Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on De. 21, 2025. Claims 1-11, 14,16-19 and 21 are pending and are currently examined.
Claim Objection
(Previous objection- withdrawn) Claim 1 is objected because the “comma” after “at a time point (X)”. For consistency, a “semicolon” should be used.
Claims 19 and 20 are identical.
Claim 20 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 19. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
This objection is withdrawn in view of the amendment filed on Dec. 21, 2025.
(New) The base claim 18 is objected to because of the following informalities:
Claim 18 recites “…encoded by the B-cells…”, which should be “…encoded by nucleic acids…”.
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.
(Previous rejection- withdrawn) Claim 12 is rejected under 35 U.S.C. §101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
The claim 12 recites an antibody or antigen binding fragment identified by a method according to any one of claims 1, where the antibody or antigen binding fragment are from one or more human subjects.
This rejection is withdrawn in view of the amendment filed on Dec. 21, 2025.
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.
(Previous rejection- withdrawn) Claims 1-12, 14 and 16-20 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.
This rejection is withdrawn in view of the amendment filed on Dec. 21, 2025.
(New Rejection-necessitated by amendment) claims 2-3 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.
Claim 2 recites a phrase “…sample is collected at a second time point, wherein second time point is at least 3 months earlier or later than the first time point” that renders the claim indefinite. It is not clear how the sample can be collected at a second time point that is at least 3 months earlier than the first time point. After the samples were taken at the first time point, one cannot go back 3 months for a second time point sample collection.
Claim 3 recites a phrase “…plasma samples from the subject collected at a second time point that an earlier or later time point than the first time point” that renders the claim indefinite. It is unclear how the plasma samples can be collected at a second time point that is earlier than the first time point. It is not reasonable that a time point for a sample collection can go back after the first time point sample collection.
Claim Rejections - 35 USC § 112 (d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS. —Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 14 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 14 is improperly depend on the new added claim 21 after the claim 14. 35 U.S.C. § 112(d) states that “a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
IN GENERAL. —The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
(New Rejection-necessitated by amendment) Claims 1-3 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The amendments to the base claim 1 and claims 2-3 introduce new matter.
The claims 1-3 are amended to add limitations of “first time point” and “second time point” for plasma and/or PBMC samples collections. The instant specification discloses that the plasma/PBMC samples can be collected at time point (X) (See [0013] and [0015]) and at a time point (Y) (See [0057] and [0062]. However, the limitations of “first time point” and “second time point” were not disclosed in the originally filed specification. Therefore, these claims introduce new matter.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
(Previous rejection- maintained except claim 14) Claims 1-11 and 16-19 are rejected under 35 U.S.C. 103 as being unpatentable over Ng et al. (bioRxiv preprint doi: https://doi.org/10.1101/2020.05.14.095414; this version posted May 15, 2020, including the “supplementary Materials”) in view of Wec et al. (bioRxiv [Preprint]. 2020 May 16:2020.05.15.096511).
The base claim 1 is directed to a method for identifying a coronavirus cross-reacting antibody, said method comprising”
a) providing plasma samples from one or more human subjects, said samples collected, independently, at a time point (X),
b) identifying subjects having plasma samples with immunoglobulins that bind to at least two human coronaviruses (HCoV), wherein the HCoV is selected from HCoV-NL63, HCoV-OC43, HCoV-229E and HCoV-HKU1:
c) providing PBMC samples from said identified subjects, wherein the PBMC samples are collected at time point (X) or later and comprise B-cells selected from memory B-cells, plasma cells, and plasmablasts;
d) screening antibodies, or antigen-binding fragments thereof, encoded by the B-cells of c) for binding to at least part of the S2 ectodomain of the S (spike) protein from at least two, preferably at least four, different coronaviruses;
e) selecting antibodies, or antigen-binding fragments thereof, that bind to at least part of the S2 ectodomain of the S protein of at least one common human coronavirus selected from HCoV-NL63, HCoV-OC43, HCoV-229E and HCoV-HKUl and that bind to at least part of the S2 ectodomain of the S protein of at least one highly pathogenic human coronavirus selected from SARS-CoV-1, MERS-CoV and SARS-CoV-2.
f) selecting antibodies or antigen-binding fragments thereof from e) that inhibit viral fusion, infection, and/or replication of at least one common human coronavirus selected from HCoV-NL63, HCoV-OC43, HCoV-229E and HCoV-HKUl and that inhibit viral fusion, infection, and/or replication of at least one highly pathogenic human coronavirus selected from SARS-CoV-1, MERS-CoVand SARS-CoV-2;
g) determining the ability of the selected antibodies, or antigen-binding fragments thereof, from f) to prevent or reduce infection in an in vivo model of HCoV infection selected from SARS-CoV-1, MERS-CoV and SARS-CoV-2; and
h) selecting antibodies, or antigen-binding fragments thereof, that prevent or reduce infection in an in vivo model of HCoV infection selected from SARS-CoV-1, MERS-CoV and SARS-CoV-2.
Ng et al. describes a pre-existing and de novo humoral immunity to SARS-CoV-2 in humans, and teaches that the presence of pre-existing immunity in uninfected and unexposed humans to the new coronavirus (See Abstract). They teach that the immune cross-reactivity among seasonally spreading human coronaviruses (HCoVs) has long been hypothesized to provide cross-protection, albeit transient, against infection with distinct HCoV types and they developed a sensitive flow cytometry-based assay for detection of SARS-CoV-2-binding antibodies determine the degree of cross-reactivity between HCoVs and the recently introduced zoonotic coronavirus SARS-CoV-2 (See page 3, paragraph 1).
Accordingly, Ng et al. teaches a method through numerous serological screening test for identifying a coronavirus cross-reacting antibody as claimed. The details of the teachings are as the follows:
Ng et al. teaches a) by stating that the clinical samples are serum and plasma from different groups: 31 SARS-CoV-2-uninfected patients without recent HCoV infection (SARS-CoV-2 - HCoV -), 34 SARS-CoV-2-uninfected patients with recent HCoV infection (SARS-CoV-2 – HcoV +), 30 SARS-CoV-2-uninfected UCLH patients of unknown HCoV status, 50 SARSCoV-2-uninfected visitors of antenatal clinics (See page 7, paragraph 1 and Table S1 below).
Ng et al. teaches b) by stating the antibody/ immunoglobulins targeting HCoV-OC43 and HCoV-229E (See page 4, paragraph 5 and Fig. S12 and Table S2 below). Fig. S12 teaches that the IgG are identified in 66-years old donor with OC43 infection, and Table S2 teaches the antibodies induced by the core epitope of S protein can be cross-binding to HCoV-OC43 and HCoV-229E.
Ng et al. teaches d) and e) by stating that the SARS-CoV-2 S protein is proteolytically processed into the S1 and S2 subunits that mediate target cell attachment and entry, respectively. S2 exhibits a higher degree of homology among coronaviruses than S1 and it was likely to be the main target of cross-reactive antibodies (See page 3, paragraph 2). In Table S2 (See below), Ng et al. teaches that antibody targeting the epitope S817-824 is cross-reactive in HCoV-OC43 and HCoV-229E and Sars-COV-2, where the epitope is located at the ectodomains of S2 subunit. Ng et al. discloses that the soluble amino acids position of S2 is at 686-1273 (See page 3, paragraph 2, Supplementary Materials) that is the ectodomain of S2, so the epitope S817-824 is among the ectodomain region. Also, it is a common knowledge in the art that the antibody is produced by B-cells. In addition, Ng et al. teaches using Flow cytometry for screening/high-throughput detect antibodies of their samples as “Samples were run on a LSR Fortessa with a high-throughput sampler” (See page 7, paragraph 4) that is a highly tool for screening analysis in flow cytometry.
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Ng et al. teaches f) to h) by stating that one of the ways in which HCoV-elicited antibodies protect against SARS-CoV-2 infection is inhibition of entry into the target cell as HCoV induced antibodies cross-react with S2. It is therefore plausible that HCoV patient sera targeting the S2 also neutralize, without affecting binding to ACE2 (See page 5, paragraph 2). Here this description indicates that the antibodies or antigen-binding fragments inhibit viral entry that can be included inhibiting viral infection and fusion (See Table S2 above) for both SARS-COV-2 and other HCoV such as HCoV-OC43 or HCoV-229E (See Table S2), which teaches f). Here it is a common knowledge in the art that viral entry inhibitors can effectively inhibit virus infection by preventing the virus from entering host cells. Because the HCoV-elicited antibodies can inhibit the SARS-COV-2 infection, so they can reduce or prevent both HCoV and SARS-COV-2 infection, which teaches g) and h). As for the “prevent or reduce infection in an in vivo model of HCoV infection selected from SARS-CoV-1, MERS-CoV and SARS-CoV-2” in g) and h), Ng et al. teaches that these observations support a model whereby exposure to HCoVs elicits humoral immunity that cross-reacts with conserved protein domains in other coronaviruses, including SARS-CoV-2 (See page 4, paragraph 5). Here Ng shows single 60-year-old patient in this cohort, sampled on day 29 post onset of symptoms, at a time-point when all other COVID-19 patients had seroconverted, had SARS-CoV-2 S-reactive IgG, but not IgM or IgA antibodies, that were detected by FACS, but not by ELISAs (Extended data Fig. 5). Again, this profile was more consistent with an anamnestic response to HCoVs, than a de novo response to SARS-CoV-2. This patient described only mild COVID-19 symptoms that did not necessitate hospitalization, but appeared chronically infected with SARS-CoV-2, having tested repeatedly positive for viral RNA for over a month (Extended data Fig. 7). (See page 4, paragraph 4).
Although Ng et al. does not explicitly teach an in vivo experiment regarding the treatment and preventing, it teaches that the apparent ability of HCoV patient sera to neutralize SARS-CoV-2 S pseudotyped raise similar concerns regarding the specificity of neutralization assays. For example, 5 of 1,000 samples from healthy Scottish blood donors collected in March 2020 neutralized SARS-CoV-2 S pseudotypes and 1 or 100 of samples collected in 2019 also had neutralizing activity in the absence of a strong ELISA signal. Notably, these samples were described to have low or no SARS-CoV-2 S-reactive IgM antibodies, a feature they would associate with immune memory of HCoVs. Prior immunity induced by one HCoV has also been reported to reduce the transmission of homologous and, importantly, heterologous HCoVs, and to ameliorate the symptoms where transmission is not prevented. A possible modification of COVID-19 severity by prior HCoV infection might account for the age distribution of COVID-19 susceptibility, where higher HCoV infection rates in children than in adults, correlates with relative protection from COVID-19 (See page 6). This description here can be considered a teaching for the antibodies or antigen-binding fragments of Ng can prevent the infection or reduce the infection of heterologous HCoV and SARS-COV-2 in vivo as claimed.
As for the base claim 1 c), it requires that providing PBMC samples from said identified subjects, wherein the PBMC samples are collected at the first time point or later and comprise B-cells selected from memory B-cells, plasma cells, and plasmablasts. However, Ng et al. does not explicitly disclose using the PBMC samples.
Wec et al. teaches that they obtained peripheral blood mononuclear cell (PBMC) samples from three healthy adult donors with serological evidence of circulating HCoV exposure and no history of SARS-CoV or SARS-CoV-2 infection, and stained the corresponding B cells with a fluorescently labeled SARS-CoV-2 S probe and the results suggest that SARS-CoV infection likely led to the activation and expansion of pre-existing cross-reactive MBCs induced by circulating HCoV exposure in this donor (See page 5, paragraph 2). With the isolated PBMC sample, Wec et al. can directly mine the memory B cell repertoire of a convalescent SARS donor and identified 200 SARS-CoV-2 binding antibodies that target multiple conserved sites on the spike (S) protein and discovered a large proportion of the antibodies display high levels of somatic hypermutation and cross-react with circulating HCoVs, suggesting recall of pre-existing memory B cells (MBCs) elicited by prior HCoV infections (See Abstract).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce PBMC samples into Ng’s study. One would have been motivated to do so to add the PBMC sample (other than the plasma sample) with the plasma sample into Ng’s research to study the functional activities of cross-reactive antibodies induced by natural SARS-CoV and SARS-CoV-2 infection (See page 3, paragraph 2).
There would have been a reasonable expectation of success to collect and analyze the PBMC samples as claimed based on the method Wec provided.
Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 2-3, In Table S1 above, Ng et al. teaches that the samples can be collected in a period time longer than three months. For example, samples can be collected in a period of 12/2019-3/2020 (Table S1-D), and some samples can be collected in a time 1/2019-4/2020 and 4/2011-12/2018. It would be obvious for one of ordinary skill in the art to collect sample in a 3-month apart based on the needs.
Regarding claim 4, Ng et al. teaches that the sera/plasma contains IgG, IgM and/or IgA antibodies that bind the HCoV such as HCoV-OC43 and HCoV-229E (See page 3, paragraph 1; page 4, paragraph 5; Fig. S12 above and Table S2), where the Fig. S12 shows the IgG in samples infected by OC43 and Table S2 indicates the cross-reaction between the HCoV-OC43 and HCoV-229E.
Regarding claims 5-8 and 11, Ng et al. teaches that the HCoV induced antibodies cross-react with S2 including the fusion peptide region (See Table S2 above), which also bind the SARS-COV-2 S2 domain and the antibody is IgM, IgA, or IgG (See page 6, paragraph 1). Ng et al. also teaches that the HCoV patient sera inhibit viral infection by inhibiting the viral entry including the SARS-COV-2 infection (See e.g., page 5, paragraph 3). Ng’s Table S2 shows the antibody target both SARS-CoV-2 and HCoV-OC43 and HCoV-229E (Page 28, Supplementary Materials and above Table S2), which teaches claim 7 and claim 11. For the in vivo model of claim 11, Ng et al. also teaches that their study supports a model whereby exposure to HCoVs elicits humoral immunity that cross-reacts with conserved protein domains in other coronaviruses, including SARS-CoV-2 (See page 4, paragraph 5). As for the claim 6, Ng teaches the antibody are analyzed by the LSR Fortessa with a high-throughput sampler (See page 7, paragraph 4), where the LSR Fortessa is an antibody screening cytometer. Ng et al. discloses that the soluble amino acids position of S2 is at 686-1273 (See page 3, paragraph 2, Supplementary Materials) that includes the HR1 heptad repeat, or the HR2 heptad repeat of the S protein.
Regarding claims 9-10, based on the description above, Ng et al. teaches HCoV-elicited antibodies can protect against SARS-CoV-2 infection by inhibition of entry into the target cells (See page 5, paragraph 2) and their study supports a model whereby exposure to HCoVs elicits humoral immunity that cross-reacts with conserved protein domains in other coronaviruses, including SARS-CoV-2 (See page 4, paragraph 5). Ng et al. teaches that the apparent ability of HCoV patient sera to neutralize SARS-CoV-2 S pseudotypes raise similar concerns regarding the specificity of neutralization assays. For example, 5 of 1,000 samples from healthy Scottish blood donors collected in March 2020 neutralized SARS-CoV-2 S pseudotypes and 1 or 100 of samples collected in 2019 also had neutralizing activity in the absence of a strong ELISA signal. Notably, these samples were described to have low or no SARS-CoV-2 S-reactive IgM antibodies, a feature we would associate with immune memory of HCoVs (See page 6, paragraph 3).
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Regarding claim 16, Ng et al. teaches a sample from an 81-year-old (See page 3, paragraph 4).
Regarding claim 17, Ng. et al. teaches that the plasma samples can bind HCoV-NL63, HCoV-OC43, HCoV-229E and HCoV-HKU1 (See Supplementary Materials, Fig. S16 and page 23), where the mapping of cross-reactive epitopes in SARS-CoV-2 S using peptide arrays with primary sera from seroconverted COVID-19 patients.
Regarding claims 18-19, based on the description above, Ng et al. teaches a method for mapping/screening and identify antibodies that are responsible for the Immune cross-reactivity responses between the common HCoV induced antibody to the SARS-COV-2 and identified that a soluble S2 domain (S686-1273) is the targeting epitope (See e.g., Fig. S16 and Table S2). Where the Flow cytometry is used for high-throughput/screening antibody analysis (See page 7, paragraph 4) and the S2 (686-1273) is the ectodomain of S2.
(New Rejection-necessitated by amendment) claims 14 and 21 is rejected under 35 U.S.C. 103 as being unpatentable over Ng et al. (bioRxiv preprint doi: https://doi.org/10.1101/2020.05.14.095414; this version posted May 15, 2020, including the “supplementary Materials”) in view of Wec et al. (bioRxiv [Preprint]. 2020 May 16:2020.05.15.096511) as applied to claims 1-11, 14 and 16-19 above, and further in view of Rockx et al. (J Virol. 2008 Apr;82(7):3220-35).
The amended claim 14 is directed to a method of treating or preventing infection by a coronavirus comprising administering locally to a subject in need thereof the composition of claim 21.
The newly added claim 21 is directed to a composition for binding a human coronavirus (HCoV), the composition comprising an antibody or antigen binding fragment thereof that has been determined to bind to at least part of the S2 ectodomain of the S protein of at least one human coronavirus selected from HCoV-NL63, HCoV-OC43, HCoV-229E and HCoV-HKU1 and bind to at least part of the S2 ectodomain of the S protein of at least one human coronavirus selected from SARS-CoV-1, MERS-CoV and SARS-CoV-2; and prevent or reduce infection in an in vivo model of HCoV infection selected from SARS-CoV-1, MERS-CoV and SARS-CoV-2; and a pharmaceutically acceptable carrier or diluent selected from the group consisting of demineralized or distilled water; saline solution; vegetable-based oils, cellulose derivatives, and polyethylene glycol.
Based on the description above, Ng and Wec teach a method for identifying a coronavirus cross-reacting antibody or antigen binding fragment that bind S2 ectodomain of the S protein of HCoV-NL63 and HCoV-OC43 and also bind to SARS-COV-2 S2 ectodomain. In addition, Ng also teaches that their observation supporting a model whereby exposure to HCoVs elicits humoral immunity that cross-reacts with conserved protein domains in other coronaviruses, including SARS-CoV-2 (See Ng et al., page 4, paragraph 5), however it is silent on the composition and pharmaceutically acceptable carrier or diluent used for the in vivo study.
Rockx et al. studies the structural basis for potent cross-neutralizing human monoclonal antibody protection against lethal human and zoonotic severe acute respiratory syndrome coronavirus challenge, and teaches using three MAbs (S109.8, S227.14, and S230.15) to test for the use in passive vaccination studies using lethal SARS-CoV challenge models for young and senescent mice with four different homologous and heterologous SARS-CoV S variants and concludes that a single human MAb can confer broad protection against lethal challenge with multiple zoonotic and human SARS-CoV isolates (See Abstract). Rpckx et al. discloses the passive immunization experiments like experiments 1-2 “12-month-old mice were injected intraperitoneally with 25 or 250 ug of various human MAbs (D2.2, S109.8, S227.14, or S230.15) in a 400-ul volume at 1 day prior to intranasal inoculation with 10^6 PFU of the different icSARS-CoV strains (n= 3 per MAb per virus per time point) (See page 3222, left column, paragraph 4). Here Rockx teaches an antibody composition being used for preventing or reducing the infection in vivo. Although Rockx does not explicitly use the term “pharmaceutically acceptable carrier or diluent”, it is obvious that a passive immunization injection including the mAbs that should be in a composition formulated together with a pharmaceutically acceptable carrier, diluent and/or adjuvant. Rockx et al. also teaches the benefit for using the neutralizing MAbs in passive immunization as “this form of immunization has the advantage of providing immediate protection in the absence of a humoral immune response and may be especially advantageous for elderly populations, since they show increased morbidity and mortality caused by infectious diseases in general and SARS-CoV in particular (See page 3232, right column, paragraph 3).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the passive immunization of Rockx into the teaching of Ng and Wec to arrive at an invention as claimed. Based on the benefit for administering Mabs in vivo taught by Rockx, one of skill in the art would have been motivated to do so to treat or prevent the virus infection by administering a composition including antibodies in vivo. There would be a reasonable expectation of success to develop such a composition and method as claimed in the instant application.
Responses to Applicant’s Remarks
Applicant’s arguments filed on Dec. 21, 2025 has been received and fully considered.
Applicant’s amendment on claim objection is considered and the objection is withdrawn.
Applicant’s amendments regarding the rejection under 35 U.S.C. § 112(b) is considered and the rejection is withdrawn.
Applicant’s amendment regarding the rejection under 35 U.S.C. § 101 is considered and the rejection is withdrawn.
Applicant’s arguments regarding rejections under 35 U.S.C. § 103 is not found persuasive as the follows:
1). Applicant argued that the study by Ng is a polyclonal characterization study, analyzing the aggregate antibody response present in the serum of different patient cohorts. In contrast, the claimed invention is a method to identify and isolate specific monoclonal antibodies from individual B-cells. This difference is reflected in the specific steps of the claim (See Remarks, page 9, paragraph 4).
Applicant’s argument is not persuasive. The base claim 1 recites “a method for identifying a coronavirus cross-reacting antibody…”, where there is no limitation for the types of “antibodies”, which can be a monoclonal antibody or polyclonal antibody. Also, Ng teaches screening antibody by Flow cytometry. One of ordinary skill in the art would understand that the monoclonal antibody can be isolated.
2). Applicant argued that Ng does not teach or suggest a “selection step” in the base claim (b) and a further B-cell sorting and monoclonal antibody development (See Remarks, page 9).
Applicant’s argument is not persuasive.
First, there is no claim limitation for B-cell sorting in the claim 1 (b).
Second, Ng teaches identifying the immunoglobulins from a plasma sample as claimed in the base claim 1 (b) that requires “identifying subjects having plasma samples with immunoglobulins that bind to at least two human coronaviruses…”. For example, Fig. S2 shown a detection of immunoglobulins from the plasma (See Supplementary Materials, page 9, Fig. S2 and below). Also, the IgG from OC43 infected sample can reacted with SARS-COV-2 as well.
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3). Applicant argued that Ng provides no disclosure, teaching, suggestion, or motivation to perform the critical in vivo steps in claim 1 (g) and (h) and does not teach the specific donor selection strategy of step (b) nor the mandatory in vivo validation and selection of steps (g) and (h) (See Remarks, page 10).
Applicant’s argument is not persuasive.
For step (b), based on the description above, Ng teaches the identifying the immunoglobulins from the plasma samples as claimed (See Fig. S2 above).
Based on the description above regarding the steps (g) and (h), Ng teaches the HCoV-elicited antibodies can inhibit the SARS-COV-2 infection, so they can reduce or prevent both HCoV and SARS-COV-2 infection (See page 5, paragraph 2) and a possible modification of COVID-19 severity by prior HCoV infection might account for the age distribution of COVID-19 susceptibility, where higher HCoV infection rates in children than in adults, correlates with relative protection from COVID-19 (See page 6, paragraph 4). Based on the antibody determination data, Ng also teaches that their observations support a model whereby exposure to HCoVs elicits humoral immunity that cross-reacts with conserved protein domains in other coronaviruses, including SARS-CoV-2 (See page 4, paragraph 5). Although Ng et al. does not explicitly teach an in vivo experiment regarding the treatment and preventing, it teaches that the apparent ability of HCoV patient sera to neutralize SARS-CoV-2 S pseudotyped raise similar concerns regarding the specificity of neutralization assays. For example, 5 of 1,000 samples from healthy Scottish blood donors collected in March 2020 neutralized SARS-CoV-2 S pseudotypes and 1 or 100 of samples collected in 2019 also had neutralizing activity in the absence of a strong ELISA signal. Notably, these samples were described to have low or no SARS-CoV-2 S-reactive IgM antibodies, a feature they would associate with immune memory of HCoVs. Prior immunity induced by one HCoV has also been reported to reduce the transmission of homologous and, importantly, heterologous HCoVs, and to ameliorate the symptoms where transmission is not prevented. A possible modification of COVID-19 severity by prior HCoV infection might account for the age distribution of COVID-19 susceptibility, where higher HCoV infection rates in children than in adults, correlates with relative protection from COVID-19 (See page 6). This description here can be considered a teaching for the antibodies or antigen-binding fragments of Ng can prevent the infection or reduce the infection of heterologous HCoV and SARS-COV-2 in vivo as claimed.
4). Applicant also argued that the gap between in vitro activity and in vivo efficacy is well-established and highly unpredictable. An antibody that is effective in a petri dish may fail in a living organism. The claimed method bridges this gap by requiring selection based on proven in vivo efficacy, which is a feature entirely absent from Ng A person of ordinary skill would not have been motivated to perform the burdensome and unpredictable steps of in vivo testing with a reasonable expectation of success based solely on the disclosure of Ng.
Applicant’s argument is not persuasive.
First, Ng teaches to use an in vivo model to study HCoVs elicits humoral immunity that cross-reacts with conserved protein domains in other coronaviruses, including SARS-CoV-2. Also, it is a common knowledge that the in vivo experimental is critical for identify if an antibody can treat or prevent viral infection because there is a gap between in vitro activity and in vivo efficacy. Therefore, a person of ordinary skill would not have been motivated to perform it in a vivo study.
Also, Ng shows single 60-year-old patient in this cohort, sampled on day 29 post onset of symptoms, at a time-point when all other COVID-19 patients had seroconverted, had SARS-CoV-2 S-reactive IgG, but not IgM or IgA antibodies, that were detected by FACS, but not by ELISAs (Extended data Fig. 5). Again, this profile was more consistent with an anamnestic response to HCoVs, than a de novo response to SARS-CoV-2. This patient described only mild COVID-19 symptoms that did not necessitate hospitalization, but appeared chronically infected with SARS-CoV-2, having tested repeatedly positive for viral RNA for over a month (Extended data Fig. 7). (See page 4, paragraph 4). Here this case can be considered as an in vivo antibody teaching.
Second, for the alleged argument on “an antibody that is effective in a petri dish may fail in a living organism”, the Office does not have the facilities and resources to provide the factual evidence needed in order to establish that the antibody of Ng does not prevent or reduce infection in an in vivo model as claimed. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed invention is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
5). Applicant also argued about claims 2-12, 14, and 16-19 based on the arguments for the base claim 1 (See Remarks, page 10, paragraph 6).
Applicant’s argument is not persuasive.
For each amended dependent claims above, the current office action addressed them in the 103 rejections with a new cited prior art refence.
Conclusion
No claims are allowed.
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 extension fee 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 date of this final action.
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/RUIXUE WANG/ Examiner, Art Unit 1672
/NICOLE KINSEY WHITE/ Primary Examiner, Art Unit 1672