CTNF 18/271,366 CTNF 101424 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia 1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Election/Restrictions 2. Applicant’s election of SEQ ID NO: 3 in the reply filed on 19 February 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). It is noted that this election reads on PCSK9 only an 08-06 AIA Claim 127 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 19 February 2026 . Claim Status 3. In the amendment filed on 19 February 2026, claims 37, 83, and 95 were canceled; claims 17, 84, and 118 were amended; and claims 125-127 were added. Claim 127 is withdrawn. Claims 1-7, 15, 17, 84, 118, and 125-126 are under consideration . Priority 4. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. The Instant Application is a 371 National Stage Application that claims priority to U.S. Provisional Application 63/135,492, filed 08 January 2021, and U.S. Provisional Application 63/237,378, filed 26 August 2021. Priority is granted to U.S. Provisional Application 63/135,492 for claims 1-7, 15, 17, 84, 118, and 125-126. Thus, the U.S. effective filing date of the Instant Application is 08 January 2021. Information Disclosure Statement 5. The information disclosure statements (IDS) submitted on 07 July 2023, 10 January 2024, 18 July 2024, and 19 February 2026 were filed on or after the mailing date of the Instant Application on 07 July 2023. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. 06-49-06 AIA 6. 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. Drawings 06-22 AIA 7. The drawings are objected to because Figures 1-4, 8, 12, 15-16, 18, 23, 25, 32, and 33 are indiscernible . Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance. Nucleotide and/or Amino Acid Sequence Disclosures 8. REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES Items 1) and 2) provide general guidance related to requirements for sequence disclosures. 37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted: In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying: the name of the ASCII text file; the date of creation; and the size of the ASCII text file in bytes; In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying: the name of the ASCII text file; the date of creation; and the size of the ASCII text file in bytes; In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended). When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824. If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical. If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical. Specific deficiencies and the required response to this Office Action are as follows: 9. Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Required response – Applicant must provide: A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of: A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version); A copy of the amended specification without markings (clean version); and A statement that the substitute specification contains no new matter. See ¶ [0192], [0207], [0212], [0282], [0283], [0297], [0301] - Table 1, [0326], [0327] - Table 2, [0328], [0345] - Table 3, [0379] - Table 6, [0383] - Table 7, [0407], [0408], [0440], [0476], [0487], [0521], [0525], and [0533]. Note that these are merely examples and all improper uses of sequences without a proper SEQ ID NO in the specification should be identified by Applicant and properly addressed. 10. Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. Required response – Applicant must provide: Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers; AND/OR A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of: A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version); A copy of the amended specification without markings (clean version); and A statement that the substitute specification contains no new matter. See Figures 8, 25, and 27 and corresponding ¶ [0048]. Note that these are merely examples and all improper uses of sequences without a proper SEQ ID NO in the drawings should be identified by Applicant and properly addressed. 11. Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above. Required response – Applicant must provide: A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of: A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version); A copy of the amended specification without markings (clean version); and A statement that the substitute specification contains no new matter. 12. Specific deficiency – Nucleotide and/or amino acid sequences appearing in the claims are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Required response – The sequences in claims 15 and 125 require proper sequence identifiers. Appropriate action is required. Specification 07-29-04 13. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http://, www., or other browser-executable code. See MPEP § 608.01. See ¶ [0343], [0347], [0407], [0409], and references on pages 157-158, 161-168, 170-172. Note that these are merely examples and all improper uses hyperlinks in the specification should be identified by Applicant and properly addressed. 14. The use of the terms “MagicMedia” (¶ [0311]), “EXPANSORB” (¶ [0314]), “Xflash” (¶ [0315]), “Pierce BCA assay kit” (¶ [0317]), and “Living Image v3.0” (¶ [0318]), which are a trade name or a mark used in commerce, has been noted in this application. The terms 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 these are merely examples and all improper uses of trademarks in the specification should be identified by Applicant and properly addressed. Claim Objections 07-29-01 AIA 15. Claim s 1-2, 4-5, 7, and 15 are objected to because of the following informalities: Regarding claim 1, the “or” before “one or more” should be removed. The commas between the items in the list in part (b) should be changed to semicolons to distinguish the items from any modifying phrases. Regarding claim 2, the commas between the items in the list in part (b) should be changed to semicolons to distinguish the items from any modifying phrases. Regarding claims 4 and 5, there are two different abbreviations for PCSK9/PSCK9, so it appears one is a typo. Regarding claim 7, the paragraph reading “wherein the epitope(s) […] is present on the outer surface” is repeated twice. In addition, the claim should read “the peptide” and “the protein fragment” instead of “a” where recited. Regarding claim 7, it appears that a word is missing before “comprising” on page 5, last line. Regarding claim 7, “comprising, or consisting essentially of, or yet further comprising” is unclear and needs to be rewritten. Regarding claim 15, “NHS” should be spelt out the first instance it occurs in the claim set . Appropriate correction is required. 07-30-03-h AIA Claim Interpretation 16. According to ¶ [0063] of the Instant Specification, “a”, “an”, and “the” include plural references unless the context clearly dictates otherwise; ¶ [0067] states that all numbers are approximations with +/- 10% and are implied to be preceded by “about”; ¶ [0068] states that “about” includes approximations that are +/- 15%; ¶ [0072] states that equivalents of polynucleotides could be at least about 70% homology/identity; and ¶ [0074] states that “substantially” or “essentially” is 95% or greater. Claim Rejections - 35 USC § 112(b) 07-30-02 AIA 17. 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. 07-34-01 18. Claims 5, 15, 17, 118, and 125-126 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. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 5 recites the broad recitation “a fragment of PSCK9” and the claim also recites the full sequence, followed by the SEQ ID NO:, which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Claims 17, 118, and 125-126, which depend on claim 5, are similarly rejected. Regarding claim 5, “an amino acid sequence selected from” is unclear because it could be interpreted the whole sequence or fragment thereof. However, the preceding language of (a)-(c) indicates that it must be a fragment. 07-34-05 AIA Claim 15 recites the limitation " the linker " in line 1 . There is insufficient antecedent basis for this limitation in the claim. The term “substantially non-toxic” in claim 118 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim and the specification defines the term as 95% or greater (¶ [0074]). However, it is unclear how non-toxic could be described as 95% or greater. One of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The term “about 50% to about 99%” and “about 1% to about 50%” in claim 126 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim and the specification defines the term as “approximations” that are +/- 15% (¶ [0068]), which is also a relative term. One of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Claim Rejections – Improper Markush Grouping 08-40 19. Claims 1, 5, 17, 84, 118, and 125-126 are 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 claim 1 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 two groups of “preventing or treating an COVID infection” and treating or preventing a cardiovascular/cholesterol-related disease do not share a “single structural similarity”. Different diseases have different pathologies, pathogenesis, and treatments. Thus, the method alternatives listed have different uses, not a common use. The Markush grouping of claim 5 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: SEQ ID NOs: 1-3 do not share a common core structure or a consensus sequence. The alternatives do possess a common use of treating or preventing a cardiovascular/cholesterol-related disease. Claims 17, 84, 118, and 125-126, which depend on claim 5, are similarly rejected. 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. Claim Rejections - 35 USC § 112(a) – Written Description 07-30-01 AIA 20. 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. 07-31-01 21. Claims 5, 17, 118, and 125-126 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. The claims above are drawn to a VLP with an epitope peptide comprising “a fragment of PSCK9… or an equivalent”. The “fragment” reads on truncated peptides and the “equivalent” can read on truncated or mutated peptides. However, the specification only shows working examples with the full length of SEQ ID NO: 3 and does not contemplate any specific fragments or mutations. Thus, it is clear that the breadth of the recited peptides in the claims far overreaches Applicant’s contribution as disclosed in the specification and so this rejection is made. One of ordinary skill in this art cannot conclude that Applicant was in possession of just any mutation of PSCK9. An enormous breadth of potential PSCK9 peptides is thus not represented by Applicant at all. Even if the prior art is aware of additional PSCK9 polypeptides that are able to treat or prevent cholesterol-related diseases, the totality of known mutated or truncated PSCK9 polypeptides would not be representative of the entire genus for the reasons discussed below. “[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co. , 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention . Vas-Cath, Inc. v. Mahurkar , 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04. An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem , 323 F.3d at 964, 63 USPQ2d at 1613. MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g. , AbbVie Deutschland GMBH v. Janssen Biotech , 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the peptide inhibitors can have any sequence, one must describe a sufficient variety of species to reflect the variation within the genus. However, one of skill in this art cannot envision the structure of any other peptides with the required function other than the few species provided by Applicant and the prior art. Therefore, since only a few species are provided to represent the genus, the claims encompassing the same clearly fail the written description requirement. Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad , 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”). For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly , 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co. , 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010). Since there is only one PSCK9 polypeptide that has the treatment effect taught by Applicant, and mutated polypeptides would vary in structure, there is no correlation between structure and function between the members of the recited or any peptide genus. Additional mutated polypeptides could read on any and all combinations of amino acids. Thus, since there is no correlation between structure and peptide function across the entire genus, functional language should not be used to define a peptide genus. Rather, structure should be used, including the core peptide sequence required for said function. Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech , 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since the genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus. Overall, at the time the invention was made, the level of skill for preparing peptides and then selecting those peptides with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify peptides with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010) . Absent the conserved structure provided by a core inhibitory peptide sequence, the skilled artisan generally would not be able to visualize or otherwise predict, a priori , what any peptide with a particular set of functional properties would look like structurally. Since no mutations are taught in the specification of the recited genus above, the instant claims above clearly fail the written description requirement. A representative number of species has not been taught to describe such a massive genus. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe said genus. Owed to the variation among the peptides of the genus as broadly as currently claimed, it is very difficult to provide adequate representation of the functionally defined peptide genus. There is unlikely to be any structure (subsequence) shared by the entire genus. If there is a subsequence common to all or some of Applicant’s species, then the claims should recite that as part of the peptide genus to provide adequate representation of the actual disclosed/possessed group. Also, the disclosure of one group of highly related peptides does not guide one of skill to the next peptide of the genus with said function. Finding a another said peptide would require mutation and it is well-known in this art that mutation of peptides leads to specific function loss. The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess et al., J. Cell Bio., 1990, 111: 2129-2138). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar et al., Molecular and Cellular Biology, 1988, 8: 1247-1252). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). Ju (PNAS, 1991, 88: 2658-2662) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide. This substitution need not be at a position where said residue would contact the target protein. Baker (Immunity, 2000, 13: 475-484) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract). In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through mutagenesis. Importantly, binding can still occur after mutation, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (J. Biol. Chem., 1997, 272: 21201-21206) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first). Thus, while applicant has described a few species within the genus recited, and the art may provide more, each genus is very large and would encompass peptide structures that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the peptide structures encompassed by the claimed/recited genus only defined by function. Any future peptide may or may not be encompassed, and if it is, it would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the entire recited genus of peptides. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, the claims are rejected here. As discussed above, an applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure , or some combination of such characteristics. Enzo Biochem , 323 F.3d at 964, 63 USPQ2d at 1613. Therefore, it is recommended that the instant claims be amended to recite that the peptide genus must comprise the core peptide responsible for the recited function as this would define the structure/function relationship of the species Applicant possesses. Claim Rejections - 35 USC § 112(a) – Enablement 07-31-03 AIA 22. Claim s 5, 17, 118, and 125-126 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, because the specification, while being enabling for a polypeptide with the full-length SEQ ID NO: 3 , does not reasonably provide enablement for any and all possible mutations of the polypeptide . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims. In making a determination as to whether an application has met the requirements forenablement under 35 U.S.C. 112 ¶ 1, the courts have put forth a series of factors. See, In reWands , 8 USPQ2d 1400, at 1404 (CAFC 1988). The factors considered include: (1) the breadth of the claims, (2) the nature of the invention, (3) the relative skill of those in the art, (4) the presence or absence of working examples, (5) the amount of direction or guidance provided, (6) the state of the prior art, (7) the level of predictability in the art, and (8) the quantity of experimentation necessary. The claims are drawn to a method for treating/preventing diseases related to cholesterol levels by administering the epitope peptide PSCK9 with SEQ ID NO: 3, which can include the full-length peptide or truncations/mutations thereof. The nature of the invention is a method of treating/preventing diseases related to cholesterol levels. The level of skill of one of ordinary skill in this art is high. The specification provides working examples for the full-length SEQ ID NO: 3, but does not contemplate any mutations of this sequence. The art teaches that protein chemistry is probably one of the most unpredictable areas of biotechnology. For example, conservative replacement of a single “lysine” residue at position 118 of acidic fibroblast growth factor by “glutamic acid” led to the substantial loss of heparin binding, receptor binding and biological activity of the protein (Burgess et al., J. Cell Bio., 1990, 111: 2129-2138). In transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen (Lazar et al., Mol. Cell. Biol., 1988, 8: 1247-1252). As these references illustrate, it is unpredictable that a polypeptide variant of a known target protein binder will also bind said target. It is also unpredictable that they would bind said target in the same way, having the same effect on the target (i.e. inhibit or activate). Ju (PNAS, 1991, 88: 2658-2662) teaches that the interleukin 1 receptor (IL-1R) antagonist IL-1ra is a naturally occurring protein with no agonist activity in vitro or in vivo (Abstract). However, substitution of a single amino acid lysine145 to aspartic acid changes the property of this peptide to a partial agonist of IL-1R (Abstract). Thus, even a single substitution can change the biological property of a peptide. This substitution need not be at a position where said residue would contact the target protein. Baker (Immunity, 2000, 13: 475-484) teaches that Tax-peptide is an agonist of the of T cell activity (Abstract). However, mutation of proline at position 6 of this peptide to alanine creates a T cell antagonist (Abstract). Importantly, this residue does not contact the T cell receptor (Abstract). In another case, Huang (J. Biol. Chem., 1997, 272(43): 27155-27159) teaches that conjugation of peptides to other proteins can change their biological properties. They teach that multiple conjugation of the peptide TGFβ1 (residues 41-65) to carrier proteins enhances its antagonist activity but also confers partial agonist activity as well (Abstract). Thus, the chemical context of a biologically active peptide is also important. Truncation of proteins can also lead to adverse effects on protein structure and thus protein function. Martindale (Nat. Genet., 1998, 18: 150-154) teaches that truncation of huntingtin leads to aggregate development which compromises cell viability (Abstract). Nonaka (Hum. Mol. Genet., 2009, 18(18): 3353-3364) teaches that truncation of TDP-43 to its C-terminal fragments causes abnormally phosphorylated and ubiquitinated inclusions of the protein (Abstract). Taken together, not just any truncation of a protein will yield a soluble, functional, protein fragment. In summary, these examples teach that the biological function of peptide variants is unpredictable because even a single mutation can abolish activity or give a different function. For example, agonist and antagonist peptides can be interconverted through conjugation or mutagenesis. Importantly, binding can still occur after mutation or conjugation in the literature examples provided above, illustrating that a simple show of binding is not predictive of the nature of a peptide’s biological activity. This point is underlined by Montrose-Rafizadeh (J. Biol. Chem., 1997, 272: 21201-21206) who teaches that receptor binding does not predict agonist or antagonist activity (Pg. 21205, Column 2, Paragraph, first full, Sentence, first). With respect to the use of peptides in the treatment of a disease such as cancer, the state of the art at the time of filing was such that it was unpredictable whether or not a peptide would function therapeutically. Their functionality depends, in part, on whether or not they reach their intended target in a sufficient quantity as to cause a therapeutic effect. Mendoza (Arch. Immunol. Ther. Exp., 2005, 53: 47-60) teaches that peptides derived from larger molecules that are important modulators of apoptosis are frequently becoming leads for the development of anticancer therapeutics (Pg. 48, Column 2, Paragraph, first partial). However, they also state that natural peptides have low bioavailability and short half-life in the mammalian circulation system, while synthetic peptides have potential cytotoxicities (Pg. 57, Column 1, Paragraph, last full). Due to these characteristics, systematic testing in in vivo as well as in vitro settings must be done rigorously to verify peptide applications in the clinic (Pg. 57, Column 1, Paragraph, last full). Taken together, barring experimental evidence, no peptide can merely be assumed to function in the treatment of a disease, for example cancer, in vivo just because it functions as an inhibitor in vitro . Since the art teaches that it is unpredictable whether or not peptide variants of known inhibitors will function as such and it is also unpredictable that even a known inhibitory peptide that functions in vitro will function in vivo , it would also be unpredictable to that the PSCK9 polypeptide variants will retain their original function. Since the specification does nothing to ameliorate these concerns, one would be burdened with undue experimentation to use the products of instant claims as broadly as they are currently claimed . Claim Rejections - 35 USC § 102 07-07-aia AIA 07-07 23. 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 – 07-08-aia AIA (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention. 07-12-aia AIA (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. 07-15 AIA 24. Claim s 1-5, 7, 17, 84, and 125 are rejected under 35 U.S.C. 102( a)(1) and 35 U.S.C. 102(a)(2 ) as being anticipated by Remaley (US 20170189503 A1; 06 July 2017) . Regarding claims 1-4, Remaley teaches “Subsequently, a fully human PCSK9 monoclonal antibody was shown to increase the recycling of LDL receptors and reduce LDL cholesterol levels […] A neutralizing anti-PCSK9 monoclonal antibody that binds an epitope on PCSK9 adjacent to the region required for LDLR interaction was shown to inhibit PCSK9 binding to the LDLR and attenuate PCSK9-mediated reduction in LDLR protein levels, thereby increasing LDL uptake.” (¶ [0004]) and “The vaccine constructs of the invention are useful in the treatment of patients having, or at risk for, elevated LDL-cholesterol or a condition associated with elevated LDL-cholesterol…” (¶ [0008]). Remaley further demonstrates that their vaccine construct works: “As demonstrated in FIG. 4, vaccination resulted in an approximate 50% decrease in total cholesterol in the PCSK9-Qbeta immunized group.” (¶ [0177], Example 4; see also claims 7 and 9). Therefore, Remaley teaches a PCSK9 vaccine, in which administration of the vaccine was used to treat elevated LDLR levels by inhibiting PSCK9 binding to the receptor and reduce LDL-C levels, as claimed. Regarding claims 5, 7, 17, 84, and 125, Remaley further teaches “This example describes the conjugation of PCSK9 peptide NVPEEDGTRFHRQASKC (SEQ ID NO: 3) to Qbeta bacteriophage VLPs using the bifunctional cross-linker SMPH… As depicted in FIG. 1, this technique links the C-terminal cysteine on the PCSK9 peptide to exposed surface lysine residues on the coat protein of Qbeta.” (¶ [0174]). SEQ ID NO: 3 of Remaley (“Db”) is a 100% match to SEQ ID NO: 3 of the Instant Application (“Qy”): PNG media_image1.png 122 579 media_image1.png Greyscale Figure 1 shows the structure of the construct: PNG media_image2.png 412 745 media_image2.png Greyscale In summary, Remaley teaches SEQ ID NO: 3 of the Instant Application, which is linked to a coat protein of the Qbeta phage by a bifunctional cross-linker. As discussed supra , the method of administering the construct is demonstrated to be effective against inhibiting LDLR and lowering LDL-C, as claimed . Claim Rejections - 35 USC § 103 07-20-aia AIA 25. 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. 07-23-aia AIA The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness. 07-21-aia AIA 26. Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Remaley (US 20170189503 A1; 06 July 2017) . Regarding claim 6, Remaley teaches the limitations of claim 1. Remaley teaches “Subsequently, a fully human PCSK9 monoclonal antibody was shown to increase the recycling of LDL receptors and reduce LDL cholesterol levels […] A neutralizing anti-PCSK9 monoclonal antibody that binds an epitope on PCSK9 adjacent to the region required for LDLR interaction was shown to inhibit PCSK9 binding to the LDLR and attenuate PCSK9-mediated reduction in LDLR protein levels, thereby increasing LDL uptake.” (¶ [0004]) and “The vaccine constructs of the invention are useful in the treatment of patients having, or at risk for, elevated LDL-cholesterol or a condition associated with elevated LDL-cholesterol…” (¶ [0008]). Remaley further demonstrates that their vaccine construct works: “As demonstrated in FIG. 4, vaccination resulted in an approximate 50% decrease in total cholesterol in the PCSK9-Qbeta immunized group.” (¶ [0177], Example 4; see also claims 7 and 9). Therefore, Remaley teaches a PCSK9 vaccine, in which administration of the vaccine was used to treat elevated LDLR levels by inhibiting PSCK9 binding to the receptor and reduce LDL-C levels, as claimed. Remaley further teaches “This example describes the conjugation of PCSK9 peptide NVPEEDGTRFHRQASKC (SEQ ID NO: 3) to Qbeta bacteriophage VLPs using the bifunctional cross-linker SMPH… As depicted in FIG. 1, this technique links the C-terminal cysteine on the PCSK9 peptide to exposed surface lysine residues on the coat protein of Qbeta.” (¶ [0174]). SEQ ID NO: 3 of Remaley (“Db”) is a 100% match to SEQ ID NO: 3 of the Instant Application (“Qy”): PNG media_image1.png 122 579 media_image1.png Greyscale Figure 1 shows the structure of the construct: PNG media_image2.png 412 745 media_image2.png Greyscale In summary, Remaley teaches SEQ ID NO: 3 of the Instant Application, which is linked to a coat protein of the Qbeta phage by a bifunctional cross-linker. As discussed supra , the method of administering the construct is demonstrated to be effective against inhibiting LDLR and lowering LDL-C, as claimed. Remaley further teaches that “Fusion of an antigenic peptide at the C-terminus of a C-terminally truncated Qbeta A1 protein leads to further preferred embodiments of the invention.” (¶ [0083]). Therefore, it would have been obvious to one of ordinary skill before the time of filing to fuse the PCSK9 protein to the C-terminus of the coat protein of the Qbeta phage by a bifunctional cross-linker, as claimed. The combination of familiar elements is likely to be obvious when it does no more than yield predictable results. See KSR International Co. v. Teleflex Inc. , 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, A.). A rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc. , 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, A. and 2143.02) . 07-21-aia AIA 27. Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Remaley (s upra ) as applied to claim 6 above, further in view of ThermoScientific (SM(Peg)n Crosslinkers, 2017) . Regarding claim 15, Remaley teaches the limitations of claim 1, as discussed supra . All discussions thereon incorporated here. While Remaley does teach a bifunctional linker, they do not specifically teach SM(PEG)8. Remaley does teach “In a preferred embodiment, the antigenic PCSK9 peptide is bound to the VLP by way of chemical cross-linking, typically using a hetero-bifunctional cross-linker. […] Several hetero-bifunctional crosslinkers are known to the art. These include the preferred cross-linkers SMPH (Pierce)” (¶ [0090]). ThermoScientific teaches “The SM(PEG)n reagents are heterobifunctional crosslinkers with N-hydroxysuccinimide (NHS) ester and maleimide groups that allow covalent conjugation of amine- and sulfhydryl-containing molecules.” (Introduction, ¶ 1) as well as the reaction to form the crosslinkage: PNG media_image3.png 158 675 media_image3.png Greyscale ThermoScientific also teaches SMPH as a related product (Table 1, Other NHS/maleimide crosslinkers). They specifically show SM(PEG)8 as a SM(PEG)n reagent (Page 1, product number 22108). Both SMPH, SM(PEG)2, and SM(PEG)8 have the same reaction moieties. If one was to look at the reaction above, the amine of protein 1 would be the lysine on the surface of the Qbeta phage and the cysteine at the end of PSCK9 (SEQ ID NO: 3) would act as the thiol from protein 2. Therefore, it would have been obvious to one of ordinary skill before the filing date to substitute the SMPH heterobifunctional crosslinker of Remaley with a similar crosslinker with the same reactive groups. The simple substitution of one known element for another is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc. , 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, B.) . 07-22-aia AIA 28. Claim s 118 and 126 are rejected under 35 U.S.C. 103 as being unpatentable over Remaley ( Supra ) and ThermoScientific ( Supra ) as applied to claim 15 above, and further in view of Lee (ACS Nano., 26 September 2018, 11(9): 8777-8789) . Regarding claims 118 and 126, Remaley teaches the limitations of claim 125, as discussed supra . All discussions thereon incorporated here. Remaley does not teach encapsulating the VLPs with a degradable polymer matrix. However, Lee teaches that PLGA is biodegradable (Page 3, ¶ 1) and “PLGA materials loaded with 10 wt % Qβ were able to generate the same levels of anti-Qβ IgG relative to a 3 injection immunization schedule in vivo . […] These results demonstrate that VLPs can be successfully melt-encapsulated with PLGA and maintain structural integrity and biochemical signature to affect the immune system in vivo .” (Conclusions). Shown below is Figure 7, where the one time PGLA implant vs the 3 injections are shown: PNG media_image4.png 363 461 media_image4.png Greyscale Therefore, it would have been obvious to one of ordinary skill before the time of filing to take the VLP of Remaley and further encapsulate it in PLGA to reduce the number of doses while still obtaining the same immune response. A rationale to support a conclusion that a claim would have been obvious is that there is some teaching, suggestion, or motivation in the prior art or in the knowledge generally available to one of ordinary skill in the art to modify the reference or combine reference teachings, and the modification or combination would have a reasonable expectation of success. See KSR International Co. v. Teleflex Inc ., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, G. and 2143.02). Conclusion 29. No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA E LY whose telephone number is (571)272-5169. The examiner can normally be reached Monday - Thursday, 8:00 am - 5:00 pm EST. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Allen can be reached at (571) 270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /KRISTINA E. LY/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671 Application/Control Number: 18/271,366 Page 2 Art Unit: 1671 Application/Control Number: 18/271,366 Page 3 Art Unit: 1671 Application/Control Number: 18/271,366 Page 4 Art Unit: 1671 Application/Control Number: 18/271,366 Page 5 Art Unit: 1671 Application/Control Number: 18/271,366 Page 6 Art Unit: 1671 Application/Control Number: 18/271,366 Page 7 Art Unit: 1671 Application/Control Number: 18/271,366 Page 8 Art Unit: 1671 Application/Control Number: 18/271,366 Page 9 Art Unit: 1671 Application/Control Number: 18/271,366 Page 10 Art Unit: 1671 Application/Control Number: 18/271,366 Page 11 Art Unit: 1671 Application/Control Number: 18/271,366 Page 12 Art Unit: 1671 Application/Control Number: 18/271,366 Page 13 Art Unit: 1671 Application/Control Number: 18/271,366 Page 14 Art Unit: 1671 Application/Control Number: 18/271,366 Page 15 Art Unit: 1671 Application/Control Number: 18/271,366 Page 16 Art Unit: 1671 Application/Control Number: 18/271,366 Page 17 Art Unit: 1671 Application/Control Number: 18/271,366 Page 18 Art Unit: 1671 Application/Control Number: 18/271,366 Page 19 Art Unit: 1671 Application/Control Number: 18/271,366 Page 20 Art Unit: 1671 Application/Control Number: 18/271,366 Page 21 Art Unit: 1671 Application/Control Number: 18/271,366 Page 22 Art Unit: 1671 Application/Control Number: 18/271,366 Page 23 Art Unit: 1671 Application/Control Number: 18/271,366 Page 24 Art Unit: 1671 Application/Control Number: 18/271,366 Page 25 Art Unit: 1671 Application/Control Number: 18/271,366 Page 26 Art Unit: 1671 Application/Control Number: 18/271,366 Page 27 Art Unit: 1671 Application/Control Number: 18/271,366 Page 28 Art Unit: 1671 Application/Control Number: 18/271,366 Page 29 Art Unit: 1671
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