DETAILED ACTION
Non-Final Rejection
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election without traverse of Group I claims 1, 6-8, 10-21, and 23-26, and a species of the antibody DH1047 (SEQ ID NO: 1125, and SEQ ID NO: 1127) in the reply filed on 01/20/2026 is acknowledged.
Elected antibody species SEQ ID NO: 1125, and SEQ ID NO: 1127 (DH1047) is free of prior art due to amended claim limitation for requirement of 90% or more amino acid identity.
A prior art search was extended to additional species of antibodies within the claim 1 (genus of antibody) to comprise 90% or more amino acid sequence identity.
Status of Claims
3. Claims 1-26 as filed in claim listing on 01/20/2026 are pending.
4. Claims 2-5, 9, and 22 are withdrawn from examination due to election/restriction.
5. Claims 1, 6-8, 10-21, and 23-26 are under examination in this office action.
Priority
6. This application claims the benefit of and priority to US Patent Application No.
63/078,666 filed on September 15, 2020, US Patent Application No. 63/126,267 filed on December 16, 2020, US Patent Application No. 63/180,564 filed on April 27, 2021, and US Patent Application No. 63/212,078 filed on June 17, 2021.
Information Disclosure Statement
7. The two-information disclosure statement (IDS) submitted on 03/15/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Objection to Specification
8. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
See, instant specification pages 100-106, 117-119, 131-134, 152-156.
9. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
See, instant specification para [0014], [0217], [0219], [0272], [0344], and [0354].
10. The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
11. Claim 1 (and dependent elected Group I claims) objected to because of the following informalities:
The instant claim 1 recites a preamble, “A recombinant coronavirus monoclonal antibody, or an antigen binding fragment thereof, which binds to coronavirus spike protein and ………..”. It is unclear to one of the ordinary skills whether a monoclonal antibody is directed against a recombinant coronavirus or whether a monoclonal antibody is recombinant. The specification indicate that the claimed antibody is a recombinant antibody.
Applicant is required to make the correction. The suggested amendment is: A recombinant a coronavirus spike protein and …………”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
12. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 6-8, 10-21, and 23-26 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.
A .The instant claim 1 recites a limitation using a term “overall” that reads as an overall 90% sequence identity to the VH and VL domains of an antibody. Upon review of the instant specification, the term “overall” is not defined in the specification. Neither the example is provided in the specification that would define the meets and bounds of the instant claim 1.
Additionally, It is not clear if the claim is intending to recite “overall” to replace the terms “average” or “about”. The term “about” is frequently used in the art to indicate quantitative data with an added degree of permissible variation, e.g. +/- 10%. Thus, it is not clear to one of ordinary skill in the art as to how the term “overall” defines the metes and bounds of the claim 1 limitation, nor does the specification provide a definition and/or examples to clarify this ambiguity. Therefore, the claim 1 is indefinite.
B. Claim 1 (and dependent claims) recites VH and VL domains of an antibody and identify the claimed amino acid sequence by assigning the SEQ ID NOs. However, it is unclear which SEQ ID NO of the paired VL and VL of the antibody is assigned to a VH or VL? The specification doesn not appear to provide a definition and/or examples to clarify this ambiguity. Therefore, the claim 1 is indefinite
C. Claim 1 recites a preamble, “A recombinant coronavirus monoclonal antibody, or an antigen binding fragment thereof, which binds to coronavirus spike protein and ………..”. It is unclear to one of the ordinary skills whether a monoclonal antibody is directed against a recombinant coronavirus or whether a monoclonal antibody is recombinant. The specification indicate that the claimed antibody encompasses a recombinant antibody but does not provide a limiting definition, nor do the examples clarify this ambiguity of scope. Therefore, the claim 1 is indefinite
Claim Rejections - 35 USC § 112
13. The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(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.
Claims 1, 6-8, 10-21, and 23-26 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.
According to the instant specification, the claimed recombinant coronavirus monoclonal antibody, or an antigen binding fragment thereof, which binds to coronavirus spike protein and comprises a variable heavy (VH) domain and a variable light (VL) domain are obtained from
that have amino acid sequences that have an overall 90% sequence identity to the VH and VL domains of an antibody are derived from B cells of SARS CoV-2 virus infected of SARS CoV recovered individuals, and or recovered individual. In certain embodiments, the invention provides monoclonal antibodies. In certain embodiments the monoclonal antibodies are produced by a clone of B-lymphocytes. In certain embodiments the monoclonal antibody is recombinant and is produced by a host cell into which an expression vector(s) encoding the antibody, or fragment thereof, has been transfected (Instant specification, para [0110], [0198]).
The scope of claim 1 is generic (very broad) because the claim recites two fifferent genera (i) a coronavirus, and (ii) a recombinant monoclonal antibody comprising 10% amino acid variation (90% amino acid identity). The claim 1 recites limitations that are generic, and the specification does not have support commensurate with the full scope of the claimed invention, “a recombinant coronavirus monoclonal antibody, or an antigen binding fragment thereof, which binds to coronavirus spike protein with an overall 90% sequence identity to the VH and VL domains of an antibody or wherein the VH domain and VL domain each have at least 90% sequence identity to the VH and VL domains, respectively, is claimed by reciting specific antibody VH and VL sequences , for e.g. DH1043 (SEQ ID NOs: 1109, 1111)”. The claim 1 allows up to 10% amino acid substitutions introducing variant species of “a claimed recombinant monoclonal antibody or antibodies”. Additionally, applicant has not quantitively defined the term “overall”. In context to how much variation is allowed by “overall” (e.g. +/- 10%), and the applicants did not recite whether the variation in identity is encompassed in both CDR and non-CDR sequence of the claimed recombinant monoclonal antibody.
The claim 1 is directed to a genus of coronavirus that comprise many species e.g. MERS CoV, and many other coronaviruses of human and mammals. The claimed recombinant antibody or recombinant antibodies is a “genus” that is interpreted to be directed to a coronavirus spike protein domains RBD, NTD, and or S2 (claims 1, and dependent claims).
The instant claims 6-7 claimed the recombinant antibody or the antigen binding fragment thereof according to claim 1, wherein the antibody or antigen binding fragment thereof, comprises a heavy chain comprising at least one CDRH1, at least one CDRH2 and at least one CDRH3 and a light chain comprising at least one CDRL1, at least one CDRL2 and at least one CDRL3, wherein at least one CDR, comprises an amino acid sequence according to a specific pairing of the VH and VL comprising CDR sequences (SEQ ID NOs). The claims 6-7 has added limitation or a functional sequence variant thereof having at least at least 90%, or more sequence identity. It is not clear whether the “variant” has substitution of amino acids in CDRs and what type of amino acids are substituted. Whether the functional variants comprise binding or additional characteristics (e.g. antibody stability / half-life increase).
It has been well known in the art that minor structural differences even among structurally related compounds or compositions can result in substantially different biological or pharmacological activities. It is known in the art that the substitution of amino acids within the protein sequence may cause the loss of function of the protein. Thus, the 10% variation (90% identity) resulting in “variant” antibody or fragments or fragments thereof encompassed by the instant claims 1, 6 and 7 may or may not be effective in achieving the neutralizing efficacy or binding affinities similar to the antibodies that are derived from wild type and recombinant amino acid sequences (without mutations/substitution/variations) in the claimed VH/VL (CDR sequences). Specifically in relation to antibody CDRs, it should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway et al 2001, Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The structure of a typical antibody molecule. Available from: ncbi.nlm.nih.gov/books/NBK27144/. See entire article). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al 1982, Single amino acid substitution altering antigen-binding specificity. Proc Natl Acad Sci U S A. 1982;79(6):1979-1983, see entire article, particularly the abstract and the middle of the left column of page 1982).
The instant specification does not have written description support by reduction to practice of example(s) showing that that the applicant possesses the claimed recombinant antibody variants (90% amino acid identity to the wildtype antibody VH+VL or six CDR sequences CDR H1-H3 and CDR L1-L3) that comprise 10% variation in amino acid sequence that is required to be satisfied through sufficient description of a representative number of species by actual reduction to practice showing similar neutralizing efficacy of a coronavirus or binding to a spike protein domains RBD, NTD or S2 of a coronavirus and cross-reactivity with different species of coronavirus genus e.g. SARS-CoV-1, MERS-CoV, 229E, NL63, HKU1,OC43, bat coronavirus, and/or pangolin coronavirus (See, instant specification, para [0060]). Many different variants of recombinant antibody or the antigen binding fragment thereof are possible and can be envisioned by the ordinary skills given 10% amino acid variation (90% identity).
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021). See MPEP 2163 “Written Description Guidelines”.
The Federal Circuit has clarified the application of the written description requirement to inventions in the field of biotechnology. See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568,43 USPQ2d l398, 1406 (Fed. Cir. 1997). The Court stated that a written description of an invention requires a precise definition, one that defines the structural features of the chemical genus that distinguishes it from other chemical structures. A definition by function does not suffice to define the genus because it is only an indication of what the genus does, rather than what it is. Further, the Court held that to adequately describe a claimed genus, an applicant must describe a representative number of species of the claimed genus, and that one of skill in the art should be able to “visualize or recognize the identity of the members of the genus.”
Amgen Inc. vs Sanofi (2017-1480, Fed Cir, 2017) states that "an adequate written description must contain enough information about the actual makeup of the claim products - a precise definition such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other material," which may be present in "function "terminology "when the art has established a correlation between structure and function" (page 17,1st paragraph).
Therefore, the ordinary skill in the art is not reasonably convinced that the applicant and inventors at the time the application was filed, had possession of the full scope of claimed invention as claimed in claims 1, 6-8, 10-21, and 23-26 since there is no or insufficient representative species and/or identifying characteristics to place applicant in possession of the generic scope of the claimed invention directed to a recombinant antibody comprising amino acid sequence with 90% identity (comprising 10% amino acid variation) and has a function of neutralizing or binding to a coronavirus genus comprising different species as recited in instant specification para [0060] e.g.SARS-CoV-1, MERS-CoV, 229E, NL63, HKU1,OC43, bat coronavirus, and/or pangolin coronavirus.
Claim Rejections - 35 USC § 112
14. Claims 24-26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for “a method of treating” by “administering an antibody for therapeutic or prophylactic”, and , does not reasonably provide enablement for "preventing coronavirus infection in a subject”. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to “use” the invention commensurate in scope with these claims. The subject matter in claims 24-26 directed to a method of preventing coronavirus infection in a subject by administration of an effective amount of the claimed antibody either as a prophylactic or therapeutic treatment is not enabling.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including the nature of the invention, the state of the prior art, the breadth of the claims, the amount of guidance in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, and the quantity of experimentation necessary. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations why the specification is not enabling, in view of the factors set forth in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1998). See also MPEP §§ 2164.01(a) and 2164.04.
Nature of the invention. The claims 24-26 recites an alternative limitation directed to a method of preventing coronavirus infection in a subject in need thereof, comprising administering the recombinant antibody of claim 1 in an amount suitable to effect treatment or prevention of coronavirus infection (instant claim 24). The method of claim 24, wherein the antibody is administered prior to coronavirus exposure or at the same time as coronavirus exposure (instant claim 25). A method of preventing coronavirus infection comprising administering a therapeutic or prophylactic amount of a composition comprising an antibody or antigen binding fragment thereof comprising a Vh and Vl sequence of claim 1, wherein the Vh and Vl sequences are comprised in a bi- or tri- specific antibody format or in a multivalent format (instant claim 26).
State of the prior art. At the time the invention was made anti-coronavirus neutralizing antibody is shown to reduce the coronavirus disease and not to completely prevent the infection of a subject. The infection scientifically is considered as infection when a virus replicates in cells (e.g. nasal or respiratory tract cells of a subject) even if the disease is not developed. However, the art does not establish that a neutralizing coronavirus antibody prevent infection. (See, e.g. not limited to Cao et al 2020, Figure 3, A-C).
Breadth of the claims. The claims are very broad, encompassing a composition and a method for preventing a coronavirus infection (comprises many species withing the coronavirus genus).
Working examples. In the specification, there is no working example reduced to practice that can demonstrate enablement of prevention of infection in subject by administering the claimed antibody as a prophylactic or therapeutic. Prevention of coronavirus disease is know in the art but not the prevention of infection.
Guidance in the specification. The specification provides experimental results on in vitro neutralization of SARS CoV-2 virus, in vivo animal model experiments showing therapeutic and prophylactic efficacy of the claimed antibodies. However, no working example demonstrate absolute prevention of infection (See, Specification, Drawings, and Figures).
Predictability of the art. Prevention of a coronavirus (a broad genus) infection by administering the claimed neutralizing antibodies with 90% amino acid sequence identity (10% variability) to cross-neutralize a broad genus coronavirus comprising many different variant coronaviruses is unpredictable. The prevention of a coronavirus (a broad genus) infection or even any virus infection is not known in the art by using or administering specific broadly cross-reactive antibody, vaccine or immunization or chemotherapy. Based on the teachings of the prior art and the claimed antibodies and a genus of coronavirus infection, it does not appear that the antibodies will prevent infection. However, prevention of the disease is known in the art.
Amount of experimentation. It is not known whether the claimed antibody/antibodies have can prevent infection of a coronavirus (genus coronavirus comprise many different antigenically divergent coronaviruses).
Given the breadth of the claims, the lack of guidance in the specification, and the lack of predictability of the art, it would require undue experimentation for one skilled in the art to use the claimed composition and reduce to the practice the full scope of the claimed method to prevent coronavirus infection.
Claim Interpretation
15. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1: The instant claim 1 is directed to a recombinant coronavirus monoclonal antibody, or an antigen binding fragment thereof, which binds to coronavirus spike protein and comprises a variable heavy (VH) domain and a variable light (VL) domain that have amino acid sequences that have an overall 90% sequence identity to the VH and VL domains of an antibody selected from the group consisting of DH1041 (SEQ ID NOS: 1101, 1103), DH1042 (SEQ IDNOS: 1105,1107), DH1043 (SEQ IDNOS: 1109,1111), ……………… or DH1159.2 (SEQ ID NOS: 1266, 1268) or
wherein the VH domain and VL domain each have at least 90% sequence identity to the VH and VL domains, respectively, of an antibody selected from the group consisting of: DH1041 (SEQ ID NOS: 1101, 1103), DH1042(SEQ ID NOS: 1105, 1107), DH1043(SEQ ID NOS:1109,1111), ……………………. or DH1159.2 (SEQ ID NOS: 1266, 1268).
The instant claim 1 is interpreted to comprise overall (entire VH + VL sequence including regions other than CDR) 10% variability (90% identity in amino acid sequence),
or alternatively, wherein the VH domain and VL domain each have at least 90% sequence identity to the VH and VL domains (VH domain and VL domain individually has 90 sequence identity), respectively at least 90% sequence identity to the VH and VL domains, respectively.
The instant claim 1 recites a preamble, “A recombinant coronavirus monoclonal antibody, or an antigen binding fragment thereof, which binds to coronavirus spike protein and ………..”. In light of the instant specification, it is interpreted that a recombinant monoclonal antibody is directed against a coronavirus.
The claimed monoclonal antibodies were recombinantly derived from a single B cell of a coronavirus infected individual (human), and or a B cell of a coronavirus infection recovered individual (See, instant specification para [0013], [0062]). In certain embodiments the monoclonal antibodies are produced by a clone of B-lymphocytes (See, instant specification para [0198], [0273]), and thus the antibody is also interpreted as a monoclonal antibody produced by single clone of plasma cell or B-lymphocytes. The monoclonal antibody is also interpreted to comprise wild type HV and VL sequence without amino acid substitution to generate a recombinant monoclonal antibody.
Claims 6-7: The instant claims 6 and 7 are interpreted to an antibody with and heavy and light chain each comprising three CDR H1-H3 and CDR L-L3 for heavy and light chain respectively with specific recited SEQ ID NOs sequences paired to form a functional antibody or a functional sequence variant thereof having at least at least 90% or higher sequence identity.
Claims 8-9, and 21: The claims 8-9, and 21 comprise antibodies that bind to RBD domain of a coronavirus. Claim 8 additionally comprise antibody that binds to coronavirus domain NTD, or S2.
Claims 13-18: A nucleic acid molecule comprising a polynucleotide encoding the antibody, or the antigen-binding fragment thereof, according to claim 1.
The instant claims are interpreted to be directed to a human codon optimized nucleic acid sequences to encode recombinant monoclonal antibody against a coronavirus spike domain RBD, NTD or S2 protein (Instant specification para [0579].
Claims 24 and 26: A method of treating or preventing coronavirus infection in a subject in need thereof, comprising administering the recombinant antibody of claim 1 in an amount suitable to effect treatment or prevention of coronavirus infection.
The instant claim 24 recites an alternative limitation, “preventing coronavirus infection in a subject”. For examination purpose, the term “prevention” is interpreted to be directed to prevention of the disease. The prevention of infection as claimed and recited in the claims 24 and 26 is interpreted as absolute prevention of infection of cells (respiratory tract cells) of a subject.
Claim Rejections - 35 USC § 101
16. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 6-8, 10, and 13-14 are rejected under 35 U.S.C. 101 because according to the broadest reasonable interpretation (BRI) in view of the instant specification, the claim 1 (and dependent claims 6-8, 10, and 13-14) are interpreted to be directed to a product of nature, an antibody, a monoclonal antibody, a recombinant monoclonal antibody that is recombinantly derived from a single B cell of a coronavirus infected individual (human), and or a B cell of a coronavirus infection recovered individual (See, instant specification para [0013], [0062]). In certain embodiments the monoclonal antibodies are produced by a clone of B-lymphocytes (See, instant specification para [0198], [0273]), and thus the antibody is also interpreted as a monoclonal antibody produced by single clone of plasma cell or B-lymphocytes. The monoclonal antibody is also interpreted to comprise wild type HV and VL sequence without amino acid substitution to generate a recombinant monoclonal antibody (See, instant specification para [0273). B cell clones or transfected host-cells of the invention can be used in various ways e.g., as a source of monoclonal antibodies, as a source of nucleic acid (DNA or mRNA) encoding a monoclonal antibody of interest, for research, etc (See, instant specification para [0282]).
Step 1: According to MPEP § 2106, the claimed invention must be to one of the four statutory categories. According to 35 U.S.C. 101 the eligibility test, the claim 1 (and dependent claims 6-8, 10, and 13-14) are directed to a statutory category, e.g. composition of matter (the claimed recombinant monoclonal antibody with a function of binding to a coronavirus spike protein), therefore, statutory category eligibility, Step 1: Yes.
Step 2: As described in the instant specification and the prior art Cao et al 2020, Zost et al 2020, and Liu et al 2020 recited below the claimed the claimed genus of recombinant monoclonal antibody or monoclonal antibody is produced by a human single B cell (plasma cell) in response to a coronavirus infection and can be termed as a monoclonal antibody which naturally comprise the antigen binding fragment, Fc, VH and VL chains. The antibody has a function of binding to spike protein (surface protein of a coronavirus) and or neutralizing a coronavirus. The claimed recombinant monoclonal antibodies uses the VL and VL sequences from the B cell and does not have markedly different characteristics or function from what exist in nature or human, and thus is “a product of nature” exception, Step 2A: Prong 1- Yes :claim 1 (and dependent claims) recite a “judicial exception” a product of nature.
The claim 1 (and dependent claims 6-8, 10, and 13-14) fails to integrate (e.g. composition of matter-the claimed recombinant monoclonal antibody with a function of binding to a coronavirus spike protein) the judicial exception into a practical application (e.g method of treatment, diagnostic assay or purification) or contain additional elements that result in a “markedly different” antibody as compared to the natural conunterpart, Step 2A: Prong 2-No.
The claim 1 (and dependent claims 6-8, 10, and 13-14) does/do not include additional elements that are sufficient to amount to significantly more to the claimed composition of matter recombinant monoclonal antibody (a genus) (than the judicial exception because the claims recite recombinant monoclonal antibody and additional antibody species in the genus, as to constitute an “inventive concept” (e.g. improvement) Step 2B: No.
Cao et al 2020 teaches a neutralizing (SARS CoV-2 spike RBD domain binding) and non-neutralizing monoclonal antibody obtained from a single B cell or plasma cell, by using recombinant DNA technology tools and methods, of an individual that was known to be infection with SARS-CoV-2 virus (See, abstract, entire article).
Zost et al 2020 teaches potent neutralizing mAbs recognizing non-overlapping sites, COV2-2196 and COV2-2130 (RBD binding or ACE2 blocking), bound simultaneously to S and synergistically neutralized authentic SARS-CoV-2 virus. A large panel of SARS-CoV-2 S protein-reactive mAbs from the B cells of two convalescing individuals who had been infected with SARS-CoV-2 in Wuhan China. The antibodies were isolated using diverse tools for isolation and cloning of single antigen-specific B cells and the antibody variable genes encoding monoclonal antibodies. The Mabs were potently neutralizing and protective human antibodies against SARS-CoV-2. The Mabs were specific for RBD, S2 and ACE2 blocking neutralizing function (See, abstract, Figure 1-2, section on Antibodies, entire article).
Liu et al 2020 teaches potent neutralizing monoclonal antibodies (recombinantly obtained using recombinant DNA technology and methods) against multiple epitopes on SARS-CoV-2 spike. Isolation of sixty-one SARS-CoV-2-neutralizing monoclonal antibodies from B cells of five patients infected with SARS-CoV-2 and admitted to hospital with severe coronavirus disease 2019 (COVID-19). Among these are nineteen antibodies that potently neutralized authentic SARS-CoV-2 in vitro, nine of which exhibited very high potency, with 50% virus-inhibitory concentrations of 0.7 to 9 ng ml−1. Epitope mapping showed that this collection of nineteen antibodies was about equally divided between those directed against the receptor-binding domain (RBD) and those directed against the N-terminal domain (NTD), indicating that both of these regions at the top of the viral spike are immunogenic. In addition, two other powerful neutralizing antibodies recognized quaternary epitopes that overlap with the domains at the top of the spike. Cryo-electron microscopy reconstructions of one antibody that targets the RBD, a second that targets the NTD, and a third that bridges two separate RBDs showed that the antibodies recognize the closed, ‘all RBD-down’ conformation of the spike. Several of these monoclonal antibodies are promising candidates for clinical development as potential therapeutic and/or prophylactic agents against SARS-CoV-2 (See, abstract, Fig 1-4, page 451 col 1 section on Isolation and construction of mAbs).
Thus, claims 1, 6-8, 10, and 13-14 are rejected under 35 U.S.C. 101 as the claimed monoclonal antibody is a product of nature without modification of the sequence and the claims are directed to a genus of monoclonal antibody that encompass entire B cell repertoire of VH and VL chain sequence comprising monoclonal antibodies from a coronavirus infected individual B cell or plasma cells as recited supra, and because the claim does not include any additional features that could add significantly more to the exception.
Claim Rejections - 35 USC § 103
17. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
18. Claims 1, and 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over Cao et al 2020 (Cell 182, 73–84), and further in view of Babb et al 2020 (US10787501B1, 09/29/2020 with an earlier priority of 06/25/2020 to US16/912,678), and Fotin-Mleczek et al 2023 (US11596699B2, 03/07/2023 with an earlier priority of 01/23/2020 to US20200023076A1).
Claims 1, and 6-7: Cao et al 2020 is in the art and partially teaches instant claims 1, and 6-7 limitations by disclosing the recombinant monoclonal antibody BD-368-2 that has potent neutralizing activity against SARS-CoV-2 virus (of SARS-CoV-2 pseudo typed virus neutralization) and binds to RBD protein domain of spike (See, abstract, page 77, Figure 2 A, B), and the recombinant antibody identified by High-Throughput Single-Cell sequencing of convalescent patients’ B cells. The selected paired heavy- and light-chain’s cDNA was codon-optimized and cloned into expression vectors containing the IgG1 constant regions of human. IgG mAbs were expressed by transfecting HEK293 cells with equal amounts of heavy- and light-chain plasmids. The mAbs were resuspended into PBS and analyzed by SDS-PAGE (See, Methods, pages e-4 and e-7 for invitro expression of Mabs).
Cao et al 2020 does not teach the claimed amino acid sequences of the VH and VL of the elected recombinant antibody species SEQ ID NOS: 1125, 1127 (named as DH1047) or other claimed (un-elected) recombinant antibody species VH and VL SEQ ID NOs. that have amino acid sequences that have an overall 90% sequence identity or wherein the VH domain and VL domain each have at least 90% sequence identity to the claimed antibody paired VH and VL domain sequences
The combined teachings of Babb et al 2020 (US10787501B1), and Fotin-Mleczek et al 2023 (US11596699B2) as recited below teaches instant recombinant antibody DH1043 that has VH domain SEQ ID NO: 1109 and VL domains 1111.
Babb et al 2020 (US10787501B1, 09/29/2020 with an earlier priority of 06/25/2020 to US16/912,678) teaches SEQ ID NO: 548 that has 93% amino acid identity (to the claimed full-length sequence) with instant SEQ ID NO: 1109.
Query Match 93.0%; Score 599; Length 123;
Best Local Similarity 91.9%;
Matches 113; Conservative 5; Mismatches 5; Indels 0; Gaps 0;
Qy 1 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSRYAINWVRQAPGQGLEWMGRIIPIFGIANY 60
|||||||||||||||||||||||||||||| ||| ||||||||||||||||||:||||||
Db 1 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAITWVRQAPGQGLEWMGRIIPMFGIANY 60
Qy 61 AQKFQGKVTITADKSTSTAYMELSSLRSEDTAVYYCARADYYYDSSGYFFDYWGQGTLVT 120
||||||:|||||||||||||||:||||||||||||||| :|||||||: ||||||||||
Db 61 AQKFQGRVTITADKSTSTAYMEVSSLRSEDTAVYYCARTPFYYDSSGYYLDYWGQGTLVT 120
Qy 121 VSS 123
|||
Db 121 VSS 123
Fotin-Mleczek et al 2023 (US11596699B2, 03/07/2023 with an earlier priority of 01/23/2020 to US20200023076A1) teaches SEQ ID NO: 1425 that has 96.3% amino acid identity (to the claimed full-length sequence) with instant SEQ ID NO: 1111.
Query Match 96.3%; Score 526; Length 107;
Best Local Similarity 96.3%;
Matches 103; Conservative 1; Mismatches 3; Indels 0; Gaps 0;
Qy 1 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQTPRLLIYGASSRATGIP 60
||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||
Db 1 EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIP 60
Qy 61 ARFSGSGSGTNFTLTISRLEPEDFAVYYCQQYSSSRTFGQGTKVEIK 107
|||||||||:||||||||||||||||||||| ||||||||||||||
Db 61 DRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSRTFGQGTKVEIK 107
The combined teachings of Cao et al, 2020, Babb et al 2020, and Fotin-Mleczek et al 2023 as recited supra teaches all limitations of instant claims 6-7 because the claims 6 and 7 has also limitation that require recombinant antibody DH1043 with VH domain SEQ ID NO: 1109 and VL domains 1111 , and these VH and VL comprise CDR H1-3 and CDR L1-3 and a functional sequence variant thereof having at least 90% sequence identity.
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 prior art teaching of Cao et al 2020 on a method or a product recombinant antibody that bind RBD domain or neutralize SARS CoV-2 virus by incorporating teachings of Babb et al 2020 on the VH SEQ ID NO: 548, and teachings of Fotin-Mleczek et al 2023 on VL domains SEQ ID NO: 1425 both having >90% sequence identity with the instant SEQ ID NOs: 1109, and 1111 to arrive at the recombinant antibody of claims 1, and 6-7. One of the ordinary skills in the art would have been motivated to modify the prior art teachings of Cao et al that teaches the entire method to produce a recombinant monoclonal antibody BD-368-2 that has potent neutralizing activity against SARS-CoV-2 virus and binds to RBD protein domain of spike and is derived from SARS-CoV-2 infection recovered convalescent patient’s B cells (See, Cao et al 2020) to obtain new recombinant antibodies from a different individual that is infected with a SARS-CoV-2 or recovered from SARS-CoV infection with binding and neutralizing function, and introduce additional variations in the CDR sequences for achieving a broader cross-reactivity to viruses within the coronavirus genus for commercial success. There would have been a reasonable expectation of success given the applied prior arts teachings and required research skills available with one of the ordinary skills in the art. 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. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 1, and 6-7. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
19. Claims 8, 10-12, and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Cao et al 2020 (Cell 182, 73–84), Babb et al 2020 (US10787501B1, 09/29/2020 with an earlier priority of 06/25/2020 to US16/912,678), and Fotin-Mleczek et al 2023 (US11596699B2, 03/07/2023 with an earlier priority of 01/23/2020 to US20200023076A1), as applied to claim 1 above, and with additional teachings of Cao et al 2020 (Cell 182, 73–84).
Claims 8, 10-12, and 17-18: The combined teachings of Cao et al 2020, Babb et al 2020, and Fotin-Mleczek et al 2023 teaches instant claims 1 as recited supra. The additional teachings of Cao et al 2020 teaches added limitations of claims 8, 10-12, and 17-18 as recited below.
Claim 8: Cao et al 2020 teaches the instant claim 8 limitation by disclosing the recombinant monoclonal antibody BD-368-2 binds to RBD domain of spike protein of SARS CoV-2, a coronavirus (See, page 77, Figure 2 A, B).
Claim 10: Cao et al 2020 teaches the instant claim 10 limitation by disclosing the recombinant monoclonal antibody BD-368-2 comprises an Fc moiety, because the method of construction of recombinant antibodies includes an Fc nucleotide sequence for expression of recombinant antibody, which is demonstrated by removal of Fc from the BD23 antibody as obtain BD23-Fab, BD-23 (2 mg/mL) was digested with papain (See, page e5 para 8).
Claim 11: Cao et al 2020 teaches the instant claim 11 limitation by disclosing the recombinant antibody BD-368-2 is a purified antibody IgG1 antibody and the concentration of BD-388-2 is shown in Fig 2 A-C in ug/ml (See, abstract, page 77 Fig 2).
Claim 12: Cao et al 2020 teaches the instant claim 12 limitation by disclosing the recombinant antibody for use as a medicament by disclosing the BD-368-2 also displayed strong therapeutic and prophylactic efficacy in SARS-CoV-2-infected hACE2-transgenic mice (See, abstract, page 78 Fig 3).
Claims 17-18: Cao et al 2020 teaches the instant claims 17-18 limitations by disclosing an expression vector comprising the codon optimized nucleic acid molecule expressing the selected paired heavy- and light-chain’s cDNA was codon-optimized and cloned into expression vectors containing the IgG1 constant regions of human. IgG mAbs were expressed by transfecting HEK293 cells with equal amounts of heavy- and light-chain plasmids. The mAbs were resuspended into PBS. The transfecting HEK293 cells expressed the BD-368-2 recombinant monoclonal antibody (See, Cao et al 2020, abstract, page e5, para 1 In Vitro expression of mAbs).
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 combined prior art teaching of Cao et al 2020, Babb et al 2020, and Fotin-Mleczek et al 2023 on the recombinant antibody of claims 1 and incorporate the additional teachings of Cao et al 2020 as recited supra to arrive at the instant claims 8, 10-12, and 17-18. One of the ordinary skills in the art would have been motivated to modify the combined prior art teachings as applied to claim 1 with Cao et al 2020 to produce recombinant antibody in large quantity by expressing in human cell culture and to purify it for developing medicament and use in therapeutics (See, Cao et al 2020) and for commercial success. There would have been a reasonable expectation of success given the applied prior arts teachings and required research skills available with one of the ordinary skills in the art. 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. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 8, 10-12, and 17-18. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
20. Claims 19-20, and 23-26 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Cao et al 2020 (Cell 182, 73–84), Babb et al 2020 (US10787501B1, 09/29/2020 with an earlier priority of 06/25/2020 to US16/912,678), and Fotin-Mleczek et al 2023 (US11596699B2, 03/07/2023 with an earlier priority of 01/23/2020 to US20200023076A1), as applied to claim 1 above, and further in view of Marasco et al 2005 (US20050249739A1, 11/10/2005), Hollinger et al 2005 (Nature Biotechnology volume 23, pages1126–1136 (2005), Johnson et al 2018 (US9963510B2, 08/05/2018), and Huang et al 2020 (Current Protocols in Immunology, 129, e95).
Claims 19-20, 23 and 24-26: The combined teachings of Cao et al 2020, Babb et al 2020, and Fotin-Mleczek et al 2023 teaches instant claims 1 as recited supra. Cao et al 2020 (additional teachings) and Marasco et al 2005 teaches added limitations of claims 19-20, 23 and methods of claims 24-26 as recited below.
Claims 19-20 and 23: Marasco et al 2005 is in the art and teaches instant claims 19-20 and 23 by disclosing antibodies against SARS-CoV and methods of use thereof. The invention provides monoclonal antibodies that neutralize SARS-CoV. Also provided are methods of treating and/or preventing a coronavirus-related disease or disorder such as SARS. The invention also provides methods of vaccinating a patient against SARS-CoV (See, abstract). The antibodies or agents of the invention (also referred to herein as “active compounds”), and derivatives, fragments, analogs and homologs thereof, can be incorporated into pharmaceutical compositions suitable for administration. Such compositions typically comprise the antibody or agent and a pharmaceutically acceptable carrier. (See, para [0137]). A pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration (See, para [0138]).
Claims 24-26: Marasco et al 2005 teaches instant claims 24-26 by disclosing a method of preventing a disease or disorder caused by a coronavirus, the method comprising administering to a person at risk of suffering from said disease or disorder, a therapeutically effective amount of the monoclonal antibody (See, claim 25). Marasco et al 2005 further teaches a method of treating a coronavirus-related disease or disorder, the method comprising administering a therapeutically effective amount of the monoclonal antibody of claim 1 to a patient suffering from a coronavirus-related disease or disorder (See, claim 31).
Cao et al 2020 teaches the recombinant monoclonal antibody BD-368-2 showed high therapeutic and prophylactic efficacy in hACE2 mice (See, page 76 col 2, last para). Cao et al 2020 further teaches (A) Experimental design for therapeutic and prophylactic testing of BD-368-2 in hACE2 transgenic mice. BD-368-2 or unrelated antibody HG1K (20 mg/kg of body
weight) was intraperitoneally injected into the transgenic mice before or after SAR-CoV-2 infection. (See, page 78, Fig 3 A, B and C).
Prior arts teaching bivalent or multivalent antibodies or antigen fragments thereof (Instant claims 20 and 26):
The instant claim 20 recites an added limitation, wherein the Vh and Vl sequences form a multivalent or multispecific antibody.
The instant claim 26 recites an added limitation, wherein the Vh and Vl sequences are comprised in a bi- or tri- specific antibody format or in a multivalent format.
Hollinger et al 2005 teaches an engineered antibody fragment and the rise of single domains and reviewed smaller recombinant antibody fragments (for example, classic monovalent antibody fragments (Fab, scFv)) and engineered variants (diabodies, triabodies, minibodies and single-domain antibodies (See, abstract, entire article).
Johnson et al 2018 (US9963510B2, 08/05/2018) teaches covalent diabodies (bivalent) comprise two polypeptide chains that associate to form at least two epitope binding sites, which may recognize the same or different epitopes on the same or differing antigens. Additionally, the antigens may be from the same or different molecules. The individual polypeptide chains of the diabody molecule may be covalently bound through non-peptide bond covalent bonds, such as, but not limited to, disulfide bonding of cysteine residues located within each polypeptide chain. In particular embodiments, the diabody molecules of the present invention further comprise an Fc region, which allows antibody-like functionality to engineered into the molecule (See, abstract, entire prior art).
Huang et al 2020 teaches Multispecific, Multivalent Antibody-Based Molecules Engineered on the DART® and TRIDENTTM Platforms. Multispecific antibodies bind two or more different antigens and enable new therapeutic applications that cannot be replicated with conventional monoclonal antibodies, such as bridging different cells or bringing soluble proteins in close proximity. The DART and TRIDENT platforms enable the engineering of such antibodies. A DART molecule combines two independent antigen-binding sites in a stabilized, diabody-like structure. A DART molecule can be expressed with or without an Fc domain and thus can be tailored to have a long or short half-life in vivo and to induce or ablate effector function. Linking two DART units or a DART unit and a Fab domain (the latter structure is called TRIDENT format) via an Fc domain creates a monospecific, bispecific, trispecific, or tetraspecific molecule with up to tetravalent targeting of antigens (See, abstract, entire protocol).
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 combined prior art teaching of Cao et al 2020, Babb et al 2020, and Fotin-Mleczek et al 2023 on the recombinant antibody of claims 1 and incorporate the additional teachings of Marasco et al 2005 and Cao et al 2020 on pharmaceutical composition and method of prophylactic and therapeutic treatment against a coronavirus infection or disease as recited supra to arrive at the instant claims 19-20, 23 and 24-26. Additional teachings of Hollinger et al 2005, Johnson et al 2018, and Huang et al 2020 on bivalent, multivalent antibody and method to produce these multiepitope specific antibodies would have led to arrival of the claims 20 and 26 added limitation on bivalent or multivalent antibodies and the pharmaceutical composition. One of the ordinary skills in the art would have been motivated to modify the combined prior art teachings as applied to claim 1 with additional teachings of Marasco et al 2005, Cao et al 2020, and teachings of Hollinger et al 2005, Johnson et al 2018, and Huang et al 2020 on bivalent, multivalent antibody to develop pharmaceutical composition comprising multivalent antibodies that target different epitopes for better efficacy and for suitable administration and method of prophylaxis and treatment against a coronavirus infection and for commercial success. There would have been a reasonable expectation of success given the applied prior arts teachings and required research skills available with one of the ordinary skills in the art. 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. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 19-20, 23 and 24-26. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
21. Claims 21-22 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Cao et al 2020 (Cell 182, 73–84), Babb et al 2020 (US10787501B1, 09/29/2020 with an earlier priority of 06/25/2020 to US16/912,678), and Fotin-Mleczek et al 2023 (US11596699B2, 03/07/2023 with an earlier priority of 01/23/2020 to US20200023076A1), as applied to claim 1 above, and further in view of Nioi et al 2019 (US10358497B2, 07/23/2019), and Gusarova et al 2019 (US10259870B2, 04/16/2019) as evidenced by Nussenzweig et al 2021 (US20210332110A1, 10/28/2021 filed on 04/28/2020 later patented US11634477B2), and as evidenced by Babb et al 2020, US10787501B1 (09/29/2020 filing date 06/25/2020).
Claim 21. A pharmaceutical composition comprising at least one RBD binding antibody and at least one NTD binding antibody of claim 8.
Claim 22. A pharmaceutical composition comprising two RBD binding antibodies or antigen binding fragments thereof, wherein the two antibodies or antigen binding fragments thereof have non-overlapping epitopes.
According to instant specification (para 0325] Table 4A), the antibody comprising SEQ ID NOs: 1129, and 1131 is a NTD binding and has a function of neutralizing SARS CoV-2 virus.
The combined teachings of Cao et al 2020, Babb et al 2020, and Fotin-Mleczek et al 2023 teaches instant claims 1 and the recombinant antibody DH1043 (SEQ IDNOS: 1109,1111) rendered obvious binds to RBD domain with neutralizing function of SARS CoV-2 (See, instant specification (para 0325] Table 4A) as recited supra, and the teachings of the prior art are incorporated here in entirety as applied to render obvious claim 1 above.
The combined teachings of Nioi et al 2019 and Gusarova et al 2019 teaches an antibody amino acid sequence (second recombinant antibody) that is reasonably expected to bind to NTD domain and neutralize SARS CoV-2 virus, and the evidence is provided by Nussenzweig et al 2021 and Babb et al 2020.
Nioi et al 2019 (US10358497B2, 07/23/2019) teaches SEQ ID NO: 32299 that has 90.3% identity with instant SEQ ID NO: 1129.
Nussenzweig et al 2021 (US20210332110A1, 10/28/2021 filed on 04/28/2020 later patented US11634477B2) provides evidence that SEQ ID NO: 873 with a similar amino acid sequence with 89.9% identity has neutralizing activity against SARS-CoV-2).
Query Match 90.3%; Score 581.5; Length 116;
Best Local Similarity 92.7%;
Matches 115; Conservative 0; Mismatches 0; Indels 9; Gaps 2;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSYISSSSSTIYY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYSMNWVRQAPGKGLEWVSYISSSSSTIYY 60
Qy 61 ADSVKGRFTISRDNAKNSLYLQMNSLRDEDTAVYYCARMAIVGAYANWG-FDYWGQGTLV 119
|||||||||||||||||||||||||||||||||||||| ||| ||||||||||
Db 61 ADSVKGRFTISRDNAKNSLYLQMNSLRDEDTAVYYCAR--------NWGYFDYWGQGTLV 112
Qy 120 TVSS 123
||||
Db 113 TVSS 116
Gusarova et al 2019 (US10259870B2, 04/16/2019) teaches SEQ ID NO: 186 that has 96.1% identity with instant SEQ ID NO: 1131.
Babb et al 2020, US10787501B1 (09/29/2020 filing date 06/25/2020) provides evidence with SEQ ID NO: 508, a similar sequence identity of 96.6% that binds to SARS-CoV-2 Spike glycoprotein.
Query Match 96.1%; Score 536; Length 107;
Best Local Similarity 97.2%;
Matches 104; Conservative 1; Mismatches 2; Indels 0; Gaps 0;
Qy 1 DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYDASNLETGVPS 60
Qy 61 RFSGSGSGTDFTFTISSLQPEDIATYYCQQYDNPLITFGQGTRLEIK 107
||||||||||||||||||||||||||||||||: ||||||||||||
Db 61 RFSGSGSGTDFTFTISSLQPEDIATYYCQQYDHLPITFGQGTRLEIK 107
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 combined prior art teaching of Cao et al 2020, Babb et al 2020, and Fotin-Mleczek et al 2023 on the recombinant antibody that is RBD binding and neutralizing of claims 1 and incorporate the additional teachings of Nioi et al 2019 and Gusarova et al 2019 on the second recombinant antibody amino acid sequence that bind to NTD domain and neutralize SARS CoV-2 virus as per the evidence is provided by Nussenzweig et al 2021 and Babb et al 2020 to arrive at the invention of claims 21 and 22 to develop a cock-tail recombinant antibody pharmaceutical composition for prophylactic and therapeutic treatment against a coronavirus infection or disease (e.g. SARS-CoV-2 virus, COVID-19) as recited supra. One of the ordinary skills in the art would have been motivated to combine the prior art as recited supra to develop cock-tail pharmaceutical composition for suitable administration and method of prophylaxis and treatment against a coronavirus infection and for commercial success. There would have been a reasonable expectation of success given the applied prior arts teachings and required research skills available with one of the ordinary skills in the art. 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. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 21-22. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
22. Claims 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Cao et al 2020 (Cell 182, 73–84), Babb et al 2020 (US10787501B1, 09/29/2020 with an earlier priority of 06/25/2020 to US16/912,678), and Fotin-Mleczek et al 2023 (US11596699B2, 03/07/2023 with an earlier priority of 01/23/2020 to US20200023076A1), as applied to claim 1 above, and further in view of Pardi et al 2017 (Nature Communication, 8:14630), Kariko et al 2012 (US8278036B2, 10/02/2012), and Ciaramella et al 2020 (US10702600B1, 07/072020).
Claims 13-14: The combined teachings of Cao et al 2020, Babb et al 2020, and Fotin-Mleczek et al 2023 teaches instant claims 1 and teaches the recombinant antibody that has VH domain SEQ ID NO: 1109 and VL domain SEQ ID NO: 1111. The combined prior art as applied to claim 1 teaches the expression in human cells of recombinant antibody comprising VH domain SEQ ID NO: 1109 and VL domain SEQ ID NO: 1111 using a plasmid expression vector comprising human codon optimized nucleic acid sequence of a recombinant antibody (See, Cao et al 2020) and thus taught a nucleic acid molecule comprising a polynucleotide encoding the antibody, or the antigen-binding fragment thereof, rendered obvious claims 13 and 14. The combined prior art taught recombinant antibody comprised nucleotide sequence that is a functional sequence variant thereof having at least 90% sequence identity. This the combined prior art teachings of Cao et al 2020, Babb et al 2020, and Fotin-Mleczek et al 2023 renders obvious claims 13-14.
One of the ordinary skills in the art would have been motivated to comprise a plasmid expression vector comprising a codon optimized claimed recombinant antibody encoding nucleic acid sequence to produce the recombinant monoclonal antibody in large quantity for therapeutics for commercial success. There would have been a reasonable expectation of success given the applied prior arts teachings and required research skills available with one of the ordinary skills in the art. 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. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 13-14. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
Claims 15-16:
Claims 15: The nucleic acid of claim 13 wherein the nucleic acid is a ribonucleic acid (RNA).
Claims 16: The nucleic acid of claim 15, wherein the RNA is suitable for use and delivery as a therapeutic mRNA.
Pardi et al 2017 is in the virology art and teaches the concept of mRNA encoded antibody for therapeutics by disclosing administration of nucleoside-modified mRNA encoding broadly neutralizing antibody protects humanized mice from HIV-1 challenge (See, abstract, entire article).
Pardi et al 2017 does not teach the recombinant antibody of instant claim 1.
Kariko et al 2012 is in the modified mRNA art and discloses RNA, oligoribonucleotide, and polyribonucleotide molecules comprising pseudouridine or a modified nucleoside, gene therapy vectors comprising same, methods of synthesizing same, and methods for the delivery of therapeutic proteins to tissue in vivo, comprising the molecules. The present invention also provides methods of reducing the immunogenicity of RNA, oligoribonucleotide, and polyribonucleotide molecules (See, abstract, claims, entire prior art).
Ciaramella et al 2020 is in the ribonucleic acid (RNA), mRNA vaccines art and teaches mRNA further comprising a 5′ untranslated region (UTR) and a 3′ UTR, poly A tail, the 5′ cap analog is 7mG(5′)ppp(5′)NlmpNp, chemical modification is a 1-methylpseudouridine modification or a 1-ethylpseudouridine modification (See, abstract, claims, entire prior art).
It would have been obvious to one of the ordinary skills in the art to modify the combined prior art teachings as applied to claim 13 with additional teachings of Pardi et al 2017, Kariko et al 2012, and Ciaramella et al 2020 to arrive at the invention of claims 15-16 comprising the claimed antibody in the form of modified mRNA sequence encoding the antibody suitable for use and delivery /administration as a therapeutic mRNA to express the antibody in vivo. The motivations to modify the nucleotides of mRNA are disclosed in the applied prior art and includes to prevent inflammatory undesirable side effect reaction in the individual and also would be leading to a commercial success as is evident in the art due to commercial availability of mRNA vaccines for infectious viral or metabolic diseases. There would have been a reasonable expectation of success given the applied prior arts teachings and required research skills available with one of the ordinary skills in the art. 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. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 15-16. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
23. Relevant Prior Art:
Liao et al 2009. High-throughput isolation of immunoglobulin genes from single human
B cells and expression as monoclonal antibodies. Journal of Virological Methods, 158 (2009) 171–179).
Kyratsous et al 2019 (US20190351049A1, 11/21/2019). Human Antibodies to Middle East Respiratory Syndrome - Coronavirus Spike Protein. Cited in incoming PCT opinion. The US20190351049A1 discloses antibody that has <90% sequence identity to the elected or claimed antibody species in the genus. Applicant has amended the claims in response to lack of unity of invention office action.
Pereira et al 2011 (US20090136510A1, 05/28/2009). Inhibition of macrophage-stimulating protein receptor (RON) and methods of treatment thereof. Cited in incoming PCT opinion.
Lightwood et al 2020 (WO2020148554A1, 07/23/2020). Antibodies to ebola virus glycoprotein. Cited in incoming PCT opinion.
Lou et al. 2020. Cross-neutralization antibodies against SARS-cOv-2 and RBD mutations from convalescent patient antibody libraries. bioRxiv 2020.06.06. 137513.
Conclusion
24. No claim is allowed.
25. Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMADHAN J JADHAO whose telephone number is (703)756-1223. The examiner can normally be reached M-F 8:00-5:00.
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/SAMADHAN JAISING JADHAO/ Examiner, Art Unit 1672
/BENNETT M CELSA/ Primary Examiner , Art Unit 1600