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 1-6 are pending. Claim 1 is amended. Claim 7 is canceled. Accordingly, claims 1-6 are 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.
Maintained Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 4 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 4 recites the limitation "the level of afucosylated Fc glycans" in line 2. There is insufficient antecedent basis for this limitation in the claim. Specifically, the term “the level” has no antecedent basis in claims 1 or 3. Instead, claim 1 recites determining “the amount of one or more of immunoglobulin fucosylation, galactosylation, and/or bisecting N-acetyl glucosamination” and, in claim 3, determining “the amount of fucosylation.” Thus, the claim does not clearly establish what previously introduced “level” is being referenced. Additionally, the term “afucosylated Fc glycans” lacks antecedent basis and is not clearly defined by the earlier claims. Claim 1 broadly recites “immunoglobulin fucosylation,” which refers to a glycosylation characteristic, whereas “afucosylated Fc glycans” denotes a specific subset of Fc glycan structures. It is unclear whether “the amount of fucosylation” recited in claims 1 and 3 corresponds directly to the “level of afucosylated Fc glycans,” or whether a different or derived measurement is intended. As such, a person having ordinary skill in the art (PHOSITA) would not be reasonably apprised of the scope of the claim. Accordingly, claim 4 is indefinite.
Maintained 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.
The rejection below under 35 U.S.C. 103 has been updated in view of Applicant’s amendment to claim 1. In particular, claim 1 has been amended to recite a method of treating a subject infected with SARS-CoV-2, including “administering to the subject an inhibitor of FcγRIIA or FcγRIIIA receptor signaling.”
Claims 1-6 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), 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), Fu et al. (Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools. Virologica Sinica. Vol. 35, No. 3, March 2020) and Goldmann et al. (Oral Bruton Tyrosine Kinase Inhibitors Block Activation of the Platelet Fc Receptor CD32a (FcγRIIA): A New Option in HIT? Blood Advances. Vol. 3, No. 23, December 2019).
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 SARS-CoV-2 nor teach a method of treating a subject infected with SARS-CoV-2, including administering to a subject an inhibitor of FcγRIIA or FcγRIIIA receptor signaling. However, Irvine et al. is explicitly pathogenic-agnostic and surveys immune responses across multiple viral infections.
Singh et al. teaches how a PHOSITA would practically implement Irvine et al.’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).
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). Importantly, Thulin et al. demonstrates that IgG Fc glycosylation, particularly fucosylation status, directly modulates Fcγ receptor interactions and downstream immune activation. Specifically, Thulin et al. teaches that “one factor that modulates the ratio of A/I FcγR signaling is the glycosylation state of the IgG Fc domains within immune complexes” (Introduction, page 2), thereby establishing that Fc glycosylation is a controlling determinant of Fcγ receptor-mediated signaling. Additionally, Thulin et al. further discloses that “afucosylation of the Fc is pro-inflammatory due to increasing affinity of the Fc for the activating FcγRIIIa” (Introduction, page 2), explicitly linking a specific glycosylation modification (afucosylation) to enhanced Fcγ receptor binding. Lastly, Thulin et al. provides direct mechanistic evidence that this altered binding translates into functional immune consequences, disclosing that “anti-dengue afucosylation, a modification that enhances Fc affinity for the activating receptor FcγRIIIa, promotes infection of FcγRIIIa+ monocytes” (Summary, page 1), and that “FcγRIIIa signaling, in turn, enhances a post-entry step of dengue virus replication” (Summary, page 1).
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).
Fu et al. teaches that modulation of Fc receptor signaling is a therapeutic strategy in the context of SARS-CoV-2 infection. Specifically, Fu et al. discloses that, “potential therapeutic tools to reduce SARS-CoV-2-induced inflammatory responses include various methods to block FcR activation” (Abstract, page 266). Furthermore, Fu et al. discloses that “small-molecule inhibitors can also be developed to interact with the Ig-binding domains of FcR to block FcR activation,” and “the inhibitory FcR, FcγRIIB, may also be targeted to inhibit FcR activation” (paragraph 4, page 269). Thus, Fu et al. proposes therapeutic strategies directed to blocking Fc receptor signaling including by small-molecule inhibitors, in the context of SARS-CoV-2 mediated inflammatory disease.
Goldmann et al. teaches that Fcγ receptor signaling can be inhibited in a biological system and that such inhibition is achievable through administration of inhibitors. In particular, Goldmann et al. discloses that, “activation of the platelet Fc-receptor CD32a (FcγRIIA) is an early and crucial step in the pathogenesis of heparin-induced thrombocytopenia type II (HIT) that has not been therapeutically targeted” (Abstract, page 4021). Furthermore, Goldmann et al. teaches “the potential to prevent FcγRIIA-induced platelet activation by Bruton tyrosine kinase (BTK) inhibitors (BTKi’s) approved (ibrutinib, acalabrutinib) or in clinical trials (zanubrutinib [BGB-3111] and tirabrutinib [ONO/GS-4059]) for B-cell malignancies, or in trials for autoimmune diseases (evobrutinib, fenebrutinib [GDC-0853])” (Abstract, page 4021). Next, Goldmann et al. discloses that “irreversible and reversible BTKi’s potently inhibit platelet activation by FcγRIIA in blood (Abstract, page 4021). Lastly, Goldmann et al. explicitly teaches administration to a subject, stating that “three healthy male physicians took a single dose of ibrutinib (280 mg)” (Results, paragraph 1), and “a single oral intake of ibrutinib (280 mg) was sufficient for a rapid and sustained suppression of platelet FcγRIIA activation” (Abstract, page 4021). These disclosures demonstrate that inhibition of Fcγ receptor signaling through administration of inhibitors to a human subject was a known and practiced approach.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the antibody glycosylation-based analytical framework of Irvine et al., as implemented using the quantitative glycoprofiling techniques of Singh et al. and applied to viral disease severity contexts as taught by Thulin et al. and Zhou et al., in view of Fu et al.’s recognition that Fc receptor-mediated inflammatory signaling contributes to SARS-CoV-2 disease severity and blocking Fc receptor activation as a therapeutic strategy., to further include administering to a subject an inhibitor of Fc receptor signaling, including inhibition of FcγRIIA or FcγRIIIA, as taught by Goldmann et al., in order to treat a subject infected with SARS-CoV-2. The combined teachings not only associate measured IgG Fc glycosylation traits with disease severity, but establish that such glycosylation directly modulates Fc receptor binding affinity and downstream Fc receptor signaling activity, thereby identifying Fc receptor activation as a mechanistic driver of disease severity. Accordingly, a PHOSITA would have been motivated to not only assess such glycosylation-based biomarkers, but to intervene therapeutically at the same Fc receptor signaling pathway identified as causally underlying inflammatory disease progression.
Lastly, a PHOSITA would have had a reasonable expectation of success in making this modification because the relationship between IgG Fc glycosylation, Fc receptor binding affinity, and Fc receptor-mediated immune activation was well-established prior to the effective filing date, and inhibition of Fc receptor signaling was a known and practiced approach for suppressing Fc receptor-mediated cellular activation. In view of the combined teachings, applying known Fc receptor signaling inhibitors in the SARS-CoV-2 context would have represented the predictable use of prior art elements according to their established functions, with a reasonable expectation that such inhibition would reduce Fc receptor-mediated inflammatory responses in infected subjects, thereby yielding no more than the expected result of treating disease associated with SARS-CoV-2 infection.
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 et al.’s antibody glycosylation biomarker framework would use IgG because it is the principal antibody isotype for Fc glycosylation profiling. As taught by Singh et al., IgG it is the standard substrate for quantitative Fc-glycan analysis, and its glycosylation patterns are routinely measured and are used to derive clinically relevant traits. Therefore, using IgG instead of another immunoglobulin would have been an obvious and routine selection yielding predictable and measurable Fc glycosylation traits, consistent with established analytical practices in the art.
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 selects Fc glycosylation as the biomarker family, as taught by Irvine et al., fucosylation would have been an obvious parameter to measure because it is explicitly identified as a primary and functionally significant glycosylation trait. Singh et al. further teaches that such glycosylation features are quantified as derived traits (including quantified fucose), demonstrating that measurement of fucosylation is part of routine glycoprofiling analysis. Additionally, Thulin et al. teaches that afucosylation impacts viral disease severity, indicating that variation in fucosylation is clinically relevant in infectious disease contexts. Accordingly, a PHOSITA would have been motivated to include fucosylation as a measured parameter when implementing Fc glycosylation-based biomarker frameworks, because it is a well-established, routinely quantified, and biologically significant variable, and its measurement would have predictably yielded relevant information for immune-based risk stratification.
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). Given that Thulin et al. teaches a specific quantitative threshold for afucosylation associated with disease susceptibility, a PHOSITA would have recognized that such cutoff values represent adjustable parameters used to stratify risk based on biomarker levels. When applying afucosylation as a prognostic marker in other viral disease contexts, including SARS-CoV-2 as suggested by the combined teachings of the prior arts, a PHOSITA would have been motivated to select and optimize threshold values to achieve appropriate sensitivity and specificity. Accordingly, the selection of specific cutoff values, such as the claimed “5% and 10%” thresholds, would have been a matter of routine optimization of a result-effective variable, where the value of the threshold is adjusted to calibrate the diagnostic or prognostic performance of the biomarker. Such calibration is a well-established and predictable practice in biomarker-based analyses, and therefore the claimed cutoff values fall within the range of values that a PHOSITA would have reasonably explored with a reasonable expectation of success.
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). This teaching demonstrates that IgG glycosylation traits are routinely interpreted by comparison to values observed in healthy individuals, establishing a baseline reference for identifying disease-associated deviations. A PHOSITA, applying Irvine et al.’s glycosylation biomarker framework, would therefore have been motivated to compare glycosylation levels in a subject sample to those of a healthy control in order to assess disease-related changes. Furthermore, Zhou et al. teaches that COVID-19 studies are conducted using human patient cohorts and emphasizes clinical evaluation of infected individuals. Accordingly, when applying glycosylation-based biomarker analysis to COVID-19, a PHOSITA would have reasonably implemented such comparisons using human biological samples, including comparisons to healthy donors, as this represents a standard and predictable approach for immune-based biomarker stratification.
Regarding claim 6, IgG is routinely obtained from blood-derived samples, including serum or plasma. Most of the cited references utilizes blood-based biological samples. Zhou et al. indicates that blood sampling is standard and expected for evaluation of SARS-CoV-2 infection, 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 disclosure demonstrates that blood-derived samples, such as serum or plasma are conventionally collected and analyzed in the clinical assessment of SARS-CoV-2 infected patients. Accordingly, a PHOSITA, implementing Fc glycosylation-based biomarker methods as taught by Irvine et al., would have routinely obtained IgG from blood, serum, or plasma samples, as these represent standard and readily accessible biological sources for immunoglobulin analysis. Therefore, selecting a blood-derived sample for obtaining IgG would have been an obvious and predictable choice consistent with established clinical and analytical practices.
Ultimately, claims 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over Irvine et al. in view of Singh et al., Thulin et al., Zhou et al., Fu et al., and Goldmann et al. As set forth above, the cited references collectively teach or suggest each and every limitation of the claimed invention, including the use of IgG glycosylation biomarkers to identify subjects with disease-associated immune profiles linked to Fc receptor-mediated inflammatory signaling, and the administration of inhibitors of Fcγ receptor signaling to treat subjects based on those profiles. The combination of references reflect the predictable use of prior art elements according to their established functions to address a known disease mechanism, and a skilled artisan would have been motivated to make the combination with a reasonable expectation of success.
Maintained 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.
The rejection below under nonstatutory double patenting has been updated in view of Applicant’s amendments.
Claims 1-6 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 Irvine et al., Singh et al., Thulin et al., Zhou et al., Fu et al., and Goldmann et al.
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. While, instant claim 1 recites a method of treating a subject infected with SARS-CoV-2 comprising obtaining a biological sample, determining IgG glycosylation features including fucosylation, galactosylation, and/or bisecting N-acetyl glucosamination, comparing the determined amount to a healthy donor, identifying reduced amounts, and administering to the subject an inhibitor of FcγRIIA or FcγRIIIA receptor signaling. Thus, both the instant claim 1 and claim 1 of ’414 share the same core framework of (i) IgG Fc glycosylation biomarker analysis, (ii) quantitative determination of glycan levels, (iii) comparison to a reference (threshold or control), and (iv) performing a clinical action based on the biomarker-driven identification. The instant claim differs in specifying SARS-CoV-2 and administering an Fc receptor signaling inhibitor rather than vaccination.
As established in the 103 rejection above, Irvine et al., Singh et al., and Thulin et al. collectively teach the IgG glycosylation biomarker framework and its relationship to disease severity, including that glycosylation states – particularly afucosylation – modulate Fcγ receptor binding and downstream immune activation. Zhou et al. teaches application of such disease stratification to SARS-CoV-2 and emphasizes the need for early identification of high-risk patients, and Fu et al. and Goldmann et al. further establish that Fc receptor-mediated inflammatory signaling is a recognized therapeutic target and that such signaling can be inhibited through administration of inhibitors. These combined teachings demonstrate that IgG Fc glycosylation is mechanistically linked to Fcγ receptor activation, thereby identifying a specific immune signaling pathway underlying disease severity and providing a direct rationale for therapeutic intervention at that pathway.
Accordingly, it would have been obvious to one of ordinary skill in the art to modify the method of claim 1 of ’414 to apply the same IgG glycosylation-based biomarker framework to SARS-CoV-2 infection and, upon identifying subjects with glycosylation profiles associated with increased Fcγ receptor-mediated inflammatory activity, to administer a therapeutic intervention targeting that same Fc receptor signaling pathway. This modification represents the predictable use of prior art elements according to their established functions, wherein the diagnostic framework identifies a disease-associated immune mechanism and the therapeutic step targets that identified mechanism. The substitution of one viral disease (Dengue virus) with another (SARS-CoV-2 virus), the use of a healthy donor comparison in place of or in addition to fixed thresholds, and the selection of a therapeutic intervention (Fc receptor signaling inhibition) in place of vaccination do not alter the underlying biomarker assay, comparison logic, or clinical decision framework. Rather, these differences constitute routine adaptions and obvious variations that would have been made by a skilled artisan in view of the recognized relationship between IgG Fc glycosylation, Fcγ receptor activation, and disease severity, and therefore do 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. Instant claim 3, which recites determining the amount of fucosylation, is not patentably distinct from claim 1 of ’414, which requires determining afucosylated Fc glycans, thereby encompassing fucosylation status. 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.
Accordingly, claims 1–6 are not patentably distinct from claims 1, 2, 4, 7, and 9 of ‘414 in view of Irvine et al., Singh et al., Thulin et al., Zhou et al., Fu et al., and Goldmann et al., because the instant claims merely apply the same IgG glycosylation biomarker-based diagnostic and clinical decision framework to a different viral disease context and implement a routine and expected therapeutic intervention directed to the same underlying immune signaling mechanism.
Response to Arguments
Applicant’s remarks filed in response to the non-final Office Action dated January 7, 2026 have been fully considered. The application has been reexamined in light of the amendments to the claims, including amended claim 1 and cancellation of claim 7. The following is the Examiner’s response.
With respect to the objection to the specification, Applicant’s arguments are persuasive. Applicant states that paragraph [0005] has been amended to correct the typographical error from “sad” to “said” and to correct the phrase concerning “symptomatic or prone.” Applicant also notes that the terminology concerning “clinically significant COVID-19 infection” and “severe COVID-19 disease” has been removed from the claims. In view of these amendments, the previously identified informality and terminology concerns no longer affect the claims presently under examination. Applicant further argues that the specification provides support for fucosylation, galactosylation, and bisection/bisecting N-acetyl glucosamination through Example 1, including paragraphs [0118] and [0119]. Upon reconsideration, the specification objection is withdrawn.
Applicant’s arguments regarding the objection to claims 1 and 7 are also persuasive. Claim 1 has been amended to correct the typographical issue concerning “said,” and the previously objected-to “symptomatic or prone” language has been omitted. Claim 7 has been cancelled. Accordingly, the claim objections to claims 1 and 7 are withdrawn.
Regarding the rejection under 35 U.S.C. § 101, Applicant argues that amended claim 1 recites a method of treatment and includes the physical step of administering to the subject an inhibitor of FcγRIIA or FcγRIIIA receptor signaling. Applicant’s argument is persuasive. Although the prior claims were rejected as directed to a natural correlation and mental process, amended claim 1 now applies the biomarker determination in the context of a recited therapeutic method. In particular, amended claim 1 requires administering a specified class of therapeutic agent, namely an inhibitor of FcγRIIA or FcγRIIIA receptor signaling, to a subject infected with SARS-CoV-2. This treatment step integrates the judicial exception into a practical application by using the biomarker information to effect a particular treatment for a disease or medical condition. Accordingly, the rejection under 35 U.S.C. § 101 is withdrawn.
Regarding the rejection under 35 U.S.C. § 112(b), Applicant’s arguments are persuasive in part. Applicant amended claim 1 to remove the phrase “reduced level” and instead recite that the amount of the specified glycosylation feature in the subject sample is less than the amount from a blood sample from a healthy adult donor. This amendment provides an objective comparator and resolves the prior indefiniteness issue directed to the relative phrase “reduced level.” Applicant also removed the previously rejected subjective terminology, including “prone to present one or more symptoms,” “prone to progress to severe COVID-19 disease,” and “clinically significant COVID-19 infection or disease.” Therefore, the prior §112(b) rejection based on those terms is withdrawn.
However, the rejection under §112(b) is maintained as to claim 4. Applicant’s remarks do not resolve the separate ambiguity created by claim 4’s recitation of “the level of afucosylated Fc glycans.” Claim 1 recites determining an “amount” of immunoglobulin fucosylation, galactosylation, and/or bisecting N-acetyl glucosamination, and claim 3 recites determining the “amount of fucosylation.” Claim 4 then introduces “the level of afucosylated Fc glycans,” but claims 1–3 do not provide antecedent basis for “the level” or for “afucosylated Fc glycans.” It remains unclear whether the “amount of fucosylation” recited in claims 1 and 3 is intended to correspond to the “level of afucosylated Fc glycans” in claim 4, or whether claim 4 introduces a different measurement, glycan subset, or calculated percentage. Accordingly, claims 1–3 and 5–6 are no longer rejected under §112(b), but claim 4 remains rejected under §112(b) as indefinite.
Applicant’s arguments concerning the rejection under 35 U.S.C. § 103 have been considered but are not persuasive. Applicant argues that Irvine, Singh, Thulin, and Zhou do not individually teach administering an inhibitor of FcγRIIA or FcγRIIIA receptor signaling for treating SARS-CoV-2 infection. However, this argument does not address the rejection as currently maintained. The present rejection has been updated in view of amended claim 1 and now relies on the combined teachings of Irvine, Singh, Thulin, Zhou, Fu, and Goldmann. The rejection does not require that Irvine alone, Singh alone, Thulin alone, or Zhou alone disclose every limitation of the amended claim. The rejection maintains that Irvine teaches the antibody glycosylation framework, including the relevance of fucosylation, galactosylation, bisection, and sialylation to disease state and Fc-mediated immune effects. Singh teaches quantitative glycoprofiling methods suitable for determining the amount of IgG glycosylation features. Thulin teaches the clinical relevance of afucosylation in viral disease severity. Importantly, Thulin further establishes that IgG Fc glycosylation, particularly afucosylation, directly modulates Fcγ receptor binding and downstream immune activation, thereby mechanistically linking the measured glycosylation traits to Fc receptor-mediated inflammatory signaling. Zhou provides the SARS-CoV-2 disease context and the recognized clinical importance of identifying patients with poor prognosis at an early stage. Fu supplies the SARS-CoV-2-specific therapeutic rationale by identifying Fc receptor-mediated inflammatory signaling as relevant to SARS-CoV-2 inflammatory pathology and by teaching blocking Fc receptor activation as a therapeutic strategy. Goldmann teaches that Fcγ receptor signaling, including FcγRIIA-mediated signaling, can be inhibited through administration of inhibitors to a subject. Thus, the additional Fu and Goldmann references do not merely supplement the prior art, but directly address the previous missing therapeutic step by teaching that the same Fc receptor signaling pathway implicated by IgG glycosylation can be targeted through administration of inhibitors.
Applicant’s argument that none of the references individually teaches the complete amended method is not persuasive because obviousness is based on what the combined teachings would have suggested to a person of ordinary skill in the art. In the present rejection, the prior art collectively links IgG Fc glycosylation traits to Fc receptor activation and disease severity, identifies SARS-CoV-2 inflammatory disease as involving Fc receptor-mediated inflammatory signaling, and teaches administration of inhibitors that suppress Fcγ receptor-mediated activation.
Accordingly, the combination establishes a unified biological pathway, and provides both the diagnostic framework and the corresponding therapeutic target within that same pathway. Therefore, a person of ordinary skill in the art would have been motivated to modify the antibody glycosylation-based analytical framework to include administering an Fc receptor signaling inhibitor to treat a subject infected with SARS-CoV-2. This modification is based on the explicit recognition in the prior art that the same Fcγ receptor-mediated pathway identified through glycosylation biomarkers is responsible for inflammatory disease severity and is amenable to therapeutic inhibition. The modification is based on the shared biological pathway taught by the prior art: IgG Fc glycosylation affects Fc receptor activation, Fc receptor activation contributes to inflammatory disease severity, and inhibition of Fc receptor signaling was a known approach for suppressing such activation.
Applicant’s reasonable expectation of success argument is likewise unpersuasive. The rejection explains that the relationship between IgG Fc glycosylation, Fc receptor activation, and inflammatory disease outcomes was known before the effective filing date, and that inhibition of Fc receptor signaling was a known and practiced approach for suppressing Fc receptor-mediated cellular activation. Given that the prior art identifies both the disease-associated signaling pathway and established methods for inhibiting that pathway, a PHOSITA would have reasonably expected that applying known Fc receptor signaling inhibitors in the SARS-CoV-2 context would reduce Fc receptor-mediated inflammatory responses. In view of the combined teachings, applying Fc receptor signaling inhibitors in the SARS-CoV-2 context would have represented the predictable use of prior art elements according to their established functions, with a reasonable expectation that such inhibition would reduce Fc receptor-mediated inflammatory responses in infected subjects. Accordingly, the rejection under 35 U.S.C. § 103 is maintained as to claims 1–6.
Applicant’s arguments concerning the nonstatutory double patenting rejection have also been considered but are not persuasive. Applicant argues that the pending claims are nonobvious over the identified claims of U.S. Patent No. 11,826,414 for reasons similar to those presented against the §103 rejection. However, the nonstatutory double patenting rejection has been updated in view of the amended claims and is maintained over claims 1, 2, 4, 7, and 9 of U.S. Patent No. 11,826,414 in view of Irvine, Singh, Thulin, Zhou, Fu, and Goldmann. The instant claims and the claims of the ’414 patent share the same core framework of IgG Fc glycosylation biomarker analysis, quantitative determination of glycan levels, comparison to a reference or threshold, and performance of a clinical action based on the biomarker-driven identification. The amendments to claim 1 do not eliminate this overlap. Rather, the amended claim applies the same general IgG glycosylation biomarker-based clinical decision framework to SARS-CoV-2 and recites a different downstream clinical intervention, namely administration of an inhibitor of FcγRIIA or FcγRIIIA receptor signaling.
As discussed in the updated ODP rejection, the substitution of one viral disease context for another and the selection of an Fc receptor signaling inhibitor as the therapeutic intervention constitute obvious variations in view of the applied secondary references. In particular, the prior art establishes that IgG Fc glycosylation profiles identify disease-associated immune activity mediated through Fcγ receptors, and further establishes that this same Fcγ receptor-mediated pathway is a recognized therapeutic target. Accordingly, modifying the ‘414 method to apply the same biomarker framework to SARS-CoV-2 and to select a therapeutic intervention directed to the identified Fc receptor-mediated mechanism represents a predictable and routine adaption of the prior art framework. Hence, the claimed differences do not reflect a distinct invention, but rather the application of the same underlying biomarker-driven clinical decision paradigm to a different disease context with a corresponding, well-known therapeutic modality targeting the same biological pathway. Therefore, Applicant’s argument does not establish patentable distinctness over the ’414 patent claims, and the nonstatutory double patenting rejection is maintained.
In summary, the objection to the specification is withdrawn. The objection to claims 1 and 7 is withdrawn. The rejection under 35 U.S.C. § 101 is withdrawn. The rejection under 35 U.S.C. § 112(b) is withdrawn as to claims 1–3 and 5–6 but maintained as to claim 4. The rejection under 35 U.S.C. § 103 is maintained as to claims 1–6. The nonstatutory double patenting rejection is maintained as to claims 1–6.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/E.O./Examiner, Art Unit 1677
/BAO-THUY L NGUYEN/Supervisory Patent Examiner, Art Unit 1677 May 4, 2026
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