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 .
This office action fully replaces the non-final action filed on 04/21/2026 to correct a typographical error on page 29, paragraph 2, i.e., “Application No. 16646239” should be “Application No. 18267355”.
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Jan. 08, 2024. Claims 1-15 are pending and are currently examined.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-15 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.
These claims recite a term “pathogen-like antigen (PLA)” that renders the claims indefinite. It is unclear what the “pathogen-like antigen (PLA)” represents for and how to define the ‘pathogen-like”. There are also no disclosures of the PLA in the instant specification. Accordingly, there is no metes and bounds of the claims.
The base claim 1 and claims 2, 3, 11 and 13 recite the term “preferably” that render the claims indefinite. It is unclear whether the limitations following the phrase are parts of the claimed invention.
The base claim 1 recites a term “variant” that renders the claim indefinite. It is not clear how much “variant” claimed. Although the instant specification discloses that “the term "variant" as used herein refers to a protein or nucleic acid molecule whose sequence is similar but not identical to a reference sequence, wherein the activity of the variant protein (or the protein encoded by the variant nucleic acid molecule) is not significantly altered. These variations in sequence may be naturally occurring variations or may be engineered using genetic engineering techniques known to those skilled in the art” (See instant specification page 14, paragraph 3). However, it is still unclear how to determine if a sequence of the ‘variant” is similar or not and how to determine if an activity of the variant protein (or the protein encoded by the variant nucleic acid molecule) is significantly changed or not. Therefore, one of ordinary skill in the art will not know the metes and bounds of the claims.
Regarding claims 9 and 10, they recite the phrase “the sequence of the first linker peptide is SEQ ID NO: 5” and “the sequence of the second linker peptide is SEQ ID NO: 6”, respectively, which renders the claims indefinite. It is unclear if it means “consist of “or “comprise” the SEQ ID NO: 5 or SEQ ID NO: 6.
For purposes of compact prosecution and applying prior art, claims 9-10 were interpreted herein to consist of the SEQ ID NO: 5 or SEQ ID NO: 6.
The claim 14 recites a term “reducing” that renders the claim indefinite. It is not clear how to reduce a connection ratio between the second fusion protein and the virus-like particle to obtain a soluble pathogen-like antigen complex. The specification also does not provide descriptions on how the connection ratio is reduced.
The recitation “reducing” is a relative term having no definite meaning and it is unclear how “reducing” is determined or what degree of the ratio reducing is necessary. Applicant has not defined the degree of reduction (e.g., 2-fold, 5-fold, etc.). Thus, the specification does not define “reducing” such that one of ordinary skill in the art would know if ratio is reduced and if the reduction can help to obtain a soluble pathogen-like antigen complex. In addition, this rejection is also extended to the term “improving” recited by claim 14, where it is not clear how to determine the solubility of the PLA complex is improved.
Accordingly, one of ordinary skill in the art will not know the metes and bounds of the claim.
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 5-8 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.
These claims require the sequence of the capsid protein of the phage AP205, the sequence of the SpyTag, and the sequence of the SpyCatcher has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with SEQ ID NO: 1, SEQ ID NO: 3 and SEQ ID NO: 4, respectively.
The written description rejection is made because the claims mean that up to 10% sequences of the capsid protein, SpyTag or SpyCatcher can vary. 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).
The instant specification discloses the sequences of capsid protein of the phage AP205, the SpyTag and the the SpyCatcher can have different percentage identity to the claimed SEQ ID NO: 1, SEQ ID NO: 3 and SEQ ID NO: 4 respectively (See page 5). However, the specification does not indicate which portions of the claimed SEQ ID NO: 1, SEQ ID NO: 3 and SEQ ID NO: 4 are essential to retain the ability to be a functional capsid protein, SpyTag and SpyCatcher or which portions of SEQ ID NO: 1 and SEQ ID NOs: 3-4 can be modified or altered up to 10% and still retain the ability to be part of the claimed soluble pathogen-like antigen (PLA) complex.
These can be evidenced by Sun and Wong’s study. Sun et al. (Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):11269-74) teaches that mutation of Asp-117 to Ala in SpyTag has been shown to abolish covalent isopeptide bond formation (See page 11270, left column, paragraph 2). Wong et al. (Int J Biol Macromol. 2025 Jun;315(Pt 2):144641. doi: 10.1016/j.ijbiomac.2025.144641. Epub 2025 May 24) teaches that the introduction of Lys14 and Ser30 mutations demonstrated a >99 % reduction in RNA binding capacity in AP205 VLPs but also reduced particle stability and reassembly fidelity (See page 144641, left column, paragraph 2). Here these descriptions indicate a point mutation can cause the function changes.
The court clearly states in Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.).
As discussed above, the skilled artisan cannot envision the detailed protein sequences and structures of the encompassed PLA complex that has at least 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the SEQ ID NO: 1, 3 and 4 as claimed.
Therefore, the full breadth of the claims does not meet the written description provision of 35 U.S.C. 112, first paragraph.
Claim Rejections - 35 USC § 112 (Scope of Enablement)
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.
Claim 15 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling to show the PLA-SARS-COV 2 with AP205 can induce neutralizing antibodies produced in macaques immunized with PLA-SARS-CoV2 vaccine and reduce the viral load in a viral challenge experiment (See examples 8-10) for preventing a disease, does not reasonably provide enablement for a method for preventing a disease associated with influenza virus, African swine fever virus or autoantigen myelin oligodendrocyte glycoprotein MOG in any subject with any viral capsid.
Claim 15 is directed to a method for preventing and/or treating diseases associated with SARS-CoV2 virus, influenza virus, African swine fever virus or autoantigen myelin oligodendrocyte glycoprotein MOG in a subject in need thereof, comprising administering a preventive and/or therapeutically effective amount of the pathogen-like antigen vaccine composition of claim 12 to the subject. Here a general VLP with a general capsid viral protein, and a general subject is claimed for preventing a disease associated with SARS-CoV2 virus, influenza virus, African swine fever virus or autoantigen myelin oligodendrocyte glycoprotein MOG.
The instant specification teaches constructing a complex comprising a SpyCatcher (SC) and SpyTag (ST) with AP205 on VLP self-assembly (See Example 1, pages 21-22). They immunized macaques with the PLA-SARS-CoV2 and disclosed the induction of Anti-RBD lgG antibodies (See example 8, page 36) and neutralizing antibodies (See example 9, page 37) and further discloses that the reduction of viral load through a viral challenge experiment in macaques for preventing the infection (See example 10, page 37). However, the specification does not provide evidence to support a method to prevent the diseases associated with influenza virus, African swine fever virus or autoantigen myelin oligodendrocyte glycoprotein MOG in any subject with any viral capsid protein except AP205.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wriqht, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).1
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:1) the nature of the invention, 2) the state of the prior art, 3) the breadth of the claims, 4) the amount of guidance in the specification, 5) the presence or absence of working examples, 6) the relative skill of those in the art, 7) the predictability or unpredictability of the art, and 8) and the quantity of experimentation necessary. Id. While it is not essential that every factor be examined in detail, those factors deemed most relevant should be considered.
M.P.E.P. §2164.03 [R-2] states: [I]n applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soil, 97 F.2d 623,624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833,839, 166 USPQ 18, 24 (CCPA 1970). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488,496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Therefore, the specification does not provide sufficient guidance to allow one skilled in the art to practice the claimed invention on the full scope with a reasonable expectation of success and without undue experimentation. In the absence of such guidance and evidence of working examples, the specification fails to provide an enabling disclosure commensurate in scope with the claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-4, 12-13 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over He et al. (WO2022005503A1, published on Jan. 06, 2022, international Filling date: Oct. 01, 2020, hereinafter, “He”) as evidenced by Forrer et al. (J Mol Biol. 2004 Nov 12;344(1):179-93) and in view of Brune et al. (Sci Rep. 2016 Jan 19;6:19234).
The base claim 1 is directed to a soluble pathogen-like antigen (PLA) complex comprising:
(1) a virus-like particle (VLP), which is self-assembled by a first fusion protein comprising a viral capsid protein or a variant thereof at its N-terminus, SpyTag at its C-terminus, and a first linker peptide linking both;
(2) a second fusion protein, comprising an antigen or a variant thereof, SpyCatcher and a second linker peptide linking both, preferably the SpyCatcher is at the N-terminus of the second fusion protein;
wherein the virus-like particle also encapsulates nucleic acid inside it, and
wherein the virus-like particle and the second fusion protein are covalently connected through the SpyCatcher and the SpyTag, so that the antigen or a variant thereof is displayed on the surface of the virus- like particle.
He teaches soluble coronavirus S protein derived immunogens that are stabilized via specific modifications in the wildtype soluble S sequences. Also provided in their invention are nanoparticle vaccines that contain the redesigned soluble S immunogens displayed on self-assembling nanoparticles (See Abstract), and the nanoparticles presenting stabilized S trimers and RBDs can be used as VLP-type coronavirus vaccines (See [0028]), where the S immunogens is a protein or a portion that is form the highly pathogenic SRAS-COV-2 (See [0026]). He also teaches using the SpyTag/SpyCatcher protein superglue system to create RBD presenting nanoparticles or VLP (See [0026]) and further disclose that SpyCatcher-SpyTag refers to a protein ligation system that is based on the internal isopeptide bond of the CnaB2 domain of FbaB, a fibronectin-binding MSCRAMM and virulence factor ofclaim 1 (1) and (2), He teaches the two fusion constructs as the follows:
He teaches two constructs: one is the RBD sequence being fused to a SpyTag, and another is a nanoparticle subunit sequence being fused to a SpyCatcher. Alternatively, the RBD sequence can be fused to a SpyCatcher motif, and the nanoparticle subunit sequence can be fused to a SpyTag motif (See [0072]). For example, if the C-terminus of RBD is fused to the N-terminus of SpyTag with a SGS linker, the C-terminus of SpyCatcher can be fused to the N-terminus of a nanoparticle subunit with a SGS linker to create a pair. SpyTag and SpyCatcher can be switched in these two constructs to create a different pair. When the two constructs are introduced into and expressed in the host cells, a recombinant vaccine protein will be formed through the binding between the SpyTag and SpyCatcher motifs (See [00142]).
Here the RBG of He is comparable to the antigen as claimed and the nanoparticle subunit sequence of He can be a viral capsid protein because He teaches that the nanoparticle subunit is a self-assembling nanoparticle composed of ferritin, E2p or 13-01 or a trimeric sequence (See [0014]), where the trimeric sequence can be a viral capsid protein SHP (teach viral capsid protein as claimed) (See [0012]). For SHP, it can be evidenced by Forrer, Forrer teaches that SHP is the capsid-stabilizing protein of lambdoid phage 21 and the structure of SHP is solved by molecular replacement in two crystal forms (Table 1). Monoclinic form I crystals (space group C2) contain a trimer in the asymmetric unit (See Abstract; page 180, left column and Table 1). He also teaches that virus-like particle (VLP) refers to a non-replicating, viral shell, derived from any of several viruses. VLPs are generally composed of one or more viral proteins, such as, but not limited to, those proteins referred to as capsid, coat, shell, surface and/or envelope proteins, or particle-forming polypeptides derived from these proteins. VLPs can form spontaneously upon recombinant expression of the protein in an appropriate expression system (See [0050]) and their invention includes a virus like particle (VLP) such as bacteriophage Qβ VLP and nanoparticles (See [0073]).
Based on the description above, He teaches the base claim 1 (1) by disclosing a construct comprising RBD antigen fused with either SpyCatcher or SpyTag as claimed, and teaches the base claim 1 (2) by disclosing another construct comprising a nanoparticle subunit sequence including a viral capsid protein fused with either SpyCatcher or SpyTag as claimed. He also teaches that upon introducing the two constructs expressing the SpyTag fusion and the SpyCatcher fusion into host or producer cells, nanoparticle vaccines displaying an array of RBD proteins on the surface will be generated as a result of SpyTag/SpyCatcher mediated ligation of RBD proteins to the self-assembled nanoparticles (See 0072]) where a covalent isopeptide bond is formed between the SpyCatcher and SpyTag (See [0046]).
As for the “virus-like particle also encapsulates nucleic acid inside it” as claimed in the base claim 1, although He does not explicitly use the phrase of “the virus-like particle encapsulates nucleic acid inside it”, He teaches the vial Capsid protein SHP contains trimerization motif (See [0082)]. Even though He’s invention focuses to use the SHP to conjugate to the C-terminus of the SARS-CoV RBD for stabilization, it is obvious that one of skilled in the art can use the Capsid protein SHP as the self-assembled nanoparticle subunit and fuse it to either SpyCatcher or SpyTag to form a self-assembled VLP, where He already teaches examples to construct a self-assembling nanoparticle comprises 13-01, E2p or ferritin (See claim 16, page 70). Furthermore, it is a common knowledge that the VLP with the viral capsid protein including SHP can encapsulate genetic materials including DNA and RNA.
Nevertheless, Brune teaches that a platform for irreversibly decorating VLPs simply by mixing with protein antigen. SpyCatcher is a genetically-encoded protein designed to spontaneously form a covalent bond to its peptide-partner SpyTag. (See Abstract), where the SpyCatcher is genetically fused to the AP205 phage coat protein (AP205 CP3) and expressed in E. coli (See Figure 1, page 2 and below). Brune teaches the virus-like particles (VLPs) are self-assembling multi-protein and enable both surface display as well as payload encapsulation (See page 1, paragraph 1), and further discloses that the imaging of the gel showed co-migration of a distinct protein band and nucleic acid band, indicating encapsulation of nucleic acid by the hybrid SpyCatcher-VLPs (Fig. 3c). AP205 VLPs have been previously shown to encapsulate various RNAs
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from their expression host (See page 7, paragraph 2).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the AP205 CP3 into He’s VLP and arrive at an invention as claimed. One of skill in the art would have been motivated to do so because Brune teaches that their platform of the AP205 CP3 SpyCatcher-VLPs provides a simple, rapid and stable linking of antigens to virus-like particles for immunization (See page 7, paragraph 7). There would be a reasonable expectation of success to construct such soluble pathogen-like antigen (PLA) complex as claimed based on the teachings of He and Brune.
Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claims 2, He teaches that upon introducing the two constructs expressing the SpyTag fusion and the SpyCatcher fusion into host or producer cells, nanoparticle vaccines displaying an array of RBD proteins on the surface will be generated as a result of SpyTag/SpyCatcher mediated ligation of RBD proteins to the self-assembled nanoparticles (See [0072]), where the host cell can be any cell such as any of a number of bacterial strains (See [0096]). Based on the description above, the viral capsid protein SHP of lambdoid phage 21 can be fused to SpyTag/SpyCatcher to form a VLP and its host cell is E. coli. In addition, Brune also teaches a SpyTag/SpyCatcher VLP platform that is expressed in E. coli that comprising a self-assembling AP205 (See Figure 1 above), where the SHP and AP205 have the features of encapsulation.
Regarding claim 3, Although He does not explicitly point out a specific capsid protein from Escherichia coli phage Qβ, MS2 or AP205 as claimed, He teaches that any heterologous scaffold can be used to present the immunogen protein or polypeptide in the construction of the vaccines of the invention. This includes a virus like particle (VLP) such as bacteriophage Qβ VLP and nanoparticles (See [0073]) that indicates a capsid protein of the phage can be used. Nevertheless, Brune teaches genetically fusing SpyCatcher to the N-terminus of the viral coat protein (CP3) of the RNA bacteriophage AP205 and expressing it in E. coli. (See Fig.1 above; page 3). It would be obvious for one of ordinary skill in the art to use the AP205 CP3 coat protein to fuse to either SpyCatcher or SpyTag to generate the VLP as claimed, and the result would be predictable based on the teachings of He and Brune.
Regarding claim 4, Regarding claim 4, He teaches that the employed coronavirus immunogen contains or is derived from the RBD domain of coronavirus S proteins (See [0072] and the coronavirus can be SARS-CoV-2 (See [00151]).
Regarding claim 12, He teaches a pharmaceutical composition comprising the vaccine composition, and a pharmaceutically acceptable carrier (See claim 24, page 72), where the vaccine composition comprising the immunogen polypeptide of claim 1 that is displayed on the surface of a self-assembling nanoparticle (See claim 14, page 70).
Regarding claim 13, He does not explicitly teach VLP purification at a specific pH value, but Brune teaches that both SpyTag and SpyCatcher can be positioned at various locations in protein chains, are reactive under a wide range of conditions (pH, buffer, temperature), and do not possess cysteines (See page 3, paragraph 2), and teaches a method for VLPs purification where the Ni-NTA elution buffer (50 mM Tris•HCl, 300 mM NaCl, 1 M imidazole, pH 7.8) can be added to a final concentration of 75 mM imidazole for the VLP purification (See Page 8, paragraph 7). Here the Brune teaches a purification pH in the range as claimed. It would be obvious for one of ordinary skill in the art to introduce the pH of Brune into He’s invention to test an optimized ratio through route experimentation, and the result would be predictable based on the teachings of He and Brune.
Regarding claim 15, He teaches that their invention provides pharmaceutical compositions that contain the vaccine composition described herein, and a pharmaceutically acceptable carrier. In another aspect, the invention provides methods for preventing or treating a coronavirus infection in a subject. These methods involve administering to the subject a pharmaceutically effective amount of a vaccine composition or a pharmaceutical composition described herein (See [0017]).
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over He et al. (WO2022005503A1, published on Jan. 06, 2022, international Filling date: Oct. 01, 2020, hereinafter, “He”) as evidenced by Forrer et al. (J Mol Biol. 2004 Nov 12;344(1):179-93) in view of Brune et al. (Sci Rep. 2016 Jan 19;6:19234) as applied to claims 1-4, 12-13 and 15 above and further in view of Aebi et al. (EP3650044 A1, published May 13, 2020).
Claim 5 requires that the sequence of the capsid protein of the phage AP205 has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with SEQ ID NO: 1.
Based on the description above, He and Brune teaches the capsid protein can be from Escherichia coli phage Qβ, MS2 or AP205, however, it is silent on the capsid protein of the phage AP205 has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with SEQ ID NO: 1.
Aebi teaches that capsid, or virus-like particle (VLP), is formed upon recombinant expression of the coat protein of the AP205 bacteriophage (AP205cp). This AP205-VLP is a well-established scaffold for presentation of vaccine antigens. It consists of 180 copies of the AP205cp assembled into a spherical capsid. The N- and C-termini of the coat protein are exposed on the surface of the assembled particle. To generate a capsid that can be N-glycosylated, a short polypeptide tag including a glycosylation sequon (Asn-x-Ser/Thr) was fused genetically at the C-terminus of the AP205cp, the engineered capsid protein is referred to as "VLP158" (SEQ ID NO: 1, Figure 2a) (See [0064]), wherein the capsid polypeptide comprises at least one 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo)-glycosylation (See Summary). It was surprisingly found that the presence of a 3-deoxy-D-manno-oct-2-ulosonic acid-(Kdo)-glycosyl residue is particularly advantageous because, e.g., this residue serves as an efficient antigen triggering an immune response in an organism (See [0011]). Here the SEQ ID NO: 1 of Aebi is 96% identical to the claimed SEQ ID NO: 1 (See Table A below).
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It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the known SEQ ID NO: 1 of Aebi into He and Brune’s invention. One of skill in the art would be motivated to substitute one viral capsid protein for another (See MPEP 2144.06: Substituting equivalents known for the same purpose). There would be a reasonable expectation of success to develop such a soluble pathogen-like antigen complex as claimed.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over He et al. as evidenced by Forrer et al. (J Mol Biol. 2004 Nov 12;344(1):179-93) in view of Brune et al. as applied to claims 1-4, 12-13 and 15 above and further in view of Franklin et al. (WO2019228995A1, published on May 12, 2019).
Claim 6 requires that the sequence of the SpyTag has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with of SEQ ID NO: 3.
Based on the description above, He and Brune teach a virus-like particle (VLP), which is self-assembled by a first fusion protein comprising a viral capsid protein or a variant thereof at its N-terminus, SpyTag at its C-terminus. However, it is silent on the sequence of the SpyTag has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with of SEQ ID NO: 3.
Franklin teaches a SpyTag peptide that is attached as a recombinant fusion to the C-terminus of the Ix subunit of α-HL, and a SpyCatcher protein fragment is attached as a recombinant fusion to the N-terminus of the strand-extending enzyme, e.g., Pol6 DNA polymerase. The SpyTag peptide and the SpyCatcher protein fragment undergo a reaction between a lysine residue of the SpyCatcher protein and an aspartic acid residue of the SpyTag peptide that results in a covalent linkage conjugating the two the α-HL subunit to the enzyme (See [0067]), and the C-terminal SpyTag peptide fusion that comprises the amino acid sequence: GSSGGSSGGAHIVMVDA YKPTKKGHHHHHH (SEQ ID NO: 9) (See [0069]), where the SEQ ID NO: 9 has 92.4% identical to the claimed SEQ ID NO: 3 (See Table B below).
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It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the known SEQ ID NO: 9 of Franklin into He and Brune’s invention. One of skill in the art would be motivated to substitute one Spytag for another (See MPEP 2144.06: Substituting equivalents known for the same purpose). There would be a reasonable expectation of success to develop such a soluble pathogen-like antigen complex with a specific SpyTag as claimed.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over He et al. as evidenced by Forrer et al. (J Mol Biol. 2004 Nov 12;344(1):179-93) in view of Brune et al. as applied to claims 1-4, 12-13 and 15 above and further in view of Frederik et al. (WO2016112921A1, published July 21, 2016).
Claim 7 requires that the sequence of the SpyCatcher has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with SEQ ID NO: 4.
Based on the description above, He teaches a virus-like particle (VLP), where one of the constructs comprising an antigen and SpyCatcher. However, it is silent on the sequence of the SpyCatcher has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with SEQ ID NO: 4.
Frederik teaches establishing a system to produce antigens fused to a SpyCatcher and/or a SpyTag polypeptide, which ensures control of the orientation of the coupled antigen (See page 4, lines 1-10), and the SpyCatcher comprises the amino acid sequence of SEQ ID NO: 60 (See page 53, lines 22-23), where the SEQ ID NO: 60 is identical to the claimed SEQ ID NO: 4 (See Table C below). Frederik also teaches that VLP generated in their system can be used to induce antibodies with increased avidity compared to the corresponding soluble protein vaccines.
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It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the known SEQ ID NO: 60 of Frederik into He and Brune’s invention. One of skill in the art would be motivated to substitute one SpyCatcher for another (See MPEP 2144.06: Substituting equivalents known for the same purpose). There would be a reasonable expectation of success to develop such a soluble pathogen-like antigen complex with a specific SpyCatcher as claimed.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over He et al. as evidenced by Forrer et al. (J Mol Biol. 2004 Nov 12;344(1):179-93) in view of Brune et al. as applied to claims 1-4, 12-13 and 15 above and further in view of Franklin et al. and Frederik et al.
Claim 8 is directed to a soluble pathogen-like antigen complex according to claim 1, wherein (1) the SpyTag has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 3;
(2) the SpyCatcher has at least 90%, 91 %, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NO: 4; and
(3) an isopeptide bond is formed between Asp at position 7 of the SpyTag sequence SEQ ID NO: 3 and Lys at position 31 of the SpyCatcher sequence SEQ ID NO: 4.
He and Brune teach the fusion protein constructs formed by SpyTag and SpyCatcher. However, it is silent on the SEQ ID NOs: 3-4.
Based on the description above, Franklin teaches a SpyTag comprises the amino acid sequence SEQ ID NO: 9, where the SEQ ID NO: 9 has 92.4% identical to the claimed SEQ ID NO: 3 (teaches claim 8 (1)). Frederik teaches the SpyCatcher comprises the amino acid sequence of SEQ ID NO: 60, where the SEQ ID NO: 60 is identical to the claimed SEQ ID NO: 4 (teaches claim 8 (2)).
As for the isopeptide bond between SpyTag and SpyCatcher, He teaches that SpyCatcher-SpyTag utilizes a modified domain from a Streptococcus pyogenes surface protein (SpyCatcher), which recognizes a cognate 13-amino-acid peptide (SpyTag). upon recognition, the two form a covalent isopeptide bond between the side chains of a lysine in SpyCatcher and an aspartate in SpyTag (See [0046]). Based on the sequences of SEQ ID NOs: 9 and 60, SEQ ID NO: 9 has the ASP (D) at the position 7 (SEQ ID NO: 9: AHIVMVDAYKPTKTG, SpyTag) and SEQ ID NO: 60 has the Lys (K) at position 31 (SEQ ID NO: 60: DSATHIKFSKRDEDGKELAGATMELRDSSGKTISTWISDGQVKDFYLYPGKYTFVETAAPDGYEVATAITFTVNEQGQVTVNGKATKGDAHI, SpyCatcher), thus, it is obvious that a isopeptide bond can be formed based on the SEQ ID NOs; 9 and 60.
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the known SEQ ID NO: 9 of Franklin and SEQ ID NO: 60 of Frederik into He and Brune’s teaching to arrive at an invention as claimed. One of skill in the art would be motivated to substitute the one sequence for another (See MPEP 2144.06: Substituting equivalents known for the same purpose). There would be a reasonable expectation of success to develop such a soluble pathogen-like antigen complex as claimed because SEQ ID NO: 9 and SEQ ID NO: 60 can provide an isopeptide bond between Asp at position 7 of the SpyTag and Lys at position 31 of the SpyCatcher, respectively.
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over He et al. as evidenced by Forrer et al. (J Mol Biol. 2004 Nov 12;344(1):179-93) in view of Brune et al. as applied to claims 1-4, 12-13 and 15 above and further in view of Paavola et al. (US 2006/0084792 A1, published on Apr. 20, 2006).
Claim 10 is directed to a soluble pathogen-like antigen complex according to claim 1, wherein the sequence of the second linker peptide is SEQ ID NO: 6.
Based on the description above, He and Brune teach a virus-like particle (VLP) complex comprising an antigen, SpyCatcher and a second linker peptide linking both. However, it is silent on a specific second linker as claimed.
Paavola teaches a chaperonin EYFP fusion protein which is modified at position 267 comprises an additional linker comprising the sequence Gly-Ser-Gly-Gly-Ser-Gly (SEQ ID NO:83) which joins the yellow fluorescent protein to the chaperonin protein (FIG. 26B), where the linker sequence of SEQ ID NO: 83 is identical the SEQ ID NO: 6 as claimed (See Table D below).
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It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the known SEQ ID NO: 83 of Paavola into He and Brune’s invention. One of skill in the art would be motivated to substitute one linker for another (See MPEP 2144.06: Substituting equivalents known for the same purpose). There would be a reasonable expectation of success to develop such a soluble pathogen-like antigen complex as claimed.
Claims 11 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over He et al. as evidenced by Forrer et al. in view of Brune et al. as applied to claims 1-4, 12-13 and 15 above and further in view of Yenkoidiok-Douti et al. (Sci Rep. 2019 Nov 14;9(1):16833) as evidenced by Li et al. (J Mol Biol. 2014 Jan 23;426(2):309-17).
Claim 11 requires the second fusion protein is connected to the virus-like particle at a ratio of less than or equal to 1 :1 according to different antigens, wherein the ratio is calculated as the ratio of the SpyCatcher on the second fusion protein to the SpyTag on the virus-like particle.
Claims 14 is directed a method for improving the solubility of a pathogen-like antigen complex comprising: (1) preparing the virus-like particle and the second fusion protein of claim 1 and (2) when connecting the second fusion protein with the virus-like particle, reducing a connection ratio between the second fusion protein and the virus-like particle to obtain a soluble pathogen-like antigen complex.
Based on the description above, He and Brune teaches a SpyTag/SpyCatcher ligation system where the antigen RBD can be fused to a SpyTag or SpyCatcher motif, and the nanoparticle subunit sequence such as viral capsid protein can be fused to a SpyCatcher or SpyTag motif (See e.g., [0072]). However, it does not explicitly teach the ratio the SpyCatcher on the second fusion protein to the SpyTag on the virus-like particle.
Yenkoidiok-Douti teaches a VLP platform comprising the AP205-SpyCatcher: SpyTag system that can induce the highest quality functional antibodies against the TBV candidate Pfs25, a vaccine that targets the ookinete stage of Plasmodium (See page 2, paragraph 3). Yenkoidiok-Douti teaches that the optimal ratio to covalently link the antigen and saturate the particle surface was established by mixing different molar rations of SpyTag-P47 and AP205-SpyCatcher (between 3.2:1 to 0.9:1 molar ratio of SpyTag-P47: AP205-SpyCatcher). The linkage reaction was very effective, and at 1:1 molar ratio (teaches claim 11) more than 95% of the AP205-SpyCatcher monomers reacted with the SpyTag-P47 antigen (Fig. S4). This can also be evidenced by Li’s study. It teaches that SpyCatcher protein was incubated with the SpyTag peptide at a 1:1 molar ratio at room temperature for 2 hours and the complex was further purified by anion exchange and size-exclusion chromatography (See page 2, paragraph 4), where the protein purification step indicates a soluble complex formed.
As for the claim 14, He and Brune teaches preparing a complex comprising RBD antigen fused with either SpyCatcher or SpyTag and a viral capsid protein as the self-assembled nanoparticle subunit fused to either SpyCatcher or SpyTag to form a self-assembled VLP (teaches claim 14 (1)). For claim 14 (2), Yenkoidiok-Douti teaches the complex need to be mixed with adjusting to an optimal ratio such as 1:1 for a soluble complex for anion exchange and size-exclusion chromatography as taught by Li.
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the optimal ratio to covalently link the antigen and saturate the particle surface such as 1:1 ratio of Yenkoidiok-Douti into He and Brune’s teachings to arrive at an invention as claimed. One of skill in the art would be motivated to do so because the linkage reaction was very effective, and at 1:1 molar ratio more than 95% of the AP205-SpyCatcher monomers reacted with the SpyTag-P47 antigen. There would be a reasonable expectation of success to develop such a soluble pathogen-like antigen complex as claimed.
Allowable Subject Matter
The SEQ ID NO: 5 in claim 9 is free of prior art.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-7, 9-12 and 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6 and 9--14 of co-pending Application No. 18267355 (reference application).
Although the conflicting claims are not identical, they are not patentably distinct from each other. Both sets of claims are directed to a soluble pathogen-like antigen complex in the base claim 1 of the instant application and the base claim 1 of the reference application.
The reference claims anticipate the instant claims as the follows:
Reference claims 1 and 10 anticipates the instant base claim 1.
Reference claim 2 anticipates the instant claim 2.
Reference claim 3 anticipates the instant claim 3.
Reference claims 4 and 5 anticipates the instant claim 5.
Reference claim 6 anticipates the instant claim 4.
Reference claim 9 anticipates the instant claims 6-7.
Reference claim 11 anticipates the instant claims 9-10.
Reference claim 12 anticipates the instant claim 11.
Reference claim 13 anticipates the instant claim 12.
Reference claim 14 anticipates the instant claim 15.
At the same time, the differences between the instant application and the reference claims are that the reference claims have a limitation for a specific sequence for the RBD antigen sequence SEQ ID NO: 2, but the instant application does not limit the SEQ ID NO: 2, and there is no limitation for a pH condition in the reference claims. Also, there is no limitation of the isopeptide bond of the instant claim 8 in the reference application.
Accordingly, claims 1-7, 9-12 and 15 of the instant application are unpatentable over claims 1-6 and 9--14 of co-pending application No. 18267355.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/RUIXUE WANG/ Examiner, Art Unit 1672
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