from blood, serum, or plasma samples when implementing Fc-glycosylation-based stratification methods.
Lastly, for Claim 7, Thulin et al. supports early identification due to disclosing that afucosylation “can be utilized to predict susceptibility to dengue disease prior to infection” (page 16). Zhou et al. links early prognosis identification to initiating “optimal antiviral interventions” (page 1054). Zhou et al.’s teaching creates an explicit clinical reason to act once poor prognosis patients are identified. If a PHOSITA adopts the biomarker stratification of Claims 1-6 for COVID prognosis, it is obvious to then treat those identified as high risk using available therapeutic approaches or vaccines. The act of administering therapy after identifying high-risk patients is a predictable expected medical workflow; it does not require a new mechanism or novel therapeutic. Ultimately, claims 1-7 are rejected under 35 U.S.C. 103 because the claimed invention represents no more than the predictable application of known IgG glycosylation biomarkers to COVID-19, motivated by a recognized clinical need and implemented using routine analytical techniques.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-7 are rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1, 2 ,4 , 7, and 9 of U.S. Patent No. 11826414 referred as ‘414, in view of the general knowledge in the art as evidenced by Zhou et al. Although the claims at issue are not identical, they are not patentably distinct from each other because of the following:
Claim 1 of ‘414 recites a method comprising: performing an assay to determine a level of afucosylated Fc glycans in IgG antibodies in a biological sample from a subject; identifying the subject not having 5 percent or greater of the IgG antibodies having the afucosylated Fc glycans; and making a clinical decision (vaccination) based on that identification. The instant claims recite the same IgG glycosylation biomarker-based identification framework, differing only in the viral disease context (COVID-19 vs. Dengue virus), and the particular clinical action (treatment vs. vaccination). The instant Claim 1 and Claim 1 of ‘414 share the same: biomarker (IgG afucosylation/fucosylation), assay, numeric thresholds, and the clinical decision-making logic. The only aspect that distinguishes both claims is that the instant Claim 1 recites COVID-19, while ‘414 recites Dengue virus. As further elaborated below, this difference constitutes an obvious variant and does not render the claims patentably distinct.
Furthermore, Claim 2 of ‘414 specifically limits the antibodies to IgG1, which is a subclass of IgG. Accordingly, instant Claim 2 lacks patentable distinctness. Additionally, determining the level of afucosylated Fc glycans is a critical step of Claim 1 of ‘414. Instant Claim 3 merely restates this step. Claim 4 of ‘414 recites 5 percent or greater and 10 percent or greater afucosylation thresholds, which are identical in scope to the thresholds recited in instant Claim 4. Claim 7 of ‘414 limits the method to a human subject, rendering instant Claim 5 not patentably distinct. Claim 9 of ‘414 highlights that the biological sample is blood or a blood fraction, which is identical in scope to instant Claim 6. Lastly, Claim 1 of ‘414 discloses vaccinating the subject based on the IgG afucosylation determination. Vaccination is a type of medical treatment. Hence, the “method of treating” step of instant Claim 7 is not patentably distinct from the vaccination step disclosed in Claim 1 of ‘414.
Therefore, the instant Claims 1-7 differ from Claims 1,2,4,7, and 9 of ‘414 only in that they: specify COVID-19 as opposed to Dengue virus and recite treatment generally instead of vaccination specifically. As revealed by Zhou et al., COVID-19 is a viral disease characterized by unpredictable severity and a recognized need for early identification of subjects at risk of progression. Applying an existing IgG afucosylation biomarker-based identification framework from one viral disease (Dengue) to another (COVID-19) would have been obvious to a PHOSITA. The substitution of one viral pathogen for another, and one form of clinical intervention for another, does not modify: the biomarker, the assay, the numeric thresholds, the clinical-decision making logic. This indicates that the instant claims represent no more than an obvious variant of the claims of ‘414.
Conclusion
No claims are allowable.
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/E.O./Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 January 5, 2026