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 .
Information Disclosure Statement
The information disclosure statements (IDS’s) submitted on 12/20/2023 and 3/25/2026 have been considered by the examiner.
Specification
The use of the term “MF59”, which is a trade name or a mark used in commerce, has been noted in paragraph [0070] of the instant published disclosure (USPgPub 2024/0238413). The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Note that “MF59” is merely an example and all improper uses of trademarks
found in the specification should be properly addressed.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claim 2 is objected to because of the following informalities: the SLA structure depicted is not clear. In contrast, the SLA structure claimed is clearly depicted in paragraph [0325] of the instant published disclosure, USPgPub 2024/0238413.
Claim 7 is objected to because POPC is presumably DOPC, as depicted in Figure 9 of the published disclosure.
Appropriate correction is required.
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 13 and 38 contain the trademark/trade name “pluronic” and “MF59”/ “AS01”, respectively. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a surfactant and adjuvants, respectively, accordingly, the identification/description is indefinite.
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 1-14, 16, 17, 38, 39, and 44 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.
Claims 1 and 14 encompass T-cell epitopes selected from:
SEQ ID NO: 73 that is 35 amino acids in length and has 8 variable residues;
SEQ ID NO: 80 that is 50 amino acids in length and has 13 variable residues;
SEQ ID NO: 94 that is 27 amino acids in length and has 8 variable residues;
SEQ ID NO: 134 that is 48 amino acids in length and has 19 variable residues;
T-cell epitopes that are 240 amino acids in length and only have at least 50% identity to SEQ ID NO: 157;
T-cell epitopes that are 65 amino acids in length and only have at least 50% identity to SEQ ID NO: 153;
T-cell epitopes that are 465 amino acids in length and only have at least 50% identity to SEQ ID NO: 160; and
T-cell epitopes that are 465 amino acids in length and only have at least 50% identity to SEQ ID NOs: 58-60.
There are no structural motifs or patterns provided in the instant disclosure that would identify the broad genus of sequences encompassed by the claims as T-cell epitopes. The sequences disclosed are not indicative of the entire genus that maintain the biological activity of a T-cell epitope. There is no specific written description that specifically identifies a range of peptide sequences or structures to permit one of skill in the art to recognize the sequences encompassed by the claims, as asserted. For these reasons, it is concluded that the specification does not reasonably convey possession of the full scope of T-cell epitope polypeptides claimed.
As taught in Greenspan et al (Nature Biotechnology. 17; 10:936-937 (1999), defining epitopes is not as easy as it seems (page 937). Epitopes have been defined in terms of the spacial organization of residues that make contact with a ligand and the structural characterization of the molecular interface for the binding of the molecules to define the epitope boundaries (page 937 middle of page). The epitope defined in this manner will likely include residues that contact the ligand but are energetically neutral or even destabilizing to binding. “In addition, a priori it will not include any residue that makes no contact with a ligand but whose substitution may profoundly affect ligand recognition through influence on the stability of the free form of the macromolecule, or participation in long-range allosteric effects”. “Even when the residues making contacts with ligands are known with certainty, say from the crystal structure of the complex, the question remains with regard to the energetic involvement of each residue (page 936 right column, first paragraph). Therefore, “amino acids should be recognized to have multiple ways of contributing to a noncovalent interaction” (page 937, middle of page). The specification teaches epitope mapping of the F5 and C1 using competition assay (page 69, lines 25-26 and figure 2), however, the results are not clear that the antibodies do in fact bind the same epitope. As evidenced by Greenspan et al a number of factors not primarily related to the contours of the contacts of the molecules contribute to the free energy change, sometimes profoundly.
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. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
Vas-Cath Inc. V. Mahurkar, 19USPQ2d 1111, clearly states "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.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116). Conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers V. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
There is no disclosure of sufficient characteristics of the nucleic acids claimed to allow persons of ordinary skill in the art to recognize that applicants were in possession of the exponential quantity of T-cell epitope polypeptides encompassed by claims. The specification does not provide adequate written description of the polypeptide sequences attributed T-cell epitopes. The specification does not clearly allow persons of ordinary skill in the art to recognize that the inventors invented what is claimed. The claims do not meet the written description provision of 35 U.S.C. 112, first paragraph.
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, 2, 14, 16, 17, 31, 38, 39, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Houghton et al. (WO 2019/173925), Wang et al. (Vaccines. 2020 Mar 13; 8 (1): 128, **Note: due to the file size, a copy of the document could not be imported as an attachment), Whitfield et al. (WO 2016/004512, **Note: due to the file size, a copy of the document could not be imported as an attachment), Akache et al. (Vaccines. 2019 Dec 3; 7 (4): 204), and Jia et al. (Pharmaceutics. 2021 Feb 2; 13 (2): 205).
Houghton et al. teach an immunogenic composition comprising one or more T-cell epitope polypeptides selected from:
a) a TP35-NS3 T-cell epitope polypeptide comprising an amino acid sequence having at least 80% amino acid sequence identity to: KSTKVPAAYAAQGYKVLVLNPSVAATLGFGAYMSK (SEQ IDNO:133), wherein the T cell
epitope polypeptide has a length of 35 amino acids, see claims 6-11. SEQ ID NO: 133 expressing the TP35-NS3 T-cell epitope shares at least 80% identity to SEQ ID NO: 73 of instant claim 1 and 100% identity to SEQ ID NO: 79 of instant claims 14 and 31;
b) a TP50C T-cell epitope polypeptide comprising an amino acid sequence having at least 80% amino acid sequence identity to:
GVYLLPRRGPRLGVRATRKTSERSQPRGRRQPIPKARRSEGRSWAQPGYP (SEQ ID
NO: 148), ), wherein the T cell epitope polypeptide has a length of 50 amino acids, see claims 6-11. SEQ ID NO: 148 expressing the TP50C T-cell epitope shares at least 80% identity to SEQ ID NO: 80 of instant claim 1 and 100% identity to SEQ ID NO: 87 of instant claims 14 and 31;
c) a TP27 T-cell epitope polypeptide comprising an amino acid sequence having at least 80% amino acid sequence identity to: LEQIKGGRHLIFCHSKKKCDELAAKLT (SEQ ID NO: 188), wherein the TP27 T-cell epitope polypeptide has a length of 27 amino acids. Claim 1 of Houghton et al. recites that the last residue, X8, is selected from T, R or S. “R” is instantly recited as the last residue of SEQ ID NO: 103 of instant claims 14 and 31. SEQ ID NO: 188 of Houghton et al. shares at least 80% identity to SEQ ID NO: 94 of instant claim 1; and
d) a TP48 T-cell epitope polypeptide comprising an amino acid sequence having at least 80% amino acid sequence identity to:
ILRRHVGPGEGAVQWMNRLIAFASRGNHVSPTHYVPESDAAARVTQIL (SEQ ID NO: 268), wherein the T-cell epitope polypeptide has a length of 48 amino acids, see claim 9 and 10, which shares 100% identity with instant SEQ ID NO: 136 of claims 14 and 31 and shares at least 80% identity with SEQ ID NO: 134 of claim 1.
Claim 14 of Houghton et al. lists an HCV E1/ E2 heterodimeric polypeptide, as required by instant claim 16. Paragraph [00440] states that the HCV E1/E2 components are derived from at least one HCV genotype, including genotype 1 and/or genotype 3, see paragraphs [00457, 00460, 00529 00530], as required by instant claim 17.
Claims 22 and 23 of Houghton et al. state that the adjuvant comprises MF59, alum, CpG oligo nucleotide, a cyclic dinucleotide, and MPL, as required by instant claim 38.
Claim 25 of Houghton et al. is drawn to a method of inducing an immune response against HCV by administering an effective amount of an immunogenic composition comprising one or more T-cell epitope polypeptides of claim 1, as recited in claim 39.
Claim 28 of Houghton requires a container comprising the immunogenic composition, as required by instant claim 44.
Claim 1(b) of Houghton recites an immune-stimulating amount of an adjuvant.
Paragraph [00339] of Houghton et al. depicts the structure of monophosphoryl lipid A: (MPL-A) (image presented in the document).
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Paragraph [00343] of Houghton et al. depicts a phosphorylated hexacycle disaccharide (PHAD) adjuvant:
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However, Houghton et al. do not teach a second-generation lipid adjuvant (SLA) that is a TLR4 agonist formulated in a stable emulsion (SE), required in claim 1(b)(i), where the SLA possesses the structure depicted in instant claim 2 (image captured from paragraph [0325] of the instant published disclosure, USPgPub 2024/0238413):
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Wang et al. depicts the following SLA structure that has a higher affinity for TLR4 in Table 3:
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In Table 1, Wang et al. teach the SLA is formulated as SLA-SE. “SE” is listed in Table 1 as a stable oil-in-water emulsion comprising glycerol, phosphatidylcholine, and squalene, used for immune cell recruitment. The SLA of Wang et al. is identical to the instant SLA of instant claim 2 except for the sulfate located at in place of the phosphate group.
Whitfield et al. teach various sulfated glycolipid derivatives, including MPL-A, see the third full paragraph on page 6, and “PHAD” on page 17.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have sulfated the SLA-SE of Wang et al., as taught by Whitfield et al., because Whitfield et al. teach sulfation of glycolipid derivatives produces stable structures and adjuvating immune responses against vaccine antigens, “Detailed Description” on page 13 to the last two paragraphs on page 15.
One of ordinary skill in the art prior to the instant effective filing date would have been motivated to have used the sulfated SLA-SE of Wang et al. and Whitfield et al. as the immune-stimulating amount of an adjuvant of Houghton et al. because the sulfated SLA-SE of Wang et al. and Whitfield et al. is stable and induces adjuvating effects against vaccine antigens. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have used the sulfated SLA-SE of Wang et al. and Whitfield et al. as the immune-stimulating amount of an adjuvant of Houghton et al. because Akache et al. teach sulfated SLA combined with HCV E1/E2 results in superior anti-E1E2 IgG titers, antigen-specific IL-2, IFN-γ, and TNF-α., see the abstract and Figures 1-5. One of ordinary skill in the art prior to the effective filing date would have had a reasonable expectation of success for combining the HCV E1/E2/ sulfated-SLA-SE composition of Wang et al., Whitfield et al., and Akache et al. with additional adjuvants taught by Houghton et al. because Jia et al. teach even further enhanced humoral and cellular immune responses when SLA is combined with various adjuvants, see Figures 2-6.
Claims 1 and 3-8 are rejected under 35 U.S.C. 103 as being unpatentable over Houghton et al., Wang et al., Whitfield et al., Akache et al., and Jia et al. as applied to claims 1, 2, 14, 16, 17, 31, 38, 39, and 44 above, and further in view of Fox et al. (USPgPub 2020/0276299).
See the teachings of Houghton et al., Wang et al., Whitfield et al., Akache et al., and Jia et al. above. None of the references teach the SLA is formulated in a liposomal composition comprising a saponin (LSQ), recited in instant claim 1(b)(ii), where the saponin is selected from QS21, QS17, QS7, synthetic QS21 (SQS21), Quil-A, QS21-Api, and QS21-Xyl, recited in instant claim 8. The saponin is complexed with cholesterol, required in instant claims 3-5. The liposome further comprises a phospholipid selected from DLPC, DMPC, DPPC, DSPC, DOPC, POPC, DLPG, DMPG, DPPG, DSPG, DOPG, DSTAP, DPTAP, DSPE, DPPE, DMPE, and DLPE, required in instant claims 6 and 7.
In example 1, Fox et al. describe an SLA-LSQ formulation, where the liposomal formulation comprises a saponin complexed with a sterol, see claim 33, and further comprises a phospholipid, see claim 34. The saponin is QS21 in claim 54. The sterol is cholesterol in claim 55 and the phospholipid is selected from DLPC, DMPC, DPPC, DSPC, DOPC, DOPC, DLPG, DMPG, DPPG, DSPG, DOPG, DSTAP, DPTAP, DSPE, DPPE, DMPE, and DLPE in claims 56 and 57.
It would have been rima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to have formulated the HCV E1/E2/ sulfated-SLA composition of Wang et al., Whitfield et al., Akache et al. and Jia et al. in the liposomal formulation of Fox et al. for vaccine compositions to “exhibit lot-to-lot consistency and that can be manufactured efficiently on an industrial scale without introducing unwanted or structurally undefined contaminants”, quote from paragraph [0010]. Also see paragraph [0020]. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have formulated the HCV E1/E2/ sulfated-SLA composition of Wang et al., Whitfield et al., Akache et al. and Jia et al. in the liposomal formulation of Fox et al. because Fox et al. teach the liposomal formulation is specific to chemically defined TLR4 agonist adjuvant components, such as SLA, see paragraphs [0016, 0053, and 0075].
Claims 9-13 are rejected under 35 U.S.C. 103 as being unpatentable over Houghton et al., Wang et al., Whitfield et al., Akache et al., Jia et al., and Fox et al. as applied to claims 1-8, 14, 16, 17, 31, 38, 39, and 44 above, and further in view of Fox et al. (USPgPub 2016/0324783, hereinafter, “Fox ‘783”).
See the teachings of Houghton et al., Wang et al., Whitfield et al., Akache et al., Jia et al., and Fox et al. above. While Fox et al. teach the liposomal formulation comprises DMPC, glycerol, and a surfactant in paragraphs [0097 and 0176], recited in instant claims 10, 11, and 12. The hydroxypropylcellulose surfactant of Fox et al. in paragraph [0176] is a functional equivalent to the “pluronic F68” surfactant, recited in instant claim 13, under the doctrine of equivalents discussed in MPEP § 2144.06 (II) and the lack of specific attributes to the recited surfactant discussed above.
None of the references teach the oil phase of the emulsion comprising from about 1% v/v of squalene and where the hydrophobic:lipophilic balance of the formulation is greater than about 9, as required in claim 9 or that the aqueous phase additionally comprises poloxamer 188, recited in claim 10.
Fox ‘783 teach squalene is a metabolizable oil present between 0.01% to 1% v/v in paragraphs [0283-0284] and paragraph [0321] teaches that poloxamer 188 and glycerol are mixed prior to dispersement into an oil phase comprising squalene. Paragraphs [0286-0288] describe the hydrophilic-lipophilic balance (HLB) of the emulsion is about 9.
It would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to have achieved the HLB taught by Fox ‘783 in the composition of Houghton et al., Wang et al., Whitfield et al., Akache et al., Jia et al., and Fox et al. to optimize the hydrophilic and lipophilic affinities within the emulsion. One of ordinary skill in the art prior to the instant effective filing date would have had a reasonable expectation of success to have achieved the HLB taught by Fox ‘783 in the composition of Houghton et al., Wang et al., Whitfield et al., Akache et al., Jia et al., and Fox et al. because all of Houghton et al., Wang et al., Whitfield et al., Akache et al., Jia et al., Fox et al. teach HCV E1/E2/ sulfated-SLA and Fox ‘783 teach vaccine comprising HCV components in paragraphs [0232, 0246] and SLA molecules in paragraphs [0323, 0326, 0344-0346] and Figures 15-19.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Khalaf et al. (Journal of Medicinal Chemistry. 2023 Oct 17; 66 (20):13900-139017) characterizes sulfated TLR4 agonists, see 8b and 17b of Figures 1, 2 and Tables 1, 2.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SHANON A FOLEY whose telephone number is (571)272-0898. The examiner can normally be reached M-F, generally 5:30 AM-5 PM, flexible.
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/Shanon A. Foley/Primary Examiner, Art Unit 1671
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