Notice of Pre-AIA or AIA Status
The present application is being examined under the first-inventor-to-file provisions of the AIA .
DETAILED ACTION
Claims Status
Claims 8, 21-22, 32-34, 42 and 44-66 are cancelled.
Claims 1-7, 9-20, 23-31, 35-41, 43 and 67-68 are under examination for their merits.
Priority
This application claims a foreign benefit associated with an Indian Provisional Patent Application (IN202141035009), filed August 3, 2021 (page 1, line 7-9). The amended disclosure, as filed 02/02/2024, differs starkly from two certified foreign versions filed on August 3, 2021 and 10/07/2021, respectively, as tabulated below:
Comparison of two earlier versions of disclosure with the instant application under examination.
Filing date
Document ID
Disclosure: main Text
Table(s)
Figure(s)
08/03/2021
IN202141035009
11 pages
0
4
10/07/2021
IN202141045615
9 pages
1 (page 8)
2
02/02/2024
US 18/294775
64 pages
2 (pp. 49-50 and pg. 54)
15
Examiner finds that the 08/03/2021 filing did contain the inventive concept for three “effective vaccination strategies” for the application of “same vaccine” and “different vaccines” through “homologous route of administration” and “heterologous route of vaccination” (Figure 1 and page 2, lines 32-35), under “a primary objective” of “combined parenteral and mucosal immunization against COVID-19” (Figure 1 and page 3, lines 28-29), with a dosing interval of “no more than about 10 weeks” between doses (Figure 1 and page 6, lines 14-15). Vaccination regimens and vaccine types as disclosed on 08/03/2021 began with “priming and boosting compositions” comprising “a recombinant chimpanzee adenovirus that contains gene segment for full length or partial genome encoding complete or partial spike protein or immunogenic part thereof from SARS-CoV-2 virus [(ChAd-36-SARS-CoV-2-S) BBV154]” (page 4, lines 8-11). Other vaccines included “a recombinant human adenovirus… BBV153” (page 4, line 15-17), “killed-inactivated recombinant respiratory syncytial virus” (page 4, lines 21-22), “killed-inactivated influenza virus (both A and B strains)” (page 4, lines 30-31), “killed-inactivated SARS-Co V-2 whole-virion vaccine (BBV152)” (page 5, lines 24-25), “nucleic acid- (DNA or mRNA) or protein [subunit (spike, RBD, SI)] based COVID-19 vaccines” (page 6, lines 6-7), “adjuvanted inactivated SARS-CoV-2 virus” (page 8, line 21-22), “inactivated rabies vectored virus” (page 9, line 1), “adjuvanted subunit (complete or partial spike protein) vaccines” (page 9, lines 15-16), “adjuvanted mRNA vaccines encoding complete or partial spike protein or immunogenic part thereof from SARS-CoV-2 virus” (page 9, lines 29-31). Immune responses, as assessed by IgG, IgA and “SASR-CoV-2 neutralizing titer” were available for immunized rabbits (Figure 2 and page 7, lines 11-14) and BALB/c mice (Figures 3-4 and page 7, lines 15-30). However, neither the 08/03/2021 disclosure nor the 10/07/2021 disclosure cited any dose amount or any dose concentration other than “BALB/c male and female mice were immunized intranasal (IN) or intramuscular (IM) with BBV154 or Ch-Ad vector control of 5x1010 VP in 50 μl” (page 7, lines 27-28 in 08/03/2021 disclosure). Other amendments, including adenovirus-vectored vaccines encoding “SASR-CoV2-S1” subunit (FIGURE 4), immunization in “Swiss Albino” rats (FIGURE 5), “Wistar rats” (FIGURE 5), “BBV154 three doses” (FIGURE 6), and contents corresponding to FIGURES 7-11 and 13-15, are only found in the 02/02/2024 disclosure. The number of “prime” dose was limited to one, while the number of “Boost” doses was up to two in the original submission, with “Boost 2” listed as optional (“if required”) in the 08/03/2021 disclosure. Thus, for purposes of this Office Action, claims 17 (two vaccines for first series followed by two vaccination in second series) and its dependents (claims 18-20, 23-24, 27-30 receive the effective filing date of 02/02/2024, while the remaining claims (1-7, 9-16, 25-26, 31, 35-41, 43 and 67-68 are accorded the benefit of the earliest potentially applicable priority date.
Information Disclosure Statement
This application does not provide any information disclosure statement for consideration. The listing of references in the specification is not a proper information disclosure statement. US 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.
Objections to Specification
The disclosure for this application is objected to because of the following informalities:
Repeated citation of "parental-mucosal immunization" (title and lines 17 and 23 on page 1; lines 2 and 12-13 on page 6; line 13 on page 7; line 10 on page 21) are inconstant with the amended invention title, which cites “parenteral and mucosal immunization.” Appropriate corrections are required, provided that such corrections do not require new matter. Examiner treats "parental-mucosal immunization" as a typographic error for “parenteral and mucosal immunization” or its equivalent (e.g., parenteral-mucosal immunization).
Multiple citations of “SARS-CoV2” (page 5, lines 5 and 9; page 52, lines 5-6, 14 and 22-23) are inconsistent with “SASR-CoV-2” disclosed in claims (e.g., claims 1 and 7). Again, appropriate corrections are required for viral nomenclatures, provided that such corrections do not require the addition of new matter. For compact prosecution, examiner takes the conventional nomenclature of SARS-CoV-2 as the correct one.
Objections to Claims
Claims 11-17, 27-30, 35-36, 38-39, 41, 43 and 67-68 are objected to as containing undefined, unclear and/or inconsistent abbreviations of virus names:
Claims 11-17, 27-29, 35-36, 38-39, 41 and 43 repeatedly cite “SARS-CoV-2-S” (claim 11, line 3; claim 12, line 4; claim 13, line 2; claim 14, line 2; claim 15, line 2; claim 16, line 3; claim 17, rows 5-15; claim 27, line 2; claim 28, line 2; claim 29, line 2; claim 35, line 4; claim 36, line 3; claims 38-39, line 3; claim 41, lines 2-4; and claim 43, line 3 and 4), with S standing for spike protein, but the abbreviation does not have a full spelling in the same or any preceding claims of record. Human and chimpanzee viruses cited as hAd and ChAd, respectively, in these claims should also be accompanied by full spelling when each abbreviation is mentioned for the first time, as these nomenclatures are not used uniformly in the field for a generic use.
Claims 12, 14, 16-17, 27-28, 35-36, 38-39 and 43 refer to a “recombinant chimpanzee adenovirus-vectored SARS-CoV-1 vaccine either as “ChAd--SARS-CoV-2-S” (claims 12, line 4; claim 14, line 2; claim 16, line 3; claim 27, line 2; claim 28, lines 1-2; claim 35, line 4; claim 38, lines 3-4) or as “ChAd-SARS-CoV-2-S” (claim 17, rows 5-9 and 11-15 in tabulation; claim 36, line 3; claim 39, line 3; claim 43, line 4). These internal inconsistencies (single versus double hyphenation) must be corrected.
Claim 13 has nCoV (line 4) as part of a vaccine name, but “nCoV” is not defined. Claim 30 has two other abbreviations cited as “RBD” and “S1”, which are again not defined anywhere in the claim or in the base claim (claim 1) that it depends on. For claims 67-68, IM and IN are not defined either. Examiner recommends a full spelling for each of these abbreviations at first mention. For compact prosecution, examiner takes “nCoV” as a synonym for SARS-COV-2, “RBD” as the receptor-binding domain of the spike protein (page 58, line 30), and S1 is a fragment of the S protein, as cited on page 52 (lines 6-7) of specification.
Claims 12-17, 27-28, 35-36, 38-39, 41, 43 and 67-68 are objected to as having improperly placed contents in parentheses and/or other informalities:
Claim 12 states that “vaccine is a recombinant chimpanzee adenovirus containing gene segment for full length or partial genome encoding complete or partial spike protein or immunogenic part thereof from SARS-CoV-2 virus (ChAd--SARS-CoV-2-S)” (lines 2-4). Here, “ChAd--SARS-CoV-2-S” would make more sense if it is placed after “a recombinant chimpanzee adenovirus-vectored vaccine containing gene segment for full-length or partial spike protein or immunogenic part thereof from SARS-CoV-2 virus.” In addition, the reading of “gene segment for full length or partial genome encoding complete or partial spike protein or immunogenic part thereof from SARS-Co V-2 virus” is awkward, because “gene segment” does not cover “full length genome”, and “partial genome” does not “encode complete spike protein.” The statement should be rewritten to make biological sense.
Claim 13 cites “a recombinant human adenovirus (hAd-SARS-CoV-2-S) containing nucleic acid encoding full length codon optimized spike protein of SARS-CoV-2 (rAd-nCoV-Spike)” (lines 2-4). Clearly, “hAd-SARS-CoV-2-S” is not a synonym for “a recombinant human adenovirus”, neither is “rAd-nCoV-Spike” for “SARS-CoV-2” or “full length codon optimized spike protein of SARS-CoV-2.” Moreover, while nCoV is a temporary synonym for SARS-CoV-2, this application was submitted at a time when “SARS-CoV-2” became a broadly adopted official name. For consistency within and beyond this application, examiner recommends the use of “SARS-CoV-2” instead of “nCoV” to avoid unnecessary confusion.
For claims 14-16, “wherein both primary and secondary series of vaccines comprise recombinant chimpanzee adenovirus (ChAd--SARS-CoV-2-S) with the genome encoding complete or partial spike protein or immunogenic part thereof from SARS-CoV-2” (claim 14, lines 1-3), “wherein both primary and secondary series of vaccines comprise of recombinant human adenovirus (hAd-SARS-CoV-2-S) with nucleic acid encoding full length codon optimized spike protein of SARS-CoV-2 (rAd-nCoV-Spike)” (claim 15, lines 1-3), “wherein the primary series of vaccine comprises of killed-inactivated SARS-CoV-2 whole-virion vaccine and the secondary series of vaccine comprises recombinant chimpanzee adenovirus (ChAd--SARS-CoV-2-S) with the genome encoding complete or partial spike protein or immunogenic part thereof from SARS-CoV-2” (claim 16, lines 1-4) have the same problems with improper contents in parentheses and/or improper placement of parentheses as cited for claim 11 above and should be corrected accordingly.
Claim 17 continues with improper contents in parentheses when citing “recombinant human adenovirus (hAd-SARS-Co V-2-S)” (rows 5 and 7-9 in tabulation) and “recombinant chimpanzee adenovirus (ChAd-SARS-Co V-2-S)” (rows 6-9 in tabulation). The contents in tabulation (rows 1-15, each with four columns) should be converted to a readable form as a continuous sentence, breaking down into steps if needed.
Claims 27-28 depend on claim 17, and their citation of “recombinant chimpanzee adenovirus vaccine (ChAd--SARS-CoV-2-S) (claim 27, lines 2-3)) and “the dose concentration of (ChAd--SARS-CoV-2-S) vaccine” (claim 28, lines 1-2) needs the same remedy applicable to claim 17 for the two DNA vaccines. In addition, “the dose concentration of (ChAd--SARS-CoV-2-S) vaccine” is also wrong for its improper placement – “ChAd--SARS-CoV-2-S” is a vectored vaccine, not a “dose concentration of.”
Claims 35-36 again cite a “recombinant chimpanzee adenovirus (ChAd--SARS-CoV-2-S) vaccine” (claim 35, line 4; claim 38, lines 2-3) and “wherein the recombinant chimpanzee adenovirus contains gene segment encoding complete or partial spike protein or immunogenic part thereof from SARS-CoV-2 virus (ChAd-36-SARS-CoV-2-S) (claim 36, lines 1-3; claim 39, lines 2-3). The problems are the same as those cited for claims 11-12 above and should be fixed. In addition, claim 36 needs to properly end with a period.
Claims 41 and 43 cite a “recombinant humans adenovirus (ChAd--SARS-CoV-2-S) vaccine” (claim 41, lines 2-4; claim 43, lines 2-3) and “recombinant chimpanzee adenovirus (ChAd--SARS-CoV-2-S) vaccine” (claim 43, line 4); in each case, the content in parentheses should be placed after “vaccine” and defined properly as a vectored vaccine expressing the SARS-CoV-2-S immunogen.
Claims 11, 14, 24 and 41 are objected to as bearing incorrect English grammar:
Claim 11 cites several “virus vectored” vaccines (lines 3-5) as “”rabies vectored vaccine, respiratory syncytial virus vectored vaccine (RSV), influenza virus (both A and B strains) or other respiratory virus vectored vaccine.” Here rabies is a disease, not a virus. When viruses serve as vaccine vectors, the convention is to define the product as “x-vectored y,” where “x” is the name of the specific virus/agent, and “y” is the final product for use. For example, “rabies virus-vectored vaccine” would make more sense than “rabies vectored vaccine”, and “other respiratory virus vectored vaccine” should be written as “another respiratory virus-vectored vaccine” because many other respiratory viruses exist beyond RSV and influenza viruses cited in claim 11. Appropriate corrections are required.
As for claim 14, it discloses a limitation for claim 1: “wherein one vaccine of primary series and two vaccines are secondary series are administered through heterologous routes.” The sentence is correct and should be amended to improve readability.
Claim 24 discloses that “wherein one vaccine of primary series and two vaccines are secondary series are administered through heterologous routes.” The sentence is correct and should be amended to improve readability. For compact prosecution, examiner reads the sentence as “wherein one vaccine of primary series and two vaccines of secondary series are administered through heterologous routes” in a 3-dose immunization regimen.
Claim 41 cites “one or recombinant human adenovirus vaccine” (lines 3-4). The sentence is incomplete, clearly missing a word after “or”. For compact prosecution, examiner reads the sentence as “one or more recombinant human adenovirus vaccine”, matching the content recited on line 2 of claim 41.
Claims 17, 36, 39 and 67-68 are objected to because of improper punctuation. These claims all need to close with a period. Periods may not be used elsewhere in the claims except for abbreviations, so the use of periods for numbers within claim 17 is improper and should be removed. Appropriate corrections are required.
Claim 43 is objected to under 37 CFR 1.75 as being a substantial duplicate of claim 41. 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). In the instant case, claim 41 is drawn to “a method of generating robust immune response in mammals against SARS- CoV-2 antigen by administering one or more recombinant human adenovirus (hAd-SARS-CoV- 2-S) vaccine through intramuscular or intradermal route and one or recombinant human adenovirus (hAd-SARS-CoV-2-S) vaccine through intranasal or oral or mucosal route.” Claim 43 repeats the same limitations by switching the alternative of “intramuscular or intradermal route” in claim 41 to “intramuscular or intradermal route” in claim 43. Applicant is required to either cancel one or amend one to avoid redundant claims.
Claims 67-68 are further objected to as having improper tabulations. The table within each claim should be replaced by a plain sentence.
Claim Rejections under 35 U.S.C. §112
The following is a quotation of 35 U.S.C. §112(b) which forms the basis for indefiniteness rejections set forth in this Office action:
(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.
Claims 1-7, 9-20, 23-31, 35-41, 43 and 67-68 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The terms “robust” in claims 1, 35, 38, 41 and 43, “superior” in claim 31 and “about” in claim 26 are relative terms which render these claims indefinite. The three terms cited above are not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The same applies to the following dependent claims: a) claims 2-7, 9-10, 14-17, 25-26, 31 and 67-68 as dependents of claim 1; b) claim 11 as a dependent of claims 1 and 7; c) claims 18-25 and 29-30 as dependents of claim 11; d) claims 36-37 as dependents of claim 25; and e) claims 39-40 as dependents of claim 38.
Specifically, “robust” and “superior” outcomes require objective outcome measures, and to claim “superiority” would further require at least two comparison groups, which is not provided in the claims or elsewhere in the application. As for the term “about”, MPEP §2173.05(b) Relative Terminology [R-01.2024] (III. APPROXIMATIONS) cites: in determining the range encompassed by the term "about," one must consider the context of the term as it is used in the specification and claims of the application. … the court held that claims reciting "at least about" were invalid for indefiniteness where there was close prior art and there was nothing in the specification, prosecution history, or the prior art to provide any indication as to what range of specific activity is covered by the term "about." Amgen, Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991). In light of the reasons outlined above, claims 17 and 26 are also indefinite under 35 U.S.C. 112(b).
MPEP 2173.05(b) Relative Terminology [R-01.2024] further states the following: If the specification does not provide some standard for measuring that degree, a determination must be made as to whether one of ordinary skill in the art could nevertheless ascertain the scope of the claim (e.g., a standard that is recognized in the art for measuring the meaning of the term of degree). For example, in Ex parte Oetiker, 23 USPQ2d 1641 (Bd. Pat. App. & Inter. 1992), the phrases "relatively shallow," "of the order of," "the order of about 5mm," and "substantial portion" were held to be indefinite because the specification lacked some standard for measuring the degrees intended. In the instant case, “robust”, “superior” and “about” are recited without specific measures of relative degree, so claims for robustness, superiority and approximation in claims 1-7, 9-20, 23-31, 35-41, 43 and 67-68 are indefinite in the absence of a clear standard or definition of three relative terms.
Claims 11, 15-24 and 27-30 are rendered indefinite by contents placed in several parentheses that differ in scope from corresponding terms preceding them.
In claim 11, “recombinant chimpanzee adenovirus” and “recombinant human adenovirus” may or may not carry a “gene segment for full length or partial spike protein or immunogenic part thereof from SARS-CoV-2 virus” (line 3). Likewise, “influenza virus” have four subtypes, well beyond the “A and B strains” cited in parentheses (lines 4-5). Besides, A and B are subtypes of influenza virus, not strains. As for “respiratory syncytial virus vectored vaccine (RSV)”, RSV stands for respiratory syncytial virus but not for “respiratory syncytial virus vectored vaccine.” Appropriate corrections are required such that, for each case, the equivalency or synonymity of contents before and inside the parentheses is established and verified for consistency and accuracy.
In claim 15, “hAd-SARS-CoV-2-S” in first set of parentheses (line 2) refers to a “recombinant human adenovirus”, but a recombinant human adenovirus may or may not have the SARS-CoV-2-S insert in vaccination formulation. In claim 16, “ChAd-SARS-CoV-2-S” in parentheses (line 3) refers to a “recombinant chimpanzee adenovirus”, but a recombinant chimpanzee adenovirus may or may not have the SARS-CoV-2-S insert in vaccination formulation. In claim 17, “hAd-SARS-CoV-2-S” in parentheses (rows 5, 7, 9-10, 12, and 15 in tabulation) and “ChAd-SARS-CoV-2-S” in parentheses (rows 6-9 and 11-15 in tabulation) share the same issues with claims 15-16. Claims 18-24, 27 and 29-30 depend on claim 17 without any remedy for the problem from claim 17, while claim 28 depends on claims 17 and 27, without any remedy for the problem with claim 17 or claim 27. Thus, claims 11, 15-24 and 27-30 all have an indefiniteness issue with the claimed recombinant human adenovirus and/or recombinant chimpanzee adenovirus in a vaccine formulation. Appropriate corrections are required such that the equivalency or synonymity of contents before and inside the parentheses is established and verified for consistency and accuracy.
Claim 17-24 and 27-30 are further rendered indefinite by “may be selected from…” cited in claim 17 (line 2): the term “may be” in claim 17 can be interpreted in different ways: it is unclear if the selection/option is an alternative or a required step/element. Claims 18-24, 27 and 29-30 depend on claim 17 without any remedy for the problem with claim 17, while claim 28 depend on claims 1 and 17 without any remedy for the problem from claims 17 and 27. Thus, claims 17-24 and 27-30 all share the same (claim 17-related) indefiniteness issue with selection/option of various vaccines. Appropriate corrections are required such that the selection of alternative vaccines is made clear without ambiguity.
Claims 27-28 are rendered indefinite by their “dose concentration of… ChAd--SARS-CoV-2-S” (line 2): the “dose concentration” in claim 27 depends on claim 17, which recites “recombinant chimpanzee adenovirus” that may or may not be limited to a component encoding “SARS-CoV-2-S”. It is not clear if the dose “between 1010 VP/dose - 1012 VP/dose in 0.2-0.5ml dose volume” in claim 27 and “1011 VP/dose in 0.2-0.5ml dose volume” is based on all vaccine components or just the “ChAd--SARS-CoV-2-S” part that encodes SARS-CoV-2 S-protein. Claim 28 depends on claim 27 and inherits the indefiniteness issue from claim 27, without any remedy: it is not clear if the dose “1011 VP/dose in 0.2-0.5ml dose volume” is based on all vaccine components or just the “ChAd--SARS-CoV-2-S” part that encodes SARS-CoV-2 S-protein. Appropriate corrections are required such that the dose amount for each claimed ChAd-vectored vaccine is made clear without ambiguity.
The following is a quotation of 35 U.S.C. 112(d) which forms the basis for rejection of improper dependent claims:
(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.
Claims 2-3, 11-13 and 18 are 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.
Claims 2-3 attempt to add two limitations to claim 1 by disclosing “the method as claimed in claim 1, wherein the homologous route of administration comprises administering primary and secondary series of vaccines through same route” (claim 2) and that “wherein the heterologous route of administration comprises administering primary and secondary series vaccines through different routes (claim 3). However, claim 1 already cites “a method of generating… immune response in mammals against SARS-CoV-2 antigen by administering two or more doses of same or different COVID-19 vaccines through same or different routes, wherein at least one vaccine is selected from a primary series of vaccines and at least one vaccine is selected from a secondary series of vaccines and wherein vaccines of primary and secondary series are administered through homologous or heterologous routes.” Claim 1 already has all the limitations cited in claims 2-3. Claims 2 and 3 are explaining the definitions of the two routes, but they fail to further limit the method of claim 1 on which they depend. Thus, neither claim 2 nor claim 3 adds any further limitation to claim 1.
Claim 11 extends claim 7 with a limitation that “wherein recombinant adenovectored SARS-CoV-2 virus vaccine is selected from recombinant chimpanzee adenovirus (ChAd-SARS-CoV-2-S), recombinant human adenovirus (hAd-SARS-CoV-2-S), rabies vectored vaccine, respiratory syncytial virus vectored vaccine (RSV), influenza virus (both A and B strains) or other respiratory virus vectored vaccine containing gene segment for full length or partial spike protein or immunogenic part thereof from SARS-CoV-2 virus.” However, claim 7 only has “the method as claimed in claim 1, wherein both primary and secondary series of vaccines are selected from killed-inactivated SARS-CoV-2 whole-virion vaccine and recombinant adenovectored SARS-CoV-2 virus vaccine”. Neither rabies virus (a negative-sense, single-stranded RNA virus) nor RSV or influenza virus is an adenovirus, so claim 11 is broader than claim 7, which is improper. Claims 12-13 depend on claim 11, and they both inherit the same problem from claim 11.
Claim 18 recites “the method as claimed in claim 17, wherein at least one vaccine is selected from primary series and at least one vaccine is selected from secondary series”, while claim 17 cites “the method as claimed in claim 1, wherein vaccines of primary and secondary series may be selected from…” a list of primary and secondary series, with each series having more than one vaccine. Thus, claim 18 simply repeats the limitations of claim 17 and fails to add or extend any further limitation.
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 so long as no duplicates are made, or present a sufficient showing that each and every dependent claim complies with pertinent statutory requirements.
Claim Rejections under 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 1-2, 4, 7, 9-10 and 31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by He et al. 2021 (Emerging Microbes & Infections 10: 629-637; published March 26, 2021).
He et al. taught methods of prime-boost immunization that aimed to “break the protective immune response bottleneck of COVID-19 vaccine candidates” (title), at a time when “prime-and-boost vaccination strategies” involving distinct vaccine types were made possible by “many COVID-19 vaccine candidates” (page 630, first paragraph on the left). Through a “unified evaluation” of an “Ad5-vectored vaccine” (rAd), an “inactivated vaccine (INA)”, a “recombinant RBD vaccine (rRBD)” and an “mRNA vaccine” (Table 1 and page 630, last paragraph on the right). Using a mix-and-match strategy for sequential applications, Ad5, INA and rRBD vaccines (the first three in He’s Table 1, page 631) provided eight immunization regimens (“2 × INA, 2 × rRBD, rAd > INA, INA > rAd, rAd > rRBD, rRBD > rAd, INA > rRBD, and rRBD > INA”) for comparison with a blank/control group (PBS alone) and an rAd alone group (Figure 1A and pasted below), with SARS-CoV-2-specific binding assays and neutralizing antibody (NAb) titers serving as two key readouts. Application of these vaccines “followed the respective clinical immunization protocols of each vaccine” (pages 630, last paragraph on the right; page 631, first paragraph on the left; Table 1 on page 630), except that the respective human dose (Table 1 on page 631) was cut by 80% (page 631, first paragraph on the left) before injection into BABL/c mice on day 0 and day 21 (Figure 1A and Figure 2A). “Levels of serum NAbs against SARS-CoV-2 were measured using live-and pseudoSARS-CoV-2 virus” (page 630, second paragraph on the left) “14 days after the last dose of immunization” (page 632, first paragraph on the left). Similarly, three combinations of sequential immunization with the rAd vaccine and mRNA vaccine was compared with an rAd alone group (no prime dose for rAd, as shown in Figure 2 on page 633). The “results showed that sequential immunization with adenovirus vectored vaccine followed by inactivated/recombinant subunit/mRNA vaccine administration specifically… promoted the modulation of antibody responses to predominantly neutralizing antibodies (abstract). According to NCT04560881, the “inactivated SARS-CoV-2 vaccine” (INA) used by He et al. (Table 1 on page 631) was BBIBP-CorV, which required a “2-dose” immunization schedule in a human clinical trial (started on 09/16/2020): “2-doses… are inoculated to the deltoid muscle of the upper arm” (i.e., intramuscular/IM injection). For the rAd vaccine (Ad5-nCoV), NCT04526990 (also cited in Table 1) disclosed a clinical trial of “Ad5-nCoV, single dose, intramuscular administration”, which started on 09/15/2020. In contrast, the rRBD vaccine required 2-3 IM doses in human trial (NCT04466085): “Subjects in the 2 dose group were injected with 2 doses of test vaccine or placebo in the upper arm deltoid muscle according to the 0,1 month immunization program, and subjects in the 3 dose group were injected with 3 doses of test vaccine or placebo in the upper arm deltoid muscle according to the 0, 1, 2 month immunization program” (see “Detailed Description). Thus, the first three vaccines taught by He et al and registered at “Clinicaltrials.gov” were all intended for IM immunization in human trials, requiring single, double or triple doses in clinical trials, but a mix-and-match strategy proved that IM injection of different vaccine platforms was capable of eliciting protective immunity in mice.
Mapping the teachings of He et al. 2021 to specific limitations in claims 1-2, 4, 7 and 9-10 is straightforward. First, sequential IM immunization (“Prime” and “Boost”) using the same or different vaccines on day 0 and day 21 (Figure 1A on page 632 and pasted below) provided some advantages when tested in mice, even for a vaccine (rAd) that was designed as a single IM dose in humans (Figure 1A and Figure 2A), immunization procedures “followed the respective clinical immunization protocols of each vaccine” (pages 630, last paragraph on the right; page 631, first paragraph on the left; Table 1 on page 630). For combinatory applications, He’s “sequential immunization” doses were labeled as prime-boost vaccination (Figure 1A and Figure 2A), but their mix-and-match regimens involved two series of immunization using four vaccine platforms, as represented by INA (inactivated SARS-CoV-2 vaccine), rAd (recombinant, Ad5-vectored DNA vaccine), rRBD (recombinant RBD subunit unit vaccine) and mRNA (nucleic-acid-based) vaccine (Figure 1 and Figure 2), with “SARS-CoV-2 spike protein” as a primary immunogen (Table 1 and page 630) for inducing SARS-CoV-2 antigen-specific immune responses, as measured by “total spike-specific IgG”, “serum neutralization assay”, “IFN-γ ELISPOT” and “Th1/Th2 cytokine profiling” (page 630).
PNG
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Overall, He et al. established that four COVID-19 vaccines could be used for sequential immunization against SARS-CoV-2 infection, and IM vaccination in mice (Figure 1A and Figure 2A) demonstrated that “sequential immunization with adenovirus vectored vaccine followed by inactivated/recombinant subunit/mRNA vaccine administration specifically increased levels of neutralizing antibodies and promoted the modulation of antibody responses to predominantly neutralizing antibodies.” Their mix-and-match strategy used a 2-dose IM schedule (21 days apart), but evidential evidence from three clinical trials (pertinent to the first three vaccines taught by He) further indicated that, when COVID-19 vaccines are used alone (no combination), the required dosage for each series can be single, double and even triple. These teachings meet the limitations of claims 1-2, 4, 7 and 9-10 in terms of IM (homologous) immunization using four existing vaccines, alone or in various combination to elicit virus-specific immunity in mice and humans (all are mammals), as gauged by NAb titers and other related outcomes. The dosage (single, double or triple) for each vaccine series is guided by preclinical and clinical efficacy data.
Regarding claim 31, the limitation was an intended use of immunization methods in claim 1, being placed in a “wherein” clause. The determination of whether clauses like “wherein and “whereby” are a limitation in a claim depends on the specific facts of the case. > See, e.g., Griffin v. Bertina, 283 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002) (finding that a “wherein” clause limited a process claim where the clause gave “meaning and purpose to the manipulative steps”). < In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a “‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention.” Id. However, the court noted (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. even if the intended results were given weight, they would necessarily occur in the obvious method since al method steps required are present. In the instant case, methods in claim 1 induce immune responses to SARS-CoV-2-specific antigens, as taught by He et al. 2021. In the absence of any further active step or any further function supported by evidence of record, an intended use of methods in claim 1 bears no further weight on top of its base claim. Thus, the invention of claims 1-2, 4, 7, 9-10 and 31 as a whole was fully anticipated by a single prior art, before the invention was first filed in August 2021.
Claim Rejections under 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as the following:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-7, 9-16, 25-31, 35-41 and 43 are rejected under USC §103 as being unpatentable over He et al. 2021 (Emerging Microbes & Infections 10: 629-637; published March 26, 2021) in view of Tiboni et al., 2021 (International Journal of Pharmaceutics 603: 120686; published June 15, 2021).
As applied supra for claims 1-2, 4, 7, 9-10, 16 and 31 (rejection under USC §102), He et al. taught methods of sequential immunization in mice using four vaccine formulations that have been used in human trials (including three registered with Clinicaltrials.gov). Each of these vaccines could be applied alone (e.g., 2x INA Figure 1A) or in combination (e.g., rAd>INA and INA>rAd in Figure 1A) for homologous IM injection on day 0 and day 21 (Table 1 and Figure 1A). A series of immunoassays confirmed SARS-CoV-2-specific humoral and T-cell responses (page 630, second paragraph on the left), so their teaching supports the use of a mix-and-match strategy in SARS-CoV-2 immunization using four existing vaccine platforms, while the actual dosage per vaccine (single, double or triple) can follow clinical guidelines. These elements meet the limitations of claims 1-2, 4, 7, 9-10 and 31 in the instant application in terms of IM-based sequential immunization against SARS-CoV-2/COVID-19, using human adenovirus-vectored vaccine, inactivated whole virus vaccine, recombinant RBD vaccine and mRNA vaccine, and assessment of “total spike-specific IgG”, “serum neutralization assay”, “IFN-γ ELISPOT” and “Th1/Th2 cytokine profiling” (page 630) provided objective readouts for gauging virus-specific immune responses. He's sequential immunization strategy for using the same or different vaccine platforms (Figure 1A and Figure 2A) is also flexible enough to accommodate other vaccines that require different delivery routes (by “following clinical protocols”). However, their teachings fell short of providing examples of heterologous immunization routes.
Tiboni et al. 2021 taught other delivery routes for COVID-19 vaccination, which were made possible by second-generation vaccines intended for intranasal (IN) delivery. By their disclosure, “an IM prime followed by IN booster would likely result in a… well-rounded immune response, including prevention (or strong reduction) in viral replication in the upper and lower respiratory tracts” (abstract). Their IN vaccines included the following: a) AdCOVID, a replication-deficient adenovirus type 5 (Ad5)-vectored vaccine encoding for the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein”, which “was approved by the FDA on the 25th February 2021” for a “Phase I clinical trial” (page 15, first paragraph on the right); b) ChAd-SARS-CoV-2-S (recombinant chimpanzee adenovirus that encodes a prefusion stabilised S protein) (page 15, first paragraph in section 5.2) -- “a single dose IN inoculated vaccine induced high levels of neutralising antibody (anti-SARS-CoV-2 IgA) and showed complete protection in upper and lower airways after… viral challenge” (page 15, first paragraph in section 5.2); c) ChAdOx1 nCoV-19/AZD1222 – initially used as an IM vaccine in rhesus macaques and further tested as an IN vaccine in Syrian hamsters and rhesus macaques (page 16, section 5.4); d) rNDV-S (based on “a live attenuated and vectored Newcastle Disease virus… encoding a human codon optimized S glycoprotein gene of SARS-CoV-2”) – when tested in Syrian hamsters, “IN with 2 x 104 PFU” as “a single and a double dose… totally blocked the viral shedding in the nasal cavity and in the lungs” (page 16, second paragraph in section 5.5); e) a “novel IN COVID-19 vaccine candidate based on a lentiviral vector” -- “prime/boost” doses of “1 × 107/1 × 107 transduction units (TU) as intraperitoneal (IP) injections” or “prime/target” doses of 1 × 107/3 × 107 TU for IP/IN administration” (page 17, section 5.7) “significantly reduced” lung viral load after challenge infection with “0.3 × 105 TCID50 of SARS-CoV-2” (page 17, section 5.7). Thus, Tiboni’s teachings entailed both homologous and heterologous routes of immunization for various doses: IN alone, IM alone, IP alone or IP prime followed by IN boosters, as single or double doses (e.g., 1x IN, IN/IN and IP/IN) to achieve optimal results in Syrian hamsters, rhesus macaques and humans (all are mammals).
The collective teachings of He and Toboni broaden the range of existing COVID-19 vaccine formulations (approved or under development), as well as multiple immunization routes and flexible mix-and-match strategies for homologous or heterologous immunization against SARS-CoV-2/COVID-19 in mice, Syrian hamsters, rhesus macaques and humans. For preclinical and clinical settings, vaccine efficacy is established by antibody titer, neutralizing capacity, cytokine profile, T-cell immunity, virus load after challenge infection, as well as clinical outcomes (e.g., severe disease or hospitalization). These elements meet the limitations of claims 1-7 and 9-14 in terms of (i) sequential immunization regimens (two series of immunization) for generating immune response in mammals, using different COVID-19 vaccines suitable for homologous or heterologous administration (claims 1-3), including intramuscular (IM), intradermal (ID), intraperitoneal (IP) and intranasal (IN) routes (claim 4); (ii) parenteral delivery (IM/IP) of one vaccine can be followed by IN/mucosal delivery of another or vice versa (claims 5-6); (iii) vaccine types range from inactivated whole-virus vaccine and protein subunit vaccine to DNA/mRNA vaccine and recombinant adenovirus-vectored vaccine (e.g, recombinant human Ad5-vectored vaccine and chimpanzee adenovirus-vectored vaccines) that encode full-length spike protein as the target immunogen. Since both human and chimpanzee adenoviral vectors are taught and functional, use of either in one or both of the prime or booster in a regimen is obvious here as they are taught in the prior art for the same purpose and the results, anti-SARS-CoV-2 immunity, would predictably occur. The same is true for either combined with inactivated SARS-CoV-2 whole virion vaccine. All are taught in the prior art for the same purpose and combining them in any order in a prime/booster vaccination regimen is obvious here. (claims 7 and 9-16).
For dosing interval between prime and booster doses within a series of vaccination, He et al. and Tiboni et al. taught the following: an IN delivered vaccine based on “live attenuated and vectored Newcastle Disease virus” was given 7 days apart in a “prime/booster regimen” (Tiboni et al., page 16, second paragraph on the right), while “IM injection” of “ChAdOx1-S” (“0.5 mL each”) was given at an interval of “4–12 weeks between doses” (Tiboni et al., page 8, first paragraph on the left). For AstraZeneca’s vaccine AZD1222 (“a monovalent vaccine comprising a single recombinant replication-deficient chimpanzee adenovirus vector encoding the full-length SARS-CoV-2 spike glycoprotein gene (DNA)” (Tiboni et al., page 8, second paragraph on the left), two doses of IM injection (“5 × 10^10 vp ± 1.5 × 10^10 vp” as cited in NCT04516746) at a 4-week interval proved to work in “a US phase 3 trial” (NCT04516746), which “showed a statistically significant vaccine efficacy of 79% at preventing symptomatic COVID-19 and 100% efficacy at preventing severe disease and hospitalization” (page 8, last paragraph on the left to first paragraph on the right). In contrast, He et al. used a 21-day (3-week) dosing interval for prime-boost IM regimens that used inactivated vaccine and Ad5-vectored vaccine (Figure 1A in He et al. and cited by Tiboni et al., Table 1 on page 7), and for two Newcastle Disease virus (NDV)-based vaccine known as “rNDV-WT” and “rNDT-S”, a “two weeks interval” was applied to IN delivery to Syrian hamsters (Tiboni et al., page 16, second paragraph in section 5.5.). Another “COVID-19 protein subunit vaccine” for IM delivery was given as two or three doses “30 days apart” in a phase 2 study (Tiboni et al., page 12, second paragraph on the right). Overall, the dosing intervals did vary by vaccine types, but the one week (7 days) to 12 weeks range discussed supra meet the limitations of claim 25 (“between 4-10 weeks”). For example, see the 4 week interval of NCT04516746 discussed above. The dosing interval is clearly a result-effective variable as too long will result in weaker boosted immune responses, for example, due to loss of adaptive immune cells that responded to the prime. Therefore, all dosing intervals of the instant claims will be arrived at by routine experimentation. The same argument is made for all doses of the instant claims.
For claim 30, neither series need be nucleic acid or protein as they are optional and so the obvious methods here meet the claim limitations.
For claim 31, its intended use depends on claim 1, as discussed supra in the section for “Claim Rejection under 102(a)1.” Since He et al. and Tiboni et al. render claim 1 obvious in terms of multiple embodiments (homologous and/or heterologous routes for two series of vaccines), the two references also render claim 31 obvious for the same claimed elements and reasons behind them.
For claims 35, 38 and their dependents, effective SARS-COV-2 vaccination in animals and humans (all are mammals) could also follow He’s mix-and-match strategy: priming with a killed-inactivated SARS-CoV-2 whole-virion vaccine (e.g., INA in He et al., Figure 1A and tested in mice and humans) for IM injection can be followed by an intranasal dose of “ChAd-SARS-CoV-2-S vaccine” that have been tested in non-human primates (rhesus macaques)” for “intranasal and intrabronchial routes”, as taught by Tiboni (page 15, last paragraph on the right), meeting the limitations of claim 35. Switching the order of vaccination doses, as taught by He et al. (Figure 1A and Figure 2A), meets the limitations of claim 38. Of note, inactivated SARS-CoV-2 whole-virion vaccine often requires multiple doses to be effective, as taught by He (e.g., Figure 1) and evidential evidence disclosed in NCT04466085 (as discussed supra).
Regarding claim 39, Tiboni’s ChAd-SARS-CoV-2-S is a chimpanzee adenovirus-vectored vaccine that “encodes a prefusion stabilized S protein”, with proven immunogenicity and immune protection in mice and primates after IM injection (page 15, first two paragraphs in section 5.2). The same vaccine also proved to be effective as a single IN dose in rhesus macaques – “an IN immunisation with ChAd-SARS-CoV-2-S could potentially control nasal infection and hence prevent both viruses induced disease and also transmission (page 15, last paragraph on the right). Tiboni’s ChAd-SARS-CoV-2-S alone can meet the limitation of claims 36. Replacing the human rAd vaccine (IM route) in He et al. with the ChAd-SARS-CoV-2-S (IN route) in Tiboni and then combining it with the inactivated SASR-CoV-2 whole-virus vaccine (INA) from He would meet the limitations of claim 39, in terms of an IN delivery of a recombinant chimpanzee adenovirus that contains gene segment encoding complete spike (S) protein.
Coming to claims 41 and 43, Toboni taught two human adenovirus-vectored vaccines, rAD26-S and rAD5-S (part of Sputnik V in Table 1, page 7), which “carry the gene for SARS-CoV-2 full length spike glycoprotein.” Both “received regulatory approval in Russia by the Ministry of Health of the Russian Federation” in August 2020 (page 9, first paragraph in section 3.4). “The vaccine is given as two separate component vaccines, rAD26-S as the prime IM injection and rAd5-S as the booster injection administered 21 days apart. Each dose contains 1.0 × 1011 viral particles,” “with a volume of 0.5 mL,” capable of inducing “RBD-specific (neutralising) IgGs with titres observed equal to or higher than those seen in patients recovered from COVID-19” (page 9, first paragraph in section 3.4). For IN route, Toboni taught “AdCOVI”, which is “a replication-deficient adenovirus type 5 (Ad5)-vectored vaccine encoding for the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein” for “intranasal administration… given in a volume of 50 μL”, with “a strong IgG serum neutralising activity, several fold higher than the titre recommended by the FDA, and a potent mucosal immunity with a 29-fold increase in mucosal IgA in the respiratory tract” (page 15, last paragraph on the left). In other words, three human adenovirus-vectored vaccines elicited protective immune response after IM or IN injection. Based on He’s mix-and-match strategy for sequential immunization, a skilled artisan could follow these preclinically and clinically proven examples to use a recombinant hAd-vectored vaccine like rAD26-S or rAD5-S as a primary series (IM injection) and another recombinant hAd-vectored vaccine like AdCOVI for a secondary series (IN delivery) to elicit SAS-CoV-2-specific immune response locally and systemically, as taught by He and Toboni. The results are predictable and meet the limitations of claim 41. For claim 43, Toboni taught a “ChAd-SARS-CoV-2-S” vaccine “based on chimpanzee adenovirus (simian AD-36) that encodes a prefusion stabilised S protein” and preclinical data that favored its IN route: “the IM vaccination did not completely protect against the SARS-CoV-2 infection, since substantial levels of viral RNA were still detected in the lungs. In contrast, a single dose IN inoculated vaccine induced high levels of neutralising antibody (anti-SARS-CoV-2 IgA) and showed complete protection in upper and lower airways after… viral challenge” (page 8, section 5.2). Thus, switching the second human adenovirus-vectored IN vaccine (AdCOVI) in claim 41 to an effective, chimpanzee adenovirus-vectored IN vaccine like Toboni’s “ChAd-SARS-CoV-2-S” would meet the limitations of claim 43 but also yield predictable results as simply substitution of one booster for another known in the prior art.
For a person of ordinary skill in the art, following the collective teachings of He et al. and Tiboni et al. could arrive at a sequential immunization protocol against SARS-CoV-2, using both first- and second-generation vaccines suitable for homologous or heterologous delivery routes that are guided by preclinical and clinical efficacy data. In situations where a mix-and-match protocol is preferred, vaccines designed for IM delivery (as taught by He et al.) could be replaced by other vaccines designed for non-parenteral (e.g., IN) route, because “it is considered highly attractive to administer vaccines via the nasal route, since this route has the advantage of inducing both a systemic and a strong local mucosal immune response” (Tiboni, page 2, last paragraph on the right). Moreover, “for IN administration there is no requirement for specialized medical personal to administer the dose, hence the product should have a higher patient compliance” (Tiboni et al., page 2, last paragraph on the right). Overall, it would be obvious to adopt both homologous and heterologous vaccination routes to fully utilize first- and second-generation vaccine formulations in sequential immunization against COVID-19, with both parenteral and mucosal routes of delivery to elicit SARS-CoV-2-specific humoral and cell-mediated immune responses, systemically and locally, to yield a balanced or all-rounded immune response profile, as taught by Tiboni et al. (abstract). Thus, the invention of claims 1-7, 9-14, 25, 31, 35-36, 38-39, 41 and 43 as a whole was rendered prima facie obvious by two references at the time of invention, as an example of rationales B and G in MPEP §2143: Simple substitution of one known element for another to obtain predictable results; prompted by teaching, suggestion, or motivation in the prior art, one of ordinary skill would modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Claims 1 and 15 are rejected under USC §103 as being unpatentable over He et al. 2021 (supra) in view of Tiboni et al., 2021 (supra) as applied to claims 1-7, 9-16, 25-31, 35-41 and 43, and further in view of Brussow 2021 (Microbial Biotechnology 14: 1246–1257. First published May 7, 2021).
As discussed supra, He et al. and Tiboni et al. taught methods of homologous and heterologous regimens for sequential immunization against SARS-CoV-2/COVID-19, including a mix-and-match strategy that maximizes the utility of existing vaccines suitable for parenteral and mucosal deliveries. The choice of first- and second-generation vaccine platforms is broad, including whole inactivated SARS-CoV-2 virus vaccines, adenovirus-vectored vaccines (encoding full-length or partial spike protein as the target immunogen), spike (S) protein/subunit (e.g., rRBD) vaccines, as well as mRNA vaccines, with various examples for intradermal, IM, IN and IP administration, with preclinical and clinical successes (e.g., Table 1 in He, page 631 and Table 1 in Tiboni, page 7). These teachings render the invention of claims 1-7, 9-14, 16, 25, 31, 35-36, 38-39, 41 and 43 obvious (as discussed supra), but they fell short of teaching the use of a recombinant human adenovirus with nucleic acid encoding full length codon optimized spike protein of SARS-CoV-2.
Brussow 2021, on the other hand, taught “an adenovirus, Ad5-S-nb2, carrying a codon-optimized SARS-CoV-2 spike gene” for “intramuscular (IM) or intranasal (IN) application” page 1249, last paragraph on the right): “IM vaccination induced a good serum ELISA and neutralizing antibody response, but no mucosal antibodies, while IN vaccination induced both serum and mucosal antibody titres” (page 1249, last paragraph on the right). Moreover, “IN vaccination conferred effective protection of monkeys against SARS-CoV-2 infection” (page 1249, last paragraph on the right). In other words, this codon-optimized, human adenovirus-vector vaccine is suitable for both parenteral (IM) and mucosal (IN) deliveries. A skilled artisan could use this vaccine for one of the mix-and-match sequential regimens taught by He and Tiboni (IM-IM, IM-IN, IN/IM and IN/IN) to arrive the invention of claim 15. Thus, the invention of claims 1 and 15 as a whole was rendered obvious by three references, as an example of rationale B of MPEP §2143: Simple substitution of one known element for another to obtain predictable results. The motivation for a mix-and-match immunization protocol is multi-fold, including improved efficacy and adherence, as disused supra.
Claims 1, 17-20, 23-24, and 27-30 are rejected under USC §103 as being unpatentable over He et al. 2021 (supra) in view of Tiboni et al., 2021 (supra) as applied to claims 1-7, 9-16, 25-31, 35-41 and 43, and further in view of Alu et al., 2022. (eBioMedicine 76: 103841. Published January 24, 2022).
As discussed supra, He et al. and Tiboni et al. taught methods of homologous and heterologous prime-boost regimens for immunization against SARS-CoV-2/COVID-19, through a typical prime-boost regimen or a mix-and-match schedule facilitated by a broad choice of first- and second-generation vaccine platforms suitable for intradermal, IM, IN and IP routes, using existing vaccines that range from whole inactivated SARS-CoV-2 virus vaccines, adenovirus-vectored vaccines, spike (S) protein/subunit (e.g., rRBD) vaccines, as well as mRNA vaccines with preclinical and clinical efficacy data (e.g., Table 1 Tiboni, page 7). The collective teachings of He et al. and Tiboni et al. render claims 1-7, 9-14, 16, 25, 31, 35-36, 38-39, 41 and 43 obvious, but their sequential immunization regimens rarely exceed three doses to fully meet the limitations of claims 17-20, 23-24, and 27-30, which receive an effective filing date of 02/02/2024 instead of 08/03/2021.
Alu et al., 2022 taught the success of 12 IN vaccine candidates reaching clinical trials at different phases (abstract and Table 2 on page 6), along with “preclinical studies of IN COVID-19 vaccines” being tested in ferrets, hamsters, mice, macaques, as well as humans (all are mammals). These vaccines are applied as single, double, triple or quadruple doses, often in parallel or in combination with other delivery routes (e.g., ID, IM or oral) (Table 1 on page 5). Among those that required two doses, IN/IN was applied to an “Ad5-N” vaccine with “N protein” as immunogen, IM/IM or IN/IN was applied to “AdC7-S, AdC7-RBD” with “S, RBD” as immunogen, IP/IN or IM/IN was used for a “Lentivirus-vectored vaccine” with S protein as immunogen, IN/IM for Ad5-nCoV (also cited by He and Tiboni), AVX/COVID-12-HEXAPRO (NDV-vectored vaccine) and CIGB-669, as well as IM/IN for “Razi Cov Pars” (a protein subunit vaccine). For vaccines that required three or more doses, IN/IN/IN, IM/IM/IM or ID/ID/ID was applied to a “Protein subunit vaccine” with RBD as immunogen, IM/IM/IM or IN/IN/IN/IN was used for a third “Protein subunit vaccine” with S1 protein as immunogen, and IN/IN/IN, IM/IM/IM or IN/IN was applied to a “DNA vaccine” (pQAC-CoV) that encodes S and N proteins. Overall, it is clear from the collective teachings of He, Tiboni and Alu that vaccine types suitable for ID, IM, IN, IP and oral administration routes are broad, with target immunogens like S protein, S1 subunit or just the RBD domain as the target immunogen, while the dosage for each vaccine can be single, double, triple or quadruple.
A person of ordinary skill in the art could readily connect the teachings of He et al. and Tiboni et al. with those of Alu et al. to broaden the choices of vaccine types and number of dosage per vaccine, using immunization protocols with proven preclinical and clinical data or a mix-and-match schedule taught by Het et al. to elicit both local and systemic immune. Their collective teachings meet the limitations of claims 1, 17-20, 23-24 and 27-30, in terms of (i) two doses of recombinant adenovirus-vectored SARS-CoV-2/COVID-19 vaccine in one series for either IM or IN application, followed by another two doses of recombinant adenovirus-vectored SARS-CoV-2/COVID-19 vaccine in a second series for either IM or IN route, with an alternative for using two doses of an inactivated whole-virus vaccine in first series (IM or IN route), followed by two doses of recombinant adenovirus-vectored SARS-CoV-2/COVID-19 vaccine in a second series for either IM or IN route or vice versa (claims 1 and 17-18); (ii) at least one vaccine in first series is administered through ID or IM route and at least one vaccine in second series is administered through IN or oral route (claim 19), with an alternative embodiment that at least one vaccine of primary series is administered through IN or oral route and at least one vaccine in secondary series is administered through ID or IM route (claim 20); iii) two vaccines of first series and one vaccine of a second series is administered through heterologous route (e.g., IM/IM/IN or IN/IM/IM) (claim 23); (iv) one vaccine in first series and two vaccines in a second series are administered through heterologous routes (e.g., IM/IN/IN or IN/IN/IM) (claim 24), and (v) the primary or secondary series vaccines comprise nucleic acid (mRNA)-based or protein subunit-based COVID-19 vaccines (claim 30).
Regarding immunization dosage for chimpanzee adenovirus-vectored vaccines, Tiboni et al. taught three examples: a) “ChAd-SARS-CoV-2-S” based on simian AD-36 that “encodes a prefusion stabilised S protein” – 1010 virus particles in a 50 µl for IM injection or IN inoculation in mice, with a time interval of “4 weeks” (prime-boost schedule) (page 15, first paragraph in section 5.2); b) “ChAdOx1-S” (another chimpanzee adenovirus-vectored vaccine encoding full-length spike protein) is “supplied as a ready-made aqueous suspension for IM injection” (0.5 mL doses with not less than 2.5 x 108 infectious units) -- a human prime-boost regimen used “two separate doses of 0.5 mL each with an interval of 4–12 weeks between doses” (page 8, first paragraph on the left); c) “ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles… as a single IM injection” or as IM/IM prime-boost at 28 days apart in a phase 3 trial (page 8, second paragraph on the left), but for IM/IM prime-boost schedule with a “low dose” of “2.2 × 1010 viral particles” and a “standard dose” of “3.5 × 1010 viral p--articles” for the same ChAdOx1 nCoV-19 vaccine also worked in another randomized clinical trial (page 8, third paragraph on the left). The dosage and time intervals for using chimpanzee adenovirus-vectored vaccines vary by vaccine formulation, with both low-dose and high-dose applications. For “ChAd-SARS-CoV-2-S”, the effective and safe IM and IN dose of 1010 viral particles for both IM and IN route in mice can readily translate to 4 x 1010 viral particles in humans, and the time intervals ranged from four weeks to 12 weeks. These elements did not match the exact limitations in claim 27 (“between 1010 VP/dose - 1012 VP/dose in 0.2-0.5 mL dose volume” or claim 28 (“1x1011 VP/dose at 0.5 mL volume”), but variation for a result-effective variable like dosage is known to be optimized through routine experimentation.
Pertinent to claims 27-28, it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. According to MPEP §2144.05, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). Since Applicant has not disclosed that the specific limitations recited in instant claims are for any particular purpose or solve any stated problem, and the prior art teaches that parameter magnitudes that are encompassed by instant claims, often vary according to the vaccine recipients (animals or humans) being analyzed, with various routes and volumes appearing to work equally as well, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum workable ranges of the methods disclosed by the prior art by normal optimization procedures known in the art.
Coming to immunization dosage for killed-inactivated SARS-CoV-2 whole-virion vaccine, He et al. (Table 1) taught a prime-boost dose of BBIBPCorV (inactivated whole-virus vaccine, cited as INA in Figure 1A) as “4 µg” in humans for IM route administered 21 days apart. For IM route in mice, the dose was cut by 80% (to 1 µg each) (page 631, first paragraph on the left). In other words, the actual dosage can differ by four-fold for mice and humans. Tiboni further taught that this vaccine is “dispersed in 0.5 mL sterile phosphate buffered saline and packed into prefilled syringes (page 10, second paragraph in section 3.7), with three levels of vaccine dose (2.5, 5 and 10 µg/dose) (page 10, second last paragraph). These elements meet the limitations of claim 29 (“the dose concentration of killed- inactivated SARS-CoV-2 whole-virion vaccine is 6 µg/dose in 0.5 mL volume”.
A skilled artisan could follow the collective teachings of He et al., Tiboni et al. and Alu et al. to properly use existing vaccine formulations for preclinical and clinical applications (application to in mammals), following a sequential regimen suitable for a broad range of existing vaccines with proven safety and efficacy profile (e.g., Table 1 in Tiboni et al. and Tables 1-2 in Alu et al et al.). For result-effective variables, including dosage and time interval between immunization, a specific application may or may not require routine optimization, depending on the extent of preclinical and clinical efficacy data (an evolving landscape), as taught by three references. Thus, the invention of claims 1, 17-20, 23-24 and 27-30 as a whole was rendered prima facie obvious by three references at the time of the invention, as another example of rationales B and G in MPEP §2143: Simple substitution of one known element for another to obtain predictable results, when prompted by 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 claimed invention. The motivation for a sequential, mix-and-match immunization protocol is multi-fold, including improved efficacy and adherence, as disused supra.
Claims 1, 26, 37, 40 and 67-68 are rejected under USC §103 as being unpatentable over He et al. 2021 (supra) in view of Tiboni et al., 2021 (supra), as applied to claims 1-7, 9-16, 25-31, 35-41 and 43, further in view of Leventhal et al., 2021 (Microorganisms 9: 1040; published 05/12/2021).
As discussed supra, He et al. and Tiboni et al. taught methods of sequential vaccination using homologous and/or heterologous routes for immunization against SARS-CoV-2/COVID-19, taking advantage of a variety of first- and second-generation vaccine platforms, including whole inactivated SARS-CoV-2 virus vaccines, adenovirus-vectored vaccines, spike (S) protein/subunit (e.g., rRBD) vaccines, as well as mRNA vaccines intended for parenteral (ID, IM and IP) and mucosal (IN) delivery routes, with rationales supported by preclinical and clinical efficacy data. These teachings render the invention of claims 1-7, 9-14, 16, 25, 31, 35-36, 38-39, 41 and 43 as a whole obvious (as discussed supra). He et al. and Tiboni et al. also taught various time intervals between priming and boosting doses, but still fell short of (i) providing a three-dose format that take advantages of the broad range of COVID-19 vaccines suitable for parenteral and mucosal routes in animals and/or humans, and (ii) specifying the time interval between the second dose of vaccine in first series and the first dose of vaccine in the second series. These deficiencies are overcome by Leventhal et al., 2021, as their “intranasal (IN) and intramuscular (IM) routes of administration” of “a DNA vaccine against SARS-CoV-2” in a Syrian hamster model (abstract) included “IM-IM-IM or IM-IN-IN vaccinations” (Figure 3a on page 8 of 17 and pasted below), as well as a typical IM-IM and IN-IN vaccination schedule (Figure 2 on page 6 of 17), with time intervals between second dose (first booster) and third dose (second booster) at 21 days.
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Figure 3a from Leventhal et al., 2021 (page 8 of 17). “Prime-Boost-Boost hamsters were divided into two spike-vaccinated groups receiving IM-IM-IM or IM-IN-IN vaccinations of 50 ug Sp_pVax1 DNA plasmid complexed to in vivo delivery reagent.” IM-IM and IN-IN schedules were also included (Figure 2 on page 6 of 17).
Leventhal’s IM-IM-IM or IM-IN-IN vaccinations used a “DNA-plasmid encoding the SARS-CoV-2 full length spike open reading frame (ORF)” that “induces host cells to produce spike protein and protective immune responses before exposure to infectious virus” (abstract), and “significantly reduced viral loads” were “observed in the IM-only prime-boost-boost
group” (on page 8 of 17, first paragraph in section 3.4), as “second boost significantly increased anti-RBD titers” in the IM-only group” (page 7 of 17, last paragraph). Given the flexibility of mix-and-match strategy provided by He (Figure 1A and Figure 2A) for various vaccines types, replacing Leventhal’s DNA-plasmid vaccine with an effective vaccine like rAd in He (Figure 1a) would ensure that the IM-IN-IN schedule also works, although the dosing interval between the second vaccination dose (a booster) and third vaccination does (a second booster) taught by Leventhal is not the same as the “about 10 weeks” (claim 26) or “4-10 weeks” range (claims 37 and 40. However, as discussed supra for claims 27-28, time interval between vaccine doses is also a result-effective variable, and it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. According to MPEP §2144.05, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). Since Applicant has not disclosed that the specific time intervals in instant claims are for any particular purpose or solve any stated problem, and the prior art teaches that parameter magnitudes that are encompassed by instant claims, often vary according to the vaccine recipients (animals or humans) being analyzed, with various vaccines that appear to work equally as well for time intervals between doses (as applied to claims 27-28), absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum workable ranges of the methods disclosed by the prior art by normal optimization procedures known in the art.
Regarding claims 67-68, combining the teaching of Leventhal for homologous and heterologous routes of a prime-boost-boost regimen with the principle of mix-and-mix strategy taught by He and Tiboni for the variety of vaccines suitable for ID, IM, IN and IP routes (as discussed supra) would expand the choice of vaccines for first series and second series of immunization to ensure lasting immunity, both locally (at the virus entry portal) and systemically. A skilled artisan could arrive at a three-dose vaccination regimen using homologous and heterologous routes by adopting the mix-and-match strategy taught by He for homologous administration (IM route) and then adding the homologous and heterologous routes taught by Tiboni and Leventhal, and the resulting three-dose schedule can be further simplified, as some vaccines (e.g., rAd in Figure 1 of He et al.) apparently only requires a single dose to be effective (e.g., INA in Figure 1 of He et al.), while others may two or more doses (e.g., Figures 2 and 3 in Leventhal et al.,) to induce optimal immune protection. Thus, vaccination using two series of existing vaccines can be one or two for each series (and the order can be switched, as taught by He et al.). Collectively, these elements from three references meet the limitations of claims 67-68 in terms of one or two doses in the first series and then one or two doses in a second series with homologous or heterologous routes (e.g., IM/IM/IN, IN/IM/IM and others, as dictated by preclinical and clinical efficacy data). Thus, the invention of claims 1, 26, 37, 40 and 67-68 as a whole was rendered prima facie obvious by three references at the time of the invention, as an example of rationale G in MPEP §2143: Teaching, suggestion, or motivation in the prior art would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. The main motivation for adopting a two-series immunization schedule with either homologous and heterologous delivery routes remains the same as discussed supra (improved efficacy and adherence), but Leventhal’s DNA vaccine provides another practical incentive: “DNA vaccines often require boosting” (Leventhal, page 10 of 17, second paragraph under “Discussion”).
Conclusion
No claims are allowed.
Additional Prior Art Cited but Not Applied
Schmidt et al. 2021. Immunogenicity and reactogenicity of heterologous ChAdOx1 nCoV-19/mRNA vaccination. Nature Medicine vol. 27, pages 1530–1535 (ePub July 26, 2021)
As disclosed in this prior art, “heterologous priming with the ChAdOx1 nCoV-19 vector vaccine followed by boosting with a messenger RNA vaccine (BNT162b2 or mRNA-1273) is a recommended practice in Germany” (abstract). When “a homologous vaccine regimen comprising either ChAdOx1 nCoV-19 or one of the mRNA vaccines (BNT162b2 or mRNA-1273)” was compared with “a heterologous vaccine regimen comprising a ChAdOx1 nCoV-19 priming dose followed by secondary vaccination with an mRNA vaccine”, “the time interval between the first and second dose was determined as per national guidelines and varied from 3 to 6 weeks for the homologous mRNA regimens to 9–12 weeks for the homologous ChAdOx1 nCoV-19 and the heterologous ChAdOx1 nCoV-19/mRNA regimen (Extended Data Fig. 1 and first paragraph under Methods). Their results indicated that “the heterologous vaccine regimen induced spike-specific IgG, neutralizing antibodies and spike-specific CD4 T cells, the levels of which were significantly higher than after homologous vector vaccine boost (n = 55) and higher or comparable in magnitude to homologous mRNA vaccine regimens (n = 62), while spike-specific CD8 T cell levels after heterologous vaccination were significantly higher than after both homologous regimens” (abstract and Fig. 1 on pages 1531-1532). In addition, “heterologous boosting was well tolerated and comparable to homologous mRNA boosting” (abstract). Overall, a vaccine regimen that uses ChAdOx1 nCoV-19 for priming and mRNA (BNT162b2 or mRNA-1273) for boosting, as practiced in Germany and confirmed by clinical data from Schmidt et al. 2021, not only lent strong support to the teachings of He et al., 2021 in terms of mix-and-max strategies for enhancing immune response (He et al., Figure 2A and Figure 2B) but also extend the time interval between doses from a uniform 21 days used by He (Figure 1a and Figure 2a) to a variable range (3 to 6 weeks or to 9–12 weeks), as dictated by the specific vaccines used in each immunization schedule.
Galdiero et al. 2021. SARS-CoV-2 vaccine development: where are we? Eur Rev Med Pharmacol Sci. 25: 2752-2784. Published March 26, 2021.
This prior taught that, while vaccine platforms for SARS-CoV-2 vaccine development differ in benefits and limitations, as assessed by “specific immunological advantages and disadvantages” (Figure 1 on page 2754), “a key point actually addressed by many studies is a better definition of the amount of antigen dose to be administered, the number of doses needed, the duration of immunity, and the need for boosters that depend on the technology used to produce each vaccine preparation” (page 2777, first paragraph on the right). They also taught that “vaccines require both humoral and cellular responses to provide an adequate level of protection and to induce a durable and robust immunological response (page 2777, first paragraph on the right). For vaccines divided into six major platforms (Figure 1 on page 2754), their tabulations covered a broad range (Tables II-VII), including “inactivated whole-virus candidate vaccines” (Table II on page 2758) and “viral vectored candidates” in Table V (page 2772-2773). For preferred routes of administration, intranasal (IN) delivery was applicable to “Ad 5 vector for intranasal administration” (Table V on page 2772), Newcastle disease virus vector (rNDV-FARVET) expressing RBD” (Table V on page 2773), and “live viral vectored vaccine based on attenuated influenza virus backbone” (Table V on page 2773). Vaccines intended for intramuscular administration included “BBV152B vaccine formulation… administered as a two dose intramuscular injection 28 days apart” (page 2759, first paragraph on the left) and “a prime-boost vaccination consisting of a single dose of intramuscular rAd26-S on day 0 and a subsequent dose of intramuscular rAd5-S on day 21” (page 2770, first paragraph on the left). These elements are consistent with the teachings of He et al and Toboni et al. in terms of a broad range of COVID-19 vaccines suitable for parenteral and mucosal administration.
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/JIANMING TANG/
Examiner, Art Unit 1671
/Michael Allen/ Supervisory Patent Examiner, Art Unit 1671
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