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 of species in the reply filed on 04/23/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant elected species as below:
(a) a single LTB sequence: SEQ ID NO: 1.
(b) spike protein amino acid sequence: SEQ ID NO: 15.
(d) one viral species: SARS-CoV-2.
Applicant indicated that claims 1-7, 12-13, 16-19, 21-23, 26, 29, and 42 read on the elected species.
The applicant’s election of species is made final.
Status of Claims
3. Claims: 1-7, 12-13, 16-19, 21-23, 26, 29, 37 and 42 are pending.
4. Claims: 1-7, 12-13, 16-19, 21-23, 26, 29, and 42 are under examination.
Information Disclosure Statement
5. The information disclosure statement (IDS) submitted on 03/25/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Priority
6. This application is a National Phase of PCT Patent Application No. PCT/IL2022/050217 having an international filing date of February 24, 2022, which claims the benefit of priority of U.S. Provisional Patent Application No. 63/153,545, filed February 25, 2021, and of U.S. Provisional Patent Application No. 63/184,942.
Claim Rejections - 35 USC § 112
7. 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.
8. Claims 1-7, 12-13, 16-19, 21-23, 26, 29, and 42 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. This is a written description rejection.
The instant claims 1, 21 recites a limitation “a functional analog of LTB”. The claim 21 requires at least 80% sequence identity or homology to the LTB. The instant specification para [032] and [070] recites the functional analog is characterized by having at least 70%, 80%, 90%, 95%, 97%, 99%, or 100% sequence identity or homology to the LTB, or any value and range there between. The claimed a functional analog of LTB” is a genus (instant claim 1). It is not clear whether the 20% variation in the sequence identity (as required identity is at least 80%) is due to insertion, deletion or substitution of amino acids and it may give rise to many numbers of species. The specification does not disclose reduction to practice of the claimed functional analogue of LTB by working examples.
The instant claim 23 recites a limitation immunogenic polypeptide comprising at least two viral peptides or any analogs there of having at least 80% sequence identity to said at least two viral peptides. The claimed a functional analog of viral peptides” is a genus (instant claim 23). It is not clear whether the 20% variation in the sequence identity (required identity is at least 80%) is due to insertion, deletion or substitution of amino acids and it may give rise to many numbers of species. The specification does not disclose reduction to practice of the claimed functional analogue of viral peptide by working examples.
When a claim covers a genus of inventions, the specification must provide written description support for the entire scope of the genus. Support for a genus is generally found where the applicant has provided a number of examples sufficient so that one in the art would recognize from the specification the scope of what is being claimed. However, the presence of multiple species within a claimed genus does not necessarily demonstrate possession of the genus. See, In re Smyth, 178 U.S.P.Q. 279 at 284-85 (CCPA 1973) (stating “where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus or combination claimed at a later date in the prosecution of a patent application.”); and University of California v. Eli Lilly and Co., 43 USPQ2d 1398, at 1405 (Fed Cir 1997)(citing Smyth for support). In the instant case, the specification does not provide adequate written description of sufficient number of “functional analog of LTB” or the claimed “functional analogue of viral peptide” that are reduced to the practice. The applicable standard for the written description requirement can be found in MPEP§ 2163; University of California v. Eli Lilly, 43 USPQ2d 1398 at 1407; PTO Written Description Guidelines; Enzo Biochem Inc. v. Gen-Probe Inc., 63 USPQ2d 1609; Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111; and University of Rochester v. G.D. Searle & Co., 69 USPQ2d 1886 (CAFC 2004). To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. In the instant case, the working example (reduction to practice) structure defined for “functional analog of LTB” or the claimed “functional analogue of viral peptide” is required but is not disclosed in the instant specification. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus. The instant claims encompass an infinite genus of “functional analog of LTB” or the claimed “functional analogue of viral peptide”.
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).
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description” Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, 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 applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, Fri. January 5, 2001, see especially page 1106 column 3). In the instant case, the specification does not provide adequate written description of sufficient number of “functional analog of LTB” or the claimed “functional analogue of viral peptide” is required but is not disclosed in the instant specification that are reduced to the practice. The legal standard for sufficiency of a patent's (or a specification’s) written description is whether that description "reasonably conveys to the artisan that the inventor had possession at that time of the claimed subject matter", Vas-Cath, Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991). In the instant case, the specification does not convey to the artisan that the applicant had possession at the time of invention of the claimed invention. The full breadth of the claims does not meet the written description provision of 35 U.S.C. 112, first paragraph.
9. Claim 1-7, 12-13, 16-19, 21-23, 26, 29, and 42 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 “LTB” and “viral peptides”, does not reasonably provide enablement for “functional analogues of LTB with at least 80% sequence identity” as claimed in instant claims 1 and 21 or “functional analogues of viral peptides with at least 80% sequence identity” . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The instant specification does not reasonably provide enablement for “functional analogues of LTB with at least 80% sequence identity” as claimed in instant claims 1 and 21 or “functional analogues of viral peptides with at least 80% sequence identity” as claimed in instant claim 23.
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 as follows:
Nature of the invention: The claims are drawn to a method for therapeutic effectiveness of the claimed method using the claimed composition for increasing immunization efficiency of a subject to a pathogen. The composition comprises “functional analogues of LTB with at least 80% identity (includes with 20% sequence variation from LTB sequence)” as claimed in instant claims 1 and 21 or “functional analogues of viral peptides with at least 80% sequence identity (includes with 20% sequence variation from viral peptide sequence)” as claimed in instant claim 23.
State of the prior art: At the time the invention was made Sawada et al 2018 disclosed a variant LTB SEQ ID NO: 12 with 81.5% query match and 99% local similarity to the instant LTB claimed in SEQ ID NO: 1. The prior art SEQ ID NO: 12 (Sawada et al 2018) is reported to function and have an adjuvant effect when it is administered as the fusion protein to an animal such as a pig. However, Sawada et al 2018 has taught a single variant species of LTB whereas the instant claims 1 and 21 has claimed a genus of functional analogue of LTB that comprise many different species of LTB.
Breadth of the claims: The claims are very broad, encompassing a method for therapeutic effectiveness of the claimed method using the claimed composition for increasing immunization efficiency of a subject to a pathogen. The composition comprises “functional analogues of LTB with at least 80% sequence identity” as claimed in instant claims 1 and 21 or “functional analogues of viral peptides with at least 80% sequence identity” as claimed in instant claim 23. Therefore, the claims comprise many different variant species of LTB and viral peptides.
Working examples: Reduction to practice by working example is not disclosed in the specification showing enablement for “functional analogues of LTB with at least 80% sequence identity” as claimed in instant claims 1 and 21 or “functional analogues of viral peptides with at least 80% sequence identity” as claimed in instant claim 23 to achieve the function of therapeutically effectiveness of the claimed method for increasing immunization efficiency of a subject to a pathogen.
Guidance in the specification: The specification does not provide guidance regarding practice of the claimed method by reduction to practice by working example in the specification showing enablement for “functional analogues of LTB with at least 80% sequence identity” as claimed in instant claims 1 and 21 or “functional analogues of viral peptides with at least 80% sequence identity” as claimed in instant claim 23 to achieve the function of therapeutically effectiveness of the claimed method for increasing immunization efficiency of a subject to a pathogen.
Predictability of the art. In the instant application, the Applicants have not disclosed or shown the effectiveness of the claimed functional analogue of LTB or functional analogue of viral peptides. The predictability of functioning will depend on a specific structure of the functional analogue of LTB or the functional analogue viral peptide. At the time the invention was made Sawada et al 2018 disclosed a variant LTB SEQ ID NO: 12 with 81.5% query match and 99% local similarity to the instant LTB claimed in SEQ ID NO: 1. The prior art SEQ ID NO: 12 (Sawada et al 2018) is reported to function and have an adjuvant effect when it is administered as the fusion protein to an animal such as a pig. However, Sawada et al 2018 has taught a single variant species of LTB whereas the instant claims 1 and 21 has claimed a genus of functional analogue of LTB that comprise many different species of LTB. Therefore, a high level of unpredictability exists depending on the type of variation (amino acid deletion/insertion/substitution) and region of the claimed functional analogue of LTB or functional analogue of viral peptides.
Amount of experimentation: It is not known whether the claimed method could be reduction to practice for enablement for “functional analogues of LTB with at least 80% sequence identity” as claimed in instant claims 1 and 21 or “functional analogues of viral peptides with at least 80% sequence identity” as claimed in instant claim 23 to achieve the function of therapeutically effectiveness of the claimed method for increasing immunization efficiency of a subject to a pathogen. The full scope of enablement of the claims would require an undue experimentation.
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 make and use/practice the claimed method to the full scope that comprise a genus of “functional analogues of LTB with at least 80% sequence identity” as claimed in instant claims 1 and 21 or “functional analogues of viral peptides with at least 80% sequence identity” as claimed in instant claim 23 to achieve the function of therapeutically effectiveness of the claimed method for increasing immunization efficiency of a subject to a pathogen and therefore consequently raise doubt as to the enablement of full scope of the claims.
Claim Interpretation
10. 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 method for increasing immunization efficiency of a subject to a pathogen, the method comprising administering a therapeutically effective amount of a pharmaceutical composition comprising:
a. a heat labile toxin subunit B (LTB) polypeptide or a functional analog thereof; and
b. an immunogenic polypeptide derived from said pathogen, thereby, increasing immunization efficiency of a subject to the pathogen.
The claim 1 is directed to LTB adjuvanted vaccine for induction of both mucosal (e.g. IgA antibody) and humoral immune response (e.g. IgG antibody) to an antigen from a pathogen (e.g. virus). The limitation, therapeutically effective amount of a pharmaceutical composition is interpreted that the subject was identified or diagnosed of infection with a specific pathogen prior to administration of the composition of claim 1 as a treatment in the form of LTB adjuvant comprising immunogenic polypeptide from the same pathogen.
Claim 7: The instant claim 7 has added limitation directed to assess the risk of allergenic reaction in a subject being administered the vaccine composition of claim 1 comprising a stabilizer (e.g. PEG).
Claim 21: The instant claim 21 is directed to added limitation, wherein said functional analog is characterized by having at least 80% sequence identity to said LTB (20% variation from LTB amino acid sequence). The claimed functional analogs of LTB with 20% amino acid differences introduces many variant species (deletion/insertion/substitution of amino acids).
Claim 23: The instant claim 23 comprise a limitation two viral peptides or any analogs there of having at least 80% sequence identity (20% variation from viral peptide amino acid sequence) to said at least two viral peptides. The claimed analogs of viral peptide with 20% amino acid differences introduces many variant species (deletion/insertion/substitution of amino acids).
Claim Rejections - 35 USC § 102
11. 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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 4, 12-13, 19, 21 and 42 are rejected under 35 U.S.C. 102 (a)(1) / (a)(2) or both as being anticipated by Sawada et al 2018 (US20180265553A1, published 09/20/2018).
Claims 1: Sawada et al 2018 is in the art and anticipated the instant claim 1 by disclosing a method of immunization comprising a vaccine antigen comprising antigenic peptide is a viral protein of PRRS virus and heat-labile toxin B subunit (LTB) and administration in a in non-human mammalian species that results in increased immunogenicity (increasing immunization efficiency). Sawada et al 2018 teaches immunogenicity of an antigenic peptide is increased by administering a fusion protein, which comprises an antigenic peptide and an adjuvant protein, wherein the adjuvant protein comprises an Escherichia coli derived heat-labile toxin B subunit (LTB). An antigenic peptide is a viral protein derived from a mammalian infectious virus (a pathogen) e.g. derived from a porcine reproductive and respiratory syndrome (PRRS) virus, parvovirus capsid protein VP2, feline immunodeficiency virus envelope protein gp120, porcine epidemic diarrhea virus spike protein, or rotavirus capsid protein VP7. A method for increasing immunity in a non-human mammal by administering the composition is claimed and disclosed (See, abstract, claims 1-21, para [0029], [0094]).
Claim 2: Sawada et al 2018 anticipated the added limitation of instant claim 2, wherein said administering comprises: orally administering, topically administering, or both (See, para [0003], [0107]).
Claims 12-13: Sawada et al 2018 teaches added limitations of instant claims 12 and 13, wherein said immunogenic polypeptide is derived from a viral peptide by disclosing a fusion protein, comprising: an antigenic peptide, which is other than a glycoprotein 5-derived peptide of porcine reproductive and respiratory syndrome (PRRS) virus. The fusion protein, wherein the antigenic peptide is a mammalian infectious virus-derived peptide. The fusion protein, wherein the mammalian infectious virus-derived peptide comprises a partial sequence of the parvovirus capsid protein VP2, feline immunodeficiency virus envelope protein gp120, porcine epidemic diarrhea virus spike protein, or rotavirus capsid protein VP7 (See, claims 1-2, para [0015]).
Claim 19: Sawada et al 2018 teaches added limitations of instant claim 19, wherein said increasing immunization efficiency comprises increasing any one of: the serum titer of IgG, mucosal IgA, in said subject (See, para [0003], abstract, para [0013], [0136]).
Claim 21: Sawada et al 2018 teaches added limitations of instant claim 21, wherein said functional analog is characterized by having at least 80% sequence identity to said LTB by disclosing LTB may have the same amino acid sequence as the amino acid sequence represented by SEQ ID NO: 12, except that one or several amino acids are substituted, deleted, inserted and/or added, as long as it has an adjuvant effect when it is administered as the fusion protein to an animal such as a pig (see, para [0041]-[043]). The amino acid sequence of LTB SEQ ID NO: 1 claimed in the instant application is aligned with LTB SEQ ID NO: 12 of Sawada et al 2018 indicating 81.5% query match and 99% local similarity. The prior art SEQ ID NO: 12 (Sawada et al 2018) is reported to function and have an adjuvant effect when it is administered as the fusion protein to an animal such as a pig.
Query Match 81.5%; Score 523; DB 1; Length 103;
Best Local Similarity 99.0%;
Matches 102; Conservative 1; Mismatches 0; Indels 0; Gaps 0;
PNG
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249
658
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Greyscale
Claims 4 and 42: Sawada et al 2018 teaches added limitations of instant claim 42, wherein said increasing is compared to a control subject by disclosing antibody titer measurement was carried out using an ELISA, absorbance two-fold or greater the average of absorbance of a diluted solution used as a negative control was determined to be a positive antibody titer, thus, also teaches added limitation of instant claim 4, wherein said subject is characterized by having above a predetermined threshold of immunoglobulins having specific binding affinity to said immunogenic polypeptide) and the maximum dilution rate for the positive antibody titer was determined to be the antibody titer of the serum (See, para [0108]).
Claim Rejections - 35 USC § 103
12. 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.
13. Claims 1, 2, 4, 12-13, 19, 21 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over by Sawada et al 2018 (US20180265553A1, published 09/20/2018). The teachings of Sawada et al 2018 are incorporated here in entirety to render obvious instant claims 1, 2, 4, 12-13, 19, 21 and 42.
14. Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Sawada et al 2018 (US20180265553A1, published 09/20/2018) as applied to claims 1, 2, 4, 12-13, 19, 21 and 42 above, and further in view of Vermeij 2010 (US7807184B2, 10/05/2010).
Claim 3: Sawada et al 2018 rendered instant claim 1 as recited supra however do not teaches additional limitation of instant claim 3, wherein said LTB comprises the amino acid sequence SEQ ID NO: 1.
Vermeij 2010 disclosed SEQ ID NO: 4 that has 98.3% identity with instant claimed SEQ ID NO: 1. The prior art amino acid sequence of LTB has deletion or difference of by 3 amino acids (MGN) at N-terminal of the sequence and that is less likely to adversely affect the adjuvant property of the LTB.
Query Match 98.3%; Score 631; Length 124;
Best Local Similarity 100.0%;
Matches 123; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 3 NKVKCYVLFTALLSSLYAHGAPQTITELCSEYRNTQIYTINDKILSYTESMAGKREMVII 62
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2 NKVKCYVLFTALLSSLYAHGAPQTITELCSEYRNTQIYTINDKILSYTESMAGKREMVII 61
Qy 63 TFKSGETFQVEVPGSQHIDSQKKAIERMKDTLRITYLTETKIDKLCVWNNKTPNSIAAIS 122
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 62 TFKSGETFQVEVPGSQHIDSQKKAIERMKDTLRITYLTETKIDKLCVWNNKTPNSIAAIS 121
Qy 123 MKN 125
|||
Db 122 MKN 124
15. Claims 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Sawada et al 2018 (US20180265553A1, published 09/20/2018) and Vermeij 2010 (US7807184B2, 10/05/2010) as applied to claims 1, 2-4, 12-13, 19, 21 and 42 above, and further in view of Blazevic et al 2021 (US20210000941A1, 01/07/2021) and Maeda et al 2017 (Frontiers in Immunology, September 2017, vol 8, article 1175).
Claims 5-6: Sawada et al 2018 rendered instant claim 1 as recited supra however do not teaches additional limitation of instant claims 5-6.
Blazevic et al 2021 is in the art and teaches an immunogenic composition comprising at least one Norovirus antigen and at least one adjuvant the B subunit of heat-labile E. coli exotoxin LT (LTB) and a method of preventing and/or treating norovirus infection and/or for reducing the severity of norovirus infection (See, abstract, claim 1, entire article).
Maeda et al 2017 teaches LTB adjuvant-mediated epitope specificity and enhanced neutralizing activity of antibodies targeting dengue virus envelope protein. Synthetic peptides have been largely exploited in therapeutic approaches against viral diseases, peptides may be amenable to generated protective antibody responses and therefore find both prophylactic and therapeutic applications (See, abstract, page 10 col 2 para 3, entire article).
It would have been obvious to one of the ordinary skills to combine the prior art teachings of Sawada et al 2018 on the method of LTB adjuvanted viral vaccine administration with additional teachings of Blazevic et al 2021 and Maeda et al 2017 on therapeutic treatment of LTB adjuvanted polypeptide vaccine against a pathogen infection (e.g. Norovirus) diagnosed in the subject. The motivation to pre-determine immunoglobulin (antibody) threshold level for specific binding to the same pathogen (e.g. Norovirus) would be a design choice to ensure the therapeutic vaccine administration is effective in induction of booster immune response in addition to mucosal immune response in the subject for recovery from the disease and protection in future. There would be a reasonable expectation of success based on the applied prior arts as recited supra and knowledge and skills of the ordinary in the art. 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 5-6. 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).
16. Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Sawada et al 2018 (US20180265553A1, published 09/20/2018) as applied to claims 1, 2, 4, 12-13, 19, 21 and 42 above, and further in view of Castells et al 2020 (N Engl J Med 2021; 384:643-649, published December 30, 2020).
Claim 7: Sawada et al 2018 (US20180265553A1) anticipated instant claim 1 as recited supra. However, do not disclose the added limitation of instant claim 7 related to steps preceding administration in subjects with risk of allergy to stabilizer in the claimed vaccine.
Castells et al 2020 is in the art and discloses guidelines / steps of a method recommended by US CDC to avid risk of allergenic reaction sue to the vaccine composition administration in a subject at risk or a method to prevent allergy to vaccine comprising PEG stabilizer in mRNA or other forms of viral vaccine comprising stabilizer. The step prior to administration comprises history taking of a subject regarding prior allergic reactions to vaccine, drug or food allergy and assessment of risk of a stabilizer in the vaccine composition to a subject (see, entire article, page no. 645 Figure 1 flow diagram and page 644 figure 1 legends).
It would have been obvious to one of the ordinary skills to combine the prior art teachings of Sawada et al 2018 on the method of LTB adjuvanted viral vaccine administration and Castells et al 2020 on allergy risk assessment with a motivation to ensure safety of a subject at risk of allergy with a reasonable expectation of success.
17. Claims 13 is rejected under 35 U.S.C. 103 as being unpatentable over Sawada et al 2018 (US20180265553A1, published 09/20/2018) as applied to claims 1, 2, 4, 12-13, 19, 21 and 42 above, and further in view of Yang et al 2020 (Nature 586, 572–577, 2020) and Krammer et al 2020 (Nature, 516, vol 586, 22 October 2020).
Claim 13: Sawada et al 2018 teaches claim 1 as recited supra however do not teach added limitation of claims 13 on SARS-CoV-2.
Yang et al 2020 teaches added limitation of instant claim 13, wherein said pathogen is a pathogenic virus, optionally wherein said pathogenic virus comprises a Coronavirus, and comprises any one of SARS-CoV2, SARS-CoV, or MERS-CoV, or any variant thereof by disclosing a vaccine targeting the RBD of the S protein of SARS-CoV-2 virus induces protective immunity. Here we show that a recombinant vaccine that comprises residues 319–545 of the RBD of the spike protein induces a potent functional antibody response in immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after the injection of a single vaccine dose. (See, abstract, Nature 586, 572–57, (2020).
Krammer et al 2020 teaches effects of mucosal and systemic immune responses to natural infection with respiratory viruses and to vaccination (See, page 518, Fig. 2).
It would have been obvious to one of ordinary skill in the art to combine the prior art teachings of Sawada et al 2018, Yang et al 2020 and Krammer et al 2020 to arrive at the invention of claim 13 with a reasonable expectation of success with a motivation to develop a vaccine composition to induce increased immunogenicity to develop an efficacious vaccine against a target viral pathogen SARS-CoV-2 virus for commercial success. 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 claim 13. 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).
18. Claims 16-19, 22-23, 26 are rejected under 35 U.S.C. 103 as being unpatentable over Sawada et al 2018 (US20180265553A1, published 09/20/2018) as applied to claims 1, 2, 4, 12-13, 19, 21 and 42 above, and further in view of Yang et al 2020 (Nature 586, 572–577, 2020), Krammer et al 2020 (Nature, 516, vol 586, 22 October 2020), Graham et al 2020 (NPJ vaccines, 5(1), 69), Gabitzsch et al 2020 (bioRxiv, 2020-12), Logunov et al 2020 (The Lancet, 396(10255), 887-897).
Claims 16-19, 22-23, 26: Sawada et al 2018 teaches claim 1 however does not teach added claim limitations of instant claims 16-19, 22-23, 26 on SARS CoV-2 and vaccination against COVID-19 and optional limitations on i/m or s/c or oral vaccination.
Yang et al 2020 teaches added limitation of instant claim 16, wherein said subject has vaccinated against COVID- 19 using a recombinant vaccine that comprises residues 319–545 of the RBD of the spike protein induces a potent functional antibody response in intra-muscularly immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after the injection of a single vaccine dose (See, abstract, Nature 586, 572–57, (2020).
Yang et al 2020 do not teach s/c or oral immunization and prime-boost vaccination.
Graham et al 2020 is in the art and teaches prime-boost vaccination for COVID-19 using SARS-CoV-2 Spike protein expressing replication deficient adenovirus in Rhesus macaques. Prime-boost immunization resulted in higher antibody titers including neutralizing antibodies (See, Fig 2) and SAS-CoV2 spike specific T-cell responses (See, Fig 1), (See, entire article).
Gabitzsch et al 2020 is in the art and teaches dual-antigen COVID-19 vaccine with SARS-CoV-2 spike (S-Fusion) protein and the viral nucleocapsid (N) protein expressing replication deficient hAd5 virus that provided complete protection of nasal and lung airways against SARS-CoV-2 challenge by antibody plus Th1 dominant N- and S-specific T-Cell responses to subcutaneous prime and thermally stable oral boost bivalent hAd5 vaccination in an NHP study (See, abstract, entire article).
Logunov et al 2020 is in the art and teaches safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations both carrying the gene for expression of SARS-CoV-2 spike glycoprotein in humans (phase 1/2 studies from Russia) (see, entire article).
The added limitations of instant claims 16-19, and 22-23 are taught by the prior art teachings Yang et al 2020, Graham et al 2020, Gabitzsch et al 2020, and Logunov et al 2020 (See, entire articles, abstract and figures).
Claim 26: The added limitations of claim 26 are taught by Sawada et al 2018 teaching LTB, and LTB with 81% amino acid identity, Vermeij 2010 taught LTB with 98% amino acid identity; Yang et al 2020, Graham et al 2020 and Gabitzsch et al 2020 teaches spike protein (a viral peptide) of SARS CoV-2 virus as an immunogen; and Gabitzsch et al 2020 teaches SARS CoV-2 virus nucleocapsid (N) protein as an immunogen, as recited supra.
It would have been obvious to one of ordinary skill in the art to combine the prior art teachings of Sawada et al 2018 as applied to claim 1 with additional teachings of Yang et al 2020, Graham et al 2020, Gabitzsch et al 2020, and Logunov et al 2020, Krammer et al 2020 to arrive at the invention of claims 16-19, 22-23, 26 with a reasonable expectation of success with a motivation to develop a vaccine composition comprising LTB as a mucosal adjuvant and SARS-CoV-2 spike protein and Nucleoprotein to induce increased immunogenicity by prime-boost strategy and using different routes i/m, s/c or oral to develop both humoral, cellular and mucosal immune response to optimize a method for efficacious vaccine against a target viral pathogen SARS-CoV-2 virus for commercial success. 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 16-19, 22-23, and 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).
19. Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over combined teachings of Sawada et al 2018 (US20180265553A1, published 09/20/2018), Yang et al 2020 (Nature 586, 572–577, 2020), Krammer et al 2020 (Nature, 516, vol 586, 22 October 2020), Graham et al 2020 (NPJ vaccines, 5(1), 69), Gabitzsch et al 2020 (bioRxiv, 2020-12), Logunov et al 2020 (The Lancet, 396(10255), 887-897) as applied to claims 26 above, and further in view of Wang 2020 (CN111983226A, 11/24/2020).
Claim 29: The combined teachings of prior arts as recited supra as applied to claim 26 does not teach the instant claim 29 limitation.
Wang 2020 (CN111983226A, 11/24/2020) is directed to the spike protein encoded by SARS-CoV-2 antibody detection using a spike protein and disclosed SEQ ID NO: 13 of SARS-CoV-2 spike protein that has 100% homology with instant SEQ ID NO: 15 SARS-CoV-2 spike protein (See, page number 66-67 sequence listing in PDF printout of English Translation of CN111983226A, claim 5, background).
Query Match 100.0%; Score 1099; Length 223;
Best Local Similarity 100.0%;
Matches 202; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 14 ITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLC 73
Qy 61 FTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNY 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 74 FTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNY 133
Qy 121 LYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVV 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 134 LYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVV 193
Qy 181 VLSFELLHAPATVCGPKKSTNL 202
||||||||||||||||||||||
Db 194 VLSFELLHAPATVCGPKKSTNL 215
It would have been obvious to one of ordinary skill in the art to combine the prior art teachings as applied to claim 26 with additional teachings of Wang 2020 on SARS-CoV-2 spike protein sequence and combine with LTB adjuvant to arrive at the invention of claim 29 with a reasonable expectation of success with a motivation to develop a vaccine composition comprising LTB adjuvant and SARS-CoV-2 spike protein to induce increased immunogenicity to develop an efficacious vaccine against a target viral pathogen SARS-CoV-2 virus for commercial success. 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 claim 29. 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. Relevant Prior Art:
Haan et al 2001. Nasal or intramuscular immunization of mice with influenza subunit antigen and the B subunit of Escherichia coli heat-labile toxin induces IgA- or IgG-mediated protective mucosal immunity. (Vaccine 19 (2001) 2898–2907).
Conclusion
21. No claim is allowed.
22. 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
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