DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of invention 1 in the reply filed on 4/10/2026 is acknowledged. The traversal is on the ground(s) that inventions 1 and 2 a product and a process of its use and therefore should be kept together. This is not found persuasive because as established by the teachings of Carter et al., the fusion protein of invention I does not provide a contribution over the prior art. Furthermore, based on the prior art rejections presented below, the claimed inventions lack unity.
The requirement is still deemed proper and is therefore made FINAL.
Claims 24-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 4/10/26.
Claims 1-23 and 30-36 are examined on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/9/23, 11/15/23, 3/4/24, 4/23/24 and 9/16/24 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Objections
Specification
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 for the reason(s) set forth below. The specification is objected to because description for figure 1B does not contain a specific SEQ ID NO: for each amino acid sequence presented.
Applicants must comply with sequence rules in order to be considered a complete response to this Office Action.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 17 and 30 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). Claims 17 and 30 are drawn to a cell that comprises a nucleic acid sequence, which therefore includes a human organism that comprises the nucleic acid sequence. If the claims are amended to recite “An isolated cell…”, this rejection would be overcome.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 14-17 and 30 are rejected under 35 U.S.C. 112, first paragraph, as containing subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Applicant broadly claims a host cell or expression vector or nucleic acid containing the nucleic acids of claims 14-17 and 30. The claims read on a cell within a transgenic animal or a transgene therein given that the term "isolated" is not denoted in describing the host cell, nucleic acid, or expression vector.
With respect to the unisolated host cells and transgenes as “nucleic acids” or “expression vectors “of the instant claims discussed above, the state of the art at the time of filing was such that one of skill could not predict the phenotype of transgenics. The art of transgenic animals has for many years stated that the unpredictability lies, in part, with the site or sites of transgene integration into the target genome and that "the position effect" as well as unidentified control elements are recognized to cause aberrant expression of a transgene (Wall et Al., Theriogenology, Vol. 45, Pg. 57-68, 1996).
The elements of the particular construct used to make transgenic animals are also held to be critical, and they must be designed case by case without general rules to obtain good expression of a transgene; e.g., specific promoters, presence or absence of introns, etc. (Houdebine et Al., Journal of Biotechnology, Vol. 34, Pg. 269- 287, 1994). Furthermore, transgenic animals are regarded to have within their cells, cellular mechanisms that prevent expression of the transgene, such as methylation or deletion from the genome (Kappell et Al., Current Opinions in Biotechnology, Vol. 3, Pg. 548-553, 1992). Houdebine (Comparative Immunology, Microbiology, and Infectious Diseases, Vol. 32, Pg. 107-121, 2009) teaches progress has been made in the field of transgenic animals for production of foreign proteins (Abstract); however, constructing an efficient expression vector to produce a therapeutic protein is not a standard operation (Pg. 116, Paragraph, second). Therefore, undue experimentation is required to make and use a transgene and transgenic animal to produce the antibody and antibody fragments of the instant claims.
Examples in the literature aptly demonstrate that even closely related species carrying the same transgene construct can exhibit widely varying phenotypes. Mullins (1993, Hypertension, Vol. 22, No. 4, pp. 630-633) states that not all animals express a transgene sufficiently to provide a model for a disease as the integration of a transgene into different species of animal has been reported to give divergent phenotypes. For example, several animal models of human diseases have relied on transgenic rats when the development of mouse models was not feasible. Mullins (1990, Nature, Vol. 344, 541-544) produced outbred Sprague-Dawley x WKY rats with hypertension caused by expression of a mouse Ren-2 renin transgene. Hammer (1990, Cell, Vol. 63, 1099- 1112) describes spontaneous inflammatory disease in inbred Fischer and Lewis rats expressing human class I major histocompatibility allele HLA-B27 and human 02- microglobulin transgenes. Both investigations were preceded by the failure to develop human disease-like symptoms in transgenic mice expressing the same transgenes that successfully caused the desired symptoms in transgenic rats (Mullins, 1989, EMBO J., Vol. 8, pages 183-191). Thus, the use of nonmurine species for transgenesis will continue to reflect the suitability of a particular species for the specific questions being addressed, bearing in mind that a given construct may react very differently from one species to another.
The examiner notes here, in addition to these issues, even assuming arguendo a person having ordinary skill in the art could make a host organism with functional transgene that encodes the instantly recited SEQ ID NO: 13, there is no predictability that the host will survive its expression. The transgene depends on the host for function and harm to the host, including death, renders the transgene nonfunctional and thus not enabled.
The art is well-aware of side effects caused by expressing proteins, such as therapeutic antibodies. In a transgenic cell or animal that expresses the same, the antibody will exert any possible side effect it can. It is not administered but chronically present and so such side effects are chronic and potentially more serious than any from an administered antibody. Hansel (Nature Reviews Drug Discovery, Vol. 9, Pg. 325-337, 2010) teaches in their table 1 on page 328 numerous exemplary side effects from licensed monoclonal antibodies to include: increased bleeding risk, infection, heart failure, cancer, thyroid disorder, autoimmune reactions, and cytokine release syndrome (CRS) to name only a few. One or more such effects, or similar, may occur with the therapeutic antibody instantly recited when administered and indeed be exacerbated by chronic exposure due to internal expression. The instantly encoded antibody binds a mammalian protein and so may very well target related or unrelated proteins in the transgenic host, leading to such side effects. For all these reasons, previously raised and new, transgenes are not enabled.
At the time of filing, the phenotype of a transgene and transgenic cell contained within any animal was unpredictable. The claims as written, encompassing a transgene and cell in a transgenic animal, is not adequately described in the specification as to prevent excessive experimentation by the public to generate and use the invention. Applicants can obviate the instant rejection by amending the claim to recite the term "isolated" before the recitation, "host cell" and by amending the vector and polynucleotide claims to specify they are not in a transgenic animal. Applicant may consider using purified in such claims if description is appropriate for such a term and it is not redefined away from standard meaning. Method claims using these products should also carry the appropriate adjectives above.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use transgenic animals possessing the claimed host cells, nucleic acid, or expression vector, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed host cell, nucleic acid, or expression vector, commensurate in scope with the claimed invention. The same can be said for the transgenes and transgenic animals encompassed by the instant claims. Thus, the claims are rejected here.
Claim 23 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of a devise for administering and an excipient is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the claimed device for administering and the excipient do not share a single or structural similarity and do not share a common use.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-23 and 30-36 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites, “the Spike protein is a sequence with at least 90% sequence identity to SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 14 or SEQ ID NO: 15”. However, these options for the Spike protein are not presented in a proper Markush grouping format and therefore it is unclear if additional sequences not presently claimed can be read into the claim. Therefore, it is suggested that claim 1 be amended to recite, “the Spike protein is a sequence with at least 90% sequence identity to a sequence selected from the group consisting of: SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 14 and SEQ ID NO: 15” [see MPEP 2173.05(h) for further guidance]
Claims 2-23 and 30-36 are also rejected because they depend from claim 1, but do not remedy this deficiency.
Claim 10 recites, “…wherein the amino acid sequence of the fusion protein is a sequence with at least 90% sequence identity to SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:33, or SEQ ID NO:34.”. However, these options for the fusion protein are not presented in a proper Markush grouping format and therefore it is unclear if additional sequences not presently claimed can be read into the claim. Therefore, it is suggested that claim 1 be amended to recite, “wherein the amino acid sequence of the fusion protein is a sequence with at least 90% sequence identity to a sequence selected from the group consisting of: SEQ ID NO: 12, …and SEQ ID NO: 34.” [see MPEP 2173.05(h) for further guidance]
Claim 19 recites, “An immunogenic composition comprising two or more different fusion proteins of claim 1.” However, claim 1 only recites that one fusion protein is present and claim 19 does not clarify what is different between the “two or more different fusion proteins”.
Claim 30 recites the limitation "the vector" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 31 recites the limitation "the nanoparticle" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 33 recites the limitation "the vector" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 34 recites the limitation "two or more different nanoparticles" in line 2. There is insufficient antecedent basis for this limitation in the claim.
Claim 35 recites, “An immunogenic composition comprising two or more differ nucleic acids of claim 14.” However, claim 14 only recites that one nucleic acid is present and claim 35 does not clarify what is different between the “two or more different nucleic acid”.
Claim 36 recites, “An immunogenic composition comprising two or more differ vectors of claim 15.” However, claim 15 only recites that one vector is present and claim 36 does not clarify what is different between the “two or more different vectors”.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(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.
Claim(s) 1, 2, 5-7, 9-18, 20-23, 30 and 32 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Rauch et al. (US PGPub 20240277830).
The claimed invention is drawn to a fusion protein of an artificially modified amino acid sequence of a Spike protein of a coronavirus with at least 90% sequence identity to SEQ ID NO: 3 and a ferritin subunit polypeptide. The coronavirus is SARS-CoV-2 and the ferritin subunit polypeptide is a H. pylori ferritin subunit polypeptide and the ferritin subunit polypeptide is at least 90% identical to SEQ ID NO: 2.
The fusion protein is at least 90% identical to SEQ ID NO: 12.
The Spike protein comprises a mutation that stabilize the Spike protein in a pre-fusion conformation.
The Spike protein and the ferritin subunit polypeptide are joined by a linker amino acid sequence.
The claimed invention also requires a nanoparticle comprising an oligomer of the fusion protein with surface exposed trimers of an ectodomain of the Spike protein of the coronavirus. The nanoparticle presents 8 trimeric ectodomains of the Spike protein on the surface.
The claimed invention also requires a nucleic acid encoding the fusion protein and the nucleic acid is DNA or RNA, a vector comprising the nucleic acid, a cell comprising the nucleic acid. The nucleic acid is also part of an immunogenic composition.
The claimed invention also requires an immunogenic composition comprising the fusion protein, one or more adjuvants, such as alum or the immunogenic composition is lyophilized.
The claimed invention also requires a kit comprising the immunogenic composition of claim 18 and a device for delivery of the composition.
Rauch et al. teach a fusion protein comprising the spike protein of SARS-CoV-2 fused to a ferritin subunit polypeptide. More specifically, SEQ ID NO: 4696 of Rauch et al. is 99.1 % identical to SEQ ID NO: 12 of the instant invention. This sequence possesses a linker between the ferritin and the spike protein. SEQ ID NO: 4696 comprises SEQ ID NO: 358 and SEQ ID NO: 113, which are 99.5% and 100% identical to SEQ ID NO:s 3 and 2 of the instant invention. This ferritin is from a H. pylori bacterium. Rauch et al. also teach modifications of amino acids of the spike protein in order to maintain a prefusion conformation. [see paragraphs 260-261] It is also taught that the nanoparticle formed by the ferritin possesses 24 surfaces, which would present 8 trimers of the ectodomain of the spike protein. Rauch et al. also teach nucleic acid sequences of these proteins [see paragraph 439], vectors comprising the nucleic acid sequences [see paragraphs 536-538], cells that comprises the nucleic acids or vectors [see paragraph 539]. It is also taught that immunogenic compositions can comprise the fusion protein [see paragraphs 39 and 49], that adjuvants, such as alum can also be included [see paragraphs 912-915 and 1726] and that the it can be lyophilized [see paragraph 910-911 and 1097] and that the immunogenic composition can be administered intramuscularly [see paragraphs 242 and 469], which would review a device for administering the composition to a subject.
Therefore, Rauch et al. anticipate the instant invention.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claim(s) 1, 2, 4, 5, 6, 7, 9-12, 14-18, 20-23 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Graham et al. (US PGPub 2020/0061185) and Duprex (US Patent 11,103,576).
The claimed invention is drawn to a fusion protein of an artificially modified amino acid sequence of a Spike protein of a coronavirus with at least 90% sequence identity to SEQ ID NO: 3 and a ferritin subunit polypeptide. The coronavirus is SARS-CoV-2 and the ferritin subunit polypeptide is a H. pylori ferritin subunit polypeptide and the ferritin subunit polypeptide is at least 90% identical to SEQ ID NO: 2.
The fusion protein is at least 90% identical to SEQ ID NO: 12.
The Spike protein comprises a mutation eliminating a furin recognition site and the Spike protein has one or more mutations that stabilize the Spike protein in a pre-fusion conformation.
The Spike protein and the ferritin subunit polypeptide are joined by a linker amino acid sequence.
The claimed invention also requires a nanoparticle comprising an oligomer of the fusion protein with surface exposed trimers of an ectodomain of the Spike protein of the coronavirus.
The claimed invention also requires a nucleic acid encoding the fusion protein and the nucleic acid is DNA or RNA, a vector comprising the nucleic acid, a cell comprising the nucleic acid. The nucleic acid is also part of an immunogenic composition.
The claimed invention also requires an immunogenic composition comprising the fusion protein, one or more adjuvants, such as alum or the immunogenic composition is lyophilized.
The claimed invention also requires a kit comprising the immunogenic composition of claim 18 and an excipient.
The Prior Art
Graham et al. teach the generation of recombinant SARS or MERS Spike proteins that possess mutations which stabilize trimers in the prefusion conformation and that also possess a deletion of the furin cleavage site, which is located at the S1/S2 cleavage site. [see paragraphs 5 and 165 and Figure 1C] The Spike proteins can be the ectodomain trimer and it can be included on a ferritin nanoparticle, which would result in the formation of an oligomer of the fusion proteins taught by Graham et al. [see paragraphs 10 and 238 to 240] An example of the ferritin protein is one from H. pylori. [see paragraph 241] Graham et al. also teach immunogenic compositions comprising nucleic acid sequences that encode the Spike and ferritin fusion protein and vectors that comprise these sequences and the vectors can be propagated in cells with the DNA of the vector being expressed. [see paragraphs 10 and 12 and 68] The immunogenic compositions also comprise an adjuvant, including alum and the immunogenic composition can be lyophilized. [see paragraphs 11, 34 and 80] Graham et al. further teach that antigens can be linked to carriers and their S ectodomain trimers can be linked via amino acid sequences, such as glycine-serine linkers. [see paragraphs 75 and 238 to 240] One example of a ferritin subunit is SEQ ID NO: 23, which is 93% identical to SEQ ID NO: 2 of the instant invention.
However, Graham et al. do not teach a Spike protein with at least 90% sequence identity to SEQ ID NO: 3; or that their fusion protein is at least 90% identical to SEQ ID NO: 12.
Duprex teach a spike protein from SARS-CoV-2 SEQ ID NO: 13, which is 99.6% identical to SEQ ID NO: 3. Duprex also teach that the SARS-CoV-2 spike protein possess an amino acid modification that maintains the prefusion confirmation. [see column 4, lines 50-67]
It would have been obvious to one of ordinary skill in the art to modify the compositions taught by Graham et al. in order to utilize a spike protein from SARS-CoV-2, which would include an amino acid sequence that is at least 90% identical to SEQ ID NO: 3. One would have been motivated to do so, given the suggestion by Graham et al. that the modified SARS or MERS spike proteins can be linked to carriers and that ferritin subunits can also function as a carrier and ferritin can form nanoparticles. There would have been a reasonable expectation of success, given the knowledge that the spike protein of SARS-CoV-2 was previously taught in a modified form to maintain a prefusion confirmation and that this protein also shares 99.6% amino acid sequence identity to SEQ ID NO: 3 of the instant invention, as taught by Duprex. In addition and based on the sequence identity of the ferritin of Graham et al. and their teachings of using glycine-serine linkers for their spike protein and the fusion of spike protein to carriers, which include ferritin and the teachings of Duprex of another prefusion confirmation modified coronavirus spike protein from SARS-CoV-2 which shares 99.6% identity, one of orindary skill in the art would have a reasonable expectation of success at generating a fusion protein with at least 90% identity to SEQ ID NO: 12. Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Graham et al. and Duprex as applied to claims 1, 2, 4, 5, 6, 7, 9-12, 14-18, 20-23 and 32 above, and further in view of Rottier et al. (US PGPub 2005/0186575).
The claimed invention further requires that the artificially modified amino acid sequence of the Spike protein comprises a C-terminal deletion of at least one amino acid sequence of heptad repeat 2 (HR2).
The teachings of Graham et al. and Duprex are summarized above. While Graham et al. do teach modifications to the S1/S2 furin site and prefusion stability associated mutations, they do not teach that at least one C-terminal amino acid of the HR2 domain be deleted.
Rottier et al. teach recombinant coronavirus (SARS) spike proteins with modified sequences. For example, the heptad repeats (HR1 and HR2) of the Spike proteins can be altered by deletion. [see paragraph 21] These deletions would include the deletion of at least one amino acid at the C-terminus of the HR2.
It would have been obvious to one of ordinary skill in the art to modify the compositions taught by Graham et al. and Duprex in order to also utilize a spike protein from a coronavirus with at least one C-terminal amino acid deleted from the HR2 domain. One would have been motivated to do so, given the suggestion by Graham et al. and Duprex that the modified SARS or MERS or SARS-CoV-2 spike proteins can be possess mutations, such as ones which maintain prefusion confirmation. There would have been a reasonable expectation of success, given the knowledge that the SARS spike protein can also be altered by deletions that include the HR1 and HR2, as taught by Rottier et al. Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claim(s) 8 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Graham et al. and Duprex as applied to claims 1, 2, 4, 5, 6, 7, 9-12, 14-18, 20-23 and 32 above, and further in view of Nabel et al. (US PGPub 20140302079) and Yang et al. (International Journal of Biological Macromolecules, 2017, Vol. 105, pages 252-261).
The claimed invention also requires that the nanoparticle comprises 8 of the surface-exposed trimers of the ectodomain of the Spike protein of the coronavirus and the ferritin also possesses artificial glycosylation sites.
The teachings of Graham et al. and Duprex are summarized above, however, they do not specifically teach that nanoparticles comprising the fusion protein would present 8 spike protein trimers on the surface or that the ferritin having artificial glycosylation sites.
Nabel et al. teach SEQ ID NO: 5, which is a ferritin subunit and it is identical to SEQ ID NO: 2 of the instant invention. One specific example involves a ferritin nanoparticle that includes 8 3-fold axes on its surface and presents influenza hemagglutinin proteins on its surface. This structure of the ferritin nanoparticle would facilitate the presentation of 8 proteins on the surface. [claims 6, 7, and figure 25-4, which presents a fusion protein with an SGG linker and ferritin protein.]
Yang et al. teach the use of ferritin particles as carrier molecules for therapeutics. [see abstract] Yang et al. also teach glycosylation of ferritin by chitosan, which involves artificially glycosylating the ferritin since this occurs after expression by a cell, can improve the bioavailability and absorption of bioactive compounds by the feat of the unprecedented
binding of ferritin and chitosan molecules. [see left column, pages 253]
It would have been obvious to one of ordinary skill in the art to modify the compositions taught by Graham et al. and Duprex in order to also utilize a ferritin subunit polypeptide which forms a nanoparticle that can present 8 trimers of the ectodomain of the spike protein on its surface and to add glycosylations to the ferritin subunit. One would have been motivated to do so, given the suggestion by Graham et al. that ferritin subunit polypeptides of H. pylori, which can form nanoparticles and also possess greater than 90% identity to SEQ ID NO: 2 of the instant invention can be used present other proteins on its surface. There would have been a reasonable expectation of success, given the knowledge that the ferritin subunit polypeptides with 100% identity with SEQ ID NO: 2 were previously known and that these polypeptides were capable of presenting influenza HA proteins on its surface and that the ferritin nanoparticles possess 8 faces, as taught by Rottier et al., and also given the knowledge that ferritin proteins, which can delivery therapeutic compounds, can possess beneficial in vivo properties from additional glycosylation, as taught by Yang et al. Thus the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Conclusion
No claims are allowed.
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/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671
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