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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on May 11, 2023 and Jan 14, 2025 are compliance with the provisions of 37 CFR 1.97. Accordingly, they have been considered by the examiner.
Claim Objections
Claim 7 is objected to because of the following informalities: In line 12 of claim 7 there is a repeated citation: “in the presence in the presence”. Appropriate correction is required.
The specification of the Application is objected because there is an incorporation by reference by a hyperlink on page 2 of specification. Please delete the hyperlink according to the US patent practice rule under 37 CFR 1.57(e)
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 13 is unclear and confusing with following undefined subject matters:
1). Which virus is considered as the first virus compared to the second virus,
2). The citation on line 1 of “that pseudovirion” lacks of antecedent basis because there is no any description of a “pseudovirions” prior to that citation.
3). "the viral particle " in line 2 of step (d) of the claim is undefined with two reasons: Firstly, there is insufficient antecedent basis for this limitation prior to any “viral particle” citated in the claim prior to this citation. Secondly, it is unclear which virus is referred as this particle. Is it the first virus or second virus or pseudovirions?
Applicants are reminded while a claim can be interpreted in light of the specification, any subject matter cited in the claims needs to be clearly defined. Otherwise the claim is considered to be indefinite because it is unclearly defined subject matter in the claim.
Claim 7 recites the limitation "the efficacy " in the claim. It should cited an efficacy rather than the efficacy as there is not efficacy being cited prior to the citation.
Examiner’s notes:
I). The 1st group of invention cited in claims 1-6 is drawn to a method for identifying a compound that can modulates a coronavirus infection by coculturing target cells that expresses ACE-2 and/or nAChR with a spike protein of any coronavirus in a presence or absence of a compound; A BRIs of the method is done as an in vitro assay but the samples obtained from an infected subject with or without the testing compound presence or absence represent as treated or untreated with a compound in vivo prior to the serum samples are collected explitely implicitly/ inherently.
II).The 2nd group of invention cited in claims 7-12 is directed to an method for determining an efficacy of a compound in a subject wherein the compound can modulate a production of coronavirus neutralizing antibody in the subject. The method comprises testing the spike protein mediated binding and fusion after binding ACE2 and/or nAChR expressed on the surface of the target cells, but the spike protein is a spike protein isolated from the subject infected with coronavirus selected from any SARS-CoV2 or its variant cited in claims 9 and 10.
III). the 3rd group of claims 13-20 are drawn to a method to identify a compound comprises the following steps :
A Broadest Reasonable Interpretations (BRI) of some of pending claims:
i). Target cells cited in claims can be genetic engineered target cell line or live cells isolated from or just presented in the subject :
ii). Expressing ACE2 and/or nAChR can be transfected or naturally expressed by the target cells in vitro or in vivo.. They can be found expressed together as evidenced by Oliveira et al. *Biophysical Journal 2021, Vol. 120, 983-993) although some of the coronavirus does not use both of them together as evidenced by
Iii). The transfecting SPIKE protein into cells cited in claims 12-20 of group III, the other spike protein provided by a nucleic acid molecule or viral particle can be done via coronavirus infection or a recombinant DNA technology such as plasmid DNA expression vector or pseudotyped viral vector either alone or in combination with a marker gene .
Iv). The other spike protein carried by the nucleic acid or viral particle is not only interpolated as expression plasmid or viral vector expression but also a naturally coronavirus infection.
The rejections set forth below are based on the above BRIs
Claim Rejections - 35 USC §102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3 , 5, 13-15, 18 and 20 are rejected under 35 U.S.C. 102( (a) (1)) as anticipated by Schmidt et al. (JEM, published on July 1, 2020 217 (11): e20201181. doi: 10.1084/jem.20201181,
Schmidt et al. teach that coronaviruses is dependent on the Spike protein (S) binding to its receptor ACE2 of a target cell to infect animal and elicit a neutralizing antibody for overcome the infection.. Such neutralizing antibodies are valuable for therapy and prophylaxis. Based on this notion, Schmidt et al. develop assays that comprises 1). constructing a pseudotyped viral vector that carries a heterologous sequence encoding a spike protein of a coronavirus, particularly the SARS-Cov2 or its fragment therefor essential comprising receptor binding domain (RBD) and a signal marker such as luciferase (Luc) or enhanced green florescence marker (EGF) and 2). using such viral vector to infect target cells that express the receptor of the coronavirus, ACE2 onto the target cell surface, such as 293T/ACE2. The two pseud typed viral vectors are made as HIV-1NLΔEnv-NanoLuc viral vector or rVSV/SARS-CoV-2/GFPviral vector respectively., 3). Screening a neutralizing antibody is conducted with the HIV-1NLΔEnv-NanoLuc viral vector or rVSV/SARS-CoV-2/GFPviral vector system in the presence or absence of the potential anti-SARS-CoV2 binding inhibitor or neutralizing antibody respectively. They further teach using this system to test convalescent plasma possibly comprising neutralizing antibodies and human RBD-specific mAbs (See Results Figs. 1-5 and Table S1-S2). They also demonstrate that these assays provide measurements of virus neutralization that are well correlated with a neutralizing antibody which can bind the authentic SARS-CoV-2 virions via S protein binding, hereby inhibit the virus infectivity..
Thus, considering the neutralizing antibody presented in the serum or a positive or negative control compound under the investigation, the reference anticipates claims 1-2, 5, 13-15, 18 and 20.
Claims 1-3, 5, 13-15, 18 and 20 are rejected under 35 U.S.C. 102( (a) (1) ) as anticipated by Hu et al. (Genes Dis. 2020, July 17, Vol. 7 (4), pp. 551-557).
Hu et al. established a safe and convenient assay system for studying entry inhibitors that block the SEARS-CoV2 infection. The method comprises the following steps of constructing a codon-optimized, full-length C-terminal mutant spike (S) gene of SARS-CoV-2 into a luciferase (Luc)-expressing pseudovirus construct that contain a nucleic acid sequences encoding a wild-type or mutant S protein of SARS-CoV-2 in the envelope-defective HIV-1 backbone, wherein the Luc reporter gene enables assay that can easily quantifies a coronavirus entering into that target cells via the viral receptors , i.e. angiotensin-converting enzyme 2 (ACE2) that are genetically pressed on the genetically manipulated target cells, i. e. 293T cells. The compounds under the investigation include Camostat mesylate, aloxistatin, Cathepsin (Cat)B/L inhibitor E−64d, an anti-RBD monoclonal antibody against the SARS-CoV-2 S protein that is served as positive control, a recombinant ACE2 with the fused Fc region of human IgG1 (ACE2 ACE2-Ig ) (Cat: 10108-H02H), and Patient sera samples that include neutralizing antibodies that include three convalescent COVID-19 patient sera. In particular, they also teach using the method to detecting human serum samples isolated from patients and determining if they comprise a neutralizing antibody. The cited reference anticipates clams 1-3, 5, 13-15, 18 and 20.
Claims 1-3 , 5, 13-15, 18 and 20 are rejected under 35 U.S.C. 102( (a) (1)) as anticipated by Lei et al. (Nature Communications, published on 24, April 2020, Vol. 11, no. 2070 pp. 1-5).
Lei et al. teach a method using a HIV pseudotyped viral vector to investigate if a compound is a spike protein binding inhibitor to its receptor ACE2. The method comprises administering a compound i.e. murine rACE2 fused with a Fc fragment ( rACE2-Fc) or its variant mACE2-Ig and a negative control TIGIT-Ig to a target 293Tcells or A549cells that are genetically engineered to express ACE2 receptor and co-cultured with pseudo HIV vector particle that carries the gene encoding and expressing Spike (S) glycoproteins from SARS-CoV2 or SARS-Cov as well as fluorescent (luc) or β-gal marker genes for a certain period of time and then measuring the inhibitory effects against the coronavirus infection via such blocking activity of S protein binding to ACE2, which is presented by percentage of colored target cells vs the uncolored target cells by Luc image or β-gal color matrix intensity (Supplementals Fig. 1-3 & Table 1-2 and paragraph of Results). Therefore, the reference by Lei et al. explicitly anticipates claims 1-3, 5, 13-15 18 and 20.
Claims 1, 6-7 and 12 are rejected under 35 U.S.C. 102( (a) (1)) as anticipated by Chen et al. (JID, 2017, Vol. 251, pages 1807-1815) as evidenced by Papapostolou et al. (Cells, 2023, Vol. 12 (5). Pp. 1-22).
Chen et al. teach a method for investigating if a neutralizing antibody in produced in response to a treatment of Middle East respiratory syndrome coronavirus (MERS-CoV) infection, wherein the method comprises treating animal Common Marmoset infected by MERS-CoV with a fully human neutralizing antibody, MCA1 by measuring the viral infectivity in the animals (See Fig. 4).
Because this is an in vivo neutralizing antibody treatment study, the method comprises epithelia cells in lung or other tissues in the animal that inherently expresses the ACE2 and nAcHR, both of them are expressed in various epithelial cells (like lung, colon, bladder), not as general "epithelial markers" but as specific subunits (e.g., α3, α4, α5, α7, β2, β4) Key nAChR subunits in epithelial contexts include α5 (cancer cell migration) and α7 (immune/inflammatory responses), forming channels with other subunits as evidenced by Papapostolou et al. Cells, 2023, Vol. 12 (5). Pp. 1-22). In this assay, the test samples is presented as blood with or without the neutralizing antibody MCA1 in vivo and the method comprises the step for measuring the level of the viral infectivity presented as viral titers and severity of pathological changes induced by MERS-CoV infection with or without MCA1 treatment (See Fig. 4). The cited reference is therefore considered to anticipates claims 1, 6-7 and 12.
Claims 1-2, 6-8 and 12 are rejected under 35 U.S.C. 102( (a) (1)) as anticipated by Duan et al. (PNAS, April 06, 2020 , 117 (17) , pages 9490-9496).
Duan et al. teach a method for treatment of patients infected with SARS-CoV-2 by a convalescent plasma (CP) transfusion. In the clinical trial by PC treatment, the method comprises PC that is considered as a “compound” under the investigation and the infected cells are considered as target cells inherently comprising the ACE2 receptor as well as nAChR inherently as evidenced by Papapostolou et al. (Cells, 2023, Vol. 12 (5). Pp. 1-22).The method comprises a spike protein expressed by the SARS-CoV2 naturally viruses, and the method also comprises comparative measurement of the neutralizing antibody titers changes for the patients by ELISA and virus infectivity by RT-PCT influenced by PC treatment or non-treatment (See Tables 3 & 4). The cited reference is therefore, considered to anticipates claims 1-2, 6-8 and 12.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 7-11 are rejected as obvious under 35 U.S.C. 103 over Hu et al. (Genes Dis. 2020, July 17, Vol. 7 (4), pp. 551-557) in view of Crawford et al. (Viruses, published on May 6, 2020, Vol. 12 (5): 513. Doi: 10.3390/v12050513).
Hu et al. established a safe and convenient assay system for studying entry inhibitors that block the SEARS-CoV2 infection. The method comprises the following steps of constructing a codon-optimized, full-length C-terminal mutant spike (S) gene of SARS-CoV-2 into a luciferase (Luc)-expressing pseudovirus construct that contain a nucleic acid sequences encoding a wild-type or mutant S protein of SARS-CoV-2 in the envelope-defective HIV-1 backbone, wherein the Luc reporter gene enables assay that can easily quantifies a coronavirus entering into that target cells via the viral receptors , i.e. angiotensin-converting enzyme 2 (ACE2) that are genetically pressed on the genetically manipulated target cells, i. e. 293T cells. The compounds under the investigation include Camostat mesylate, aloxistatin, Cathepsin (Cat)B/L inhibitor E−64d, an anti-RBD monoclonal antibody against the SARS-CoV-2 S protein that is served as positive control, a recombinant ACE2 with the fused Fc region of human IgG1 (ACE2 ACE2-Ig ) (Cat: 10108-H02H), and Patient sera samples that include neutralizing antibodies that include three convalescent COVID-19 patient sera. In particular, they also teach using the method to detecting human serum samples isolated from patients and determining if they comprise a neutralizing antibody.
However, Hu et al. do not teach how to make an individua SPIKE protein by pseudotyped viral vector, wherein the spike protein is from the same virus infected by the virus that infected host.
Crawford et al. teach all detail steps related to how to make a pseudotyped lentiviral vector by constructing a spike protein into HIV retrovirus and measure the neutralizing activity in human sera. In particular, Crawford et al. teach all basic strategy for making pseudotyping HIV-1-(Figure 1A) comprising the Spike isolated from particular HIV strain and also involves transfecting 293T cells with a lentiviral backbone plasmid encoding a fluorescent or luminescent reporter protein, a plasmid expressing Spike, and plasmids expressing the minimal set of lentiviral proteins necessary to assemble viral particles. The transfected cells then produce Spike-pseudotyped lentiviral particles that can be used to infect permissive cells that express the SARS-CoV-2 receptor protein, ACE2 etc. as well as how to use the pseudo typed lentivirus to check the Neutralization Assays and inhibitory fusion genic assay in detail.
Therefore, it would have been obvious for a person with an ordinarily skilled in the art to be motivated by learning both cited references to construct an individual spike protein and inserted into the backbone of the well characterized pseudotyped viral vector and test the compound or individual serum samples with an reasonable expectation antibody presented in a subject with a reasonable expectation of successfulness.
Claims 4 and 16 are rejected under 35 U.S.C. 103 as obvious over by Lei et al. (Genes Dis. 2020, July 17, Vol. 7 (4), pp. 551-557) or Hu et al. (Genes Dis. 2020, July 17, Vol. 7 (4), pp. 551-557) further in view of Wu et al.( Proc Natl Acad Sci U S A. 2009 Nov 9;106(47):
As described above, both Lei et al. and Hu et al. teach all limitations of claims 1-3, 5, 13-15 18 and 20.,however, neither Lei et al. nor Hu et al. does not teach using the assay to investigate SARS-Cov and NL62 seasonable strain.
Wu teach that NL63-CoV and SARS-CoV both use ACE2 as their receptor despite no obvious sequence homology in their S1 subunits (See Abstract and entire results and discussion from page 19971-19973). - page 106 the section of Results and Discussion).
Therefore, in view of the teachings by Wu et al. a person ordinarily skilled in the art would have been obvious to be motivated using the same method disclosed by Lei et al. or Hu et al. to investigate any compound inhibitory activity for SARS-Cov and NL62 as Wu et al. teach that they use the pseudotype HIV mediated fusion assay for the investigation on SARS-Cov and NL62 because they use the same receptor of ACE2 in light of the teaching by Wu et al. with expected result.
Conclusion
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BAO Q. LI
Examiner
Art Unit 1671
/BAO Q LI/Primary Examiner, Art Unit 1671