DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I drawn to a composition comprising antimicrobial polypeptide; and Applicants’ election without traverse of Species (A) the polypeptide of SEQ ID NO: 6 (claim 5) and (B) microbial infections for treatment (as in Pre-Grant Pub US 20240092846 paragraphs [0018] to [0022] and [0140] to [0142]) in the reply filed on March 13, 2026 is acknowledged.
The species of group I, therefore claims 1-14 which read on the elected species has been considered. Claims 1-14 are hereby examined on the merits.
Claims 15-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on March 13, 2026.
Priority
The present application claims priority under 35 U.S.C. § 119(e) of U.S. provisional application U.S. Serial No.: 63/353976, filed June 21, 2022. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C 119 (e) or under 35 U.S.C. 120, 121, or 365 (c) is acknowledged.
Status of Claims
Claims 1-20 are pending.
The amendment filed on March 13, 2026, amended claims 3 and 5. Claims 15-20 are withdrawn for further consideration.
Claims 1-14 are currently examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on February 14, 2024 and March 13, 2026 were reviewed by the Examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings are objected to because Figure 6 uses a colored overlaid 2D1H-1H TOCSY spectra of MCoTI-I and MCo-PG2 but the image is in black and white with no sample labels/legends, making it difficult to interpret. 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
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;
ii) the date of creation; and
iii) 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:
Specific deficiency - Nucleotide and/or amino acid sequences appearing in the specification (Tables 6 and 3) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d) and drawings.
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:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
o A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings (FIG 1) 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:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
o A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (see page 14, [0049]; and page 64, [0167]). 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:// or other browser-executable code. See MPEP § 608.01.
The use of the terms Triton X-100 (page 68, [0176], [0177]), Corning (page 69, [0178]), Medtronic (page 49, [0128]), ATCC (page 62, [0166]), Vydac (page 65, [0171]), Agilent, Aldrich, Novabiochem (page 65, [0171]), Applied Biosystems (page 65, [0171], page 66, [0173]), Bruker Avance (page 67, [0174]), WATERGATE (page 67, [0174]), Bruker (page 67, [0174]), Innovative research (page 68, [0176]), and Sigma Aldrich (page 69, [0178]), which are trade names or a marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms 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.
Regarding FIG 1, the specification states Cys residues are shown in color and disulfide bonds are indicated in connecting lines below the peptides (see [0018]), however, black and white drawings were provided.
Appropriate correction is required.
Claim Interpretation
Legal standard: Broadest Reasonable Interpretation (BRI):
I. “plurality” : The claim term “plurality” in claims 10-12 and 14 is not expressly defined in the specification although plurality of antimicrobials are exemplified. Accordingly, under the BRI analysis, the “plain meaning”, consistent with the specification, at the time of filing controls. See e.g., MPEP § 2111; 2111.01.
The term “plurality” broadly refers to the state of being numerous. See Merriam-Webster Dictionary (2009) at URL merriam-webster.com/dictionary/plurality.
The election of species read on claims 10-12 and 14.
II. BRI of claim 2 is an antimicrobial, wherein the PG-1 comprises the polypeptide N-X1GRLCYCRRRFCVCVGRX2-C (SEQ ID NO: 291). The claim is given this construction in view of the definition of “SEQ ID NO: 291” on page 30, [0103] of the specification, which states that X1 and X2 of PG-I are the same or different and comprise 0 to 5 amino acids selected from G, R and L. In a further aspect, X1 and X2 are the same and are G or R. In another aspect, they are different and are G or R. In one aspect they are the same and are R or G. In a further aspect, PG-I comprises, or consists of, or consists essentially of: the polypeptide of the group of RGGRLCYCRRRFCVCVGR (SEQ ID NO: 5); GGRLCYCRRRFCVCVGRR (SEQ ID NO: 6); GGCLCYCRRRFCVCVCRR (SEQ ID NO: 7); GGGRLCYCRRRFCVCVGRRG (SEQ ID NO: 8); or GRLCYCRRRFCVCVGR (SEQ ID NO: 9). This construction is consistent with the language in lines 3-4 of the claim “polypeptide”. The election of species of SEQ ID NO:6 read on claims 2-4.
III. “consisting essentially of” in Specification [0039]
It is noted that for the purposes of searching for and applying prior art under 35 U.S.C. 102 and 103, absent a clear indication in the specification or claims of what the basic and novel characteristics actually are, "consisting essentially of" will be construed as equivalent to "comprising." See, e.g., PPG, 156 F.3d at 1355, 48 USPQ2d at 1355 (see MPEP 2111.03). The instant specification provides no such teaching or guidance, thus supporting the interpretation of "consisting essentially of' as equivalent to "comprising."
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, 6-7, 10-12 and 14 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 pre-AIA the applicant regards as the invention.
Claim 1 recites “a cyclotide backbone and a protegrin PG- 1 polypeptide (PG-1)”. The language is indefinite because the structural relationship between cyclotide and protegrin PG-1 polypeptide is unclear. BRI of this limitation includes multiple, plausible combinations: (A) a mixture of cyclotide and PG-1; or (B) a compound of cyclotide and PG-1 linked together, where (i) cyclotide sequence is required to be N-terminal to the PG-1 in the peptide; (ii) cyclotide sequence may be N- or C-terminal to PG-1; and (iii) in both (i) and (ii) cyclotide sequence and PG-1 may be joined directly or with deletion or addition of intervening amino acids. The confusion comes from the word “grafted” in the instant specification, which implies that PG-1 is incorporated into one of the loops of the cyclotide sequence, however does not explain about the mode of attachment. The language is indefinite because it is not clear which peptide construction is covered (e.g., because there is more than one reasonable interpretation of what construction is included in the claim). See MPEP § 2173.04.
Claim 6 recite “the Momordica spp plants”. There is insufficient antecedent basis for this limitation in the claim 6 as no early recitation of which amino acid sequence from Momordica spp plant is being referred to. Momordica spp plant encompasses many more species, therefore it is unclear which specific sequence is intended to be encompassed by the claim. See MPEP § 2173.05(h).
Claim 6 recite “the strictly conserved cysteine”. The language is indefinite because the term “strictly” in the claim is a relative term which render the claim indefinite. The terms “strictly conserved” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 7 recite “strictly conserved cysteines”. The terms “strictly conserved” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Regarding the term “cysteines”, both claim 6 and 7 depend on claim 1, however, it is unclear what other cysteine residues are intended to be encompassed by claim 7.
Claims 6-7 recite “an equivalent of each thereof, wherein the equivalent comprises a polypeptide”. The phrase “equivalent of” is a relative term which renders the claim indefinite. The phrase “equivalent of” is not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. See MPEP §2173.05(d).
Claims 10-12 and 14 recite “plurality”. The term “plurality” is a relative term which renders the claim indefinite. The term “plurality” is not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. See MPEP §2173.05(d).
Claim 11 recite “the amino acid sequences of the plurality are the same or different from each other”. Claim 11 is indefinite because is no early recitation of which amino acid sequence is being referred to. The use of term “plurality” further renders the claim indefinite, and it is unclear what the claim limitation is referencing. Thus, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 12 recites the limitation “the carrier”. There is insufficient antecedent basis for this limitations in the claim. Claim 12 depends on claim 11, which does not recite a carrier.
Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-7, 10, and 11, are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon/natural product without significantly more.
I. Claim 1 is ineligible
Regarding claim 1, BRI of the claim includes multiple, plausible combinations, including (A) a mixture of cyclotide and PG-1; or (B) a compound of cyclotide and PG-1 linked together.
Step 1: Claim 1 recites “an antimicrobial comprising a cyclotide backbone and a protegrin PG- 1 polypeptide (PG-1).” Thus, the claimed invention is directed to a composition of matter, which is one of the statutory categories of invention.
Step 2A, Prong 1: of the patent eligible subject analysis, the claims recite a judicial exception of a natural product.
a mixture of cyclotide and PG-1:
Claim 1 recites that an antimicrobial comprising a cyclotide backbone and a protegrin PG- 1 polypeptide (PG-1). Claim 1 is directed to a product of nature, the cyclotide backbone and PG-1. Regarding cyclotide backbone, the specification states the closest counterpart to the nature-based product are fascinating micro-proteins (~30 residues long) present in plants from different families including Violaceae, Rubiaceae, Cucurbitaceae, and Fabaceae families, among others (see [0030]). Regarding PG-1, the specification states the closest counterpart to the nature-based product is an 18-amino-acid long peptide, is a prototypic antimicrobial cationic peptide of the protegrin family isolated from porcine leukocytes (see [0004]).
This judicial exception is not integrated into a practical application because the claims are drafted such that there is no difference in substance from the sequence claim to a naturally occurring (1) cyclotide backbone and (2) PG-1. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional claim elements do not integrate the judicial exceptions into something more than the judicial exception. Therefore, claim 1 recite a judicial exception (i.e., natural phenomenon/product of nature). Thus, the answer to step 2A, Prong One is YES.
a compound of cyclotide and PG-1 linked together:
Claim 1 recites that an antimicrobial comprising a cyclotide backbone and a protegrin PG- 1 polypeptide (PG-1). Regarding cyclotide backbone, the specification states the closest counterpart to the nature-based product are fascinating micro-proteins (~30 residues long) present in plants from different families including Violaceae, Rubiaceae, Cucurbitaceae, and Fabaceae families, among others (see [0030]). Regarding PG-1, the specification states the closest counterpart to the nature-based product is an 18-amino-acid long peptide, is a prototypic antimicrobial cationic peptide of the protegrin family isolated from porcine leukocytes (see [0004]). has a different structural characteristic than the natural peptides, i.e., however, each claimed peptides are otherwise structurally identical to the natural peptide, e.g., it has the same peptide backbone and amino acid sequence as cyclotide backbone amino acid sequence and PG-1 amino acid sequence in nature. This difference is not a marked difference in view of MPEP § 2106.04(c)(II)(C)(2) and the Supreme Court decision in Myriad. See, e.g., Myriad, 569 U.S. at 585, 106 USPQ2d at 1977. The specification states, the cyclotide backbone polypeptide maintains a cystine-knot scaffold and head-to-tail cyclization (see [0007]) and the PG-1 has it’s characteristic of a native beta-hairpin fold (see [0159], FIG.7). In sum, the claimed peptide is different, but not markedly different, from its naturally occurring counterparts, and thus is a natural phenomenon exception.
Step 2A, Prong 2: Claim 1 only recite the peptide, which is a natural phenomenon exception. Because there are no additional claim elements besides the judicial exception, the judicial exception is not integrated into a practical application (MPEP § 2106.04(d)(III)).
Step 2B: Claim 1 only recites the peptide, which is a natural phenomenon exception. Because there are no additional claim elements besides the judicial exception, the claim does not amount to significantly more than the judicial exception (MPEP § 2106.05).
Therefore, claim 1 is patent ineligible.
II. Claims 2-5 are ineligible
Regarding claims 2-5, PG-1 comprises or consists essentially of the polypeptide: GGRLCYCRRRFCVCVGRR (SEQ ID NO: 6).
Step 1: Claims 2-5 are to a composition of matter.
Step 2A, Prong 1: Claims 2-5 are directed to a product of nature, the peptide is a nature-based product is an 18-amino-acid long peptide, is a prototypic antimicrobial cationic peptide of the protegrin family isolated from porcine leukocytes as sated in the specification (see [0004]). Accordingly, the component, the peptide, is a natural phenomenon exception.
Step 2A, Prong 2: The claims only recite the peptide, which are natural phenomenon exceptions. Because there are no additional claim elements besides the judicial exceptions, the judicial exceptions are not integrated into a practical application (MPEP § 2106.04(d)(III)).
Step 2B: Claims 2-5 only recite the peptide, which is a natural phenomenon exception. Because there are no additional claim elements besides the judicial exception, the claim does not amount to significantly more than the judicial exception (MPEP § 2106.05).
Therefore, claims 2-5 is patent ineligible.
III. Claims 6-7 are ineligible
Regarding claims 6-7, the cyclotide backbone is selected from the group of SEQ ID NOs: 1 to 4 or 10 to 290 or the Momordica spp plants, or an equivalent of each thereof.
Step 1: Claims 6-7 are to a composition of matter.
Step 2A, Prong 1: Claims 6-7 are directed to a product of nature, the cyclotide backbone and PG-1. Regarding cyclotide backbone, the specification states the closest counterpart to the nature-based product are fascinating micro-proteins (~30 residues long) present in plants from different families including Violaceae, Rubiaceae, Cucurbitaceae, and Fabaceae families, among others (see [0030]). Accordingly, the component, the peptide, is a natural phenomenon exception.
Step 2A, Prong 2: The claims only recite the peptide, which are natural phenomenon exceptions. Because there are no additional claim elements besides the judicial exceptions, the judicial exceptions are not integrated into a practical application (MPEP § 2106.04(d)(III)).
Step 2B: Claims 6-7 only recite the peptide, which is a natural phenomenon exception. Because there are no additional claim elements besides the judicial exception, the claim does not amount to significantly more than the judicial exception (MPEP § 2106.05).
Therefore, claims 6-7 are patent ineligible.
IV. Claims 10-11 are ineligible
Regarding claims 10-11, BRI of the claim includes multiple, plausible combinations, including (A) a mixture of cyclotide and PG-1; or (B) a compound of cyclotide and PG-1 linked together and that the cyclotide backbone is selected from the group of SEQ ID NOs: 1 to 4 or 10 to 290 or the Momordica spp plants, or an equivalent of each thereof (see instant specification [0007]).
Step 1: claims 10-11 refers to the amino acid sequences of the plurality are the same or different from each other. Thus, the claimed invention is directed to a composition of matter, which is one of the statutory categories of invention.
Step 2A, Prong 1: of the patent eligible subject analysis, the claims recite a judicial exception of a natural product.
a mixture of cyclotide and PG-1:
Claim 10 recites “a plurality of the antimicrobial of claim 1” and claim 11 recites “wherein the amino acid sequences of the plurality are the same or different from each other” where the antimicrobial of claim 1 comprises a cyclotide backbone and a protegrin PG- 1 polypeptide (PG-1). As stated above, claim 1 is directed to a product of nature, the cyclotide backbone and PG-1. Regarding cyclotide backbone, the specification states the closest counterpart to the nature-based product are fascinating micro-proteins (~30 residues long) present in plants from different families including Violaceae, Rubiaceae, Cucurbitaceae, and Fabaceae families, among others (see [0030]). Regarding PG-1, the specification states the closest counterpart to the nature-based product is an 18-amino-acid long peptide, is a prototypic antimicrobial cationic peptide of the protegrin family isolated from porcine leukocytes (see [0004]).
This judicial exception is not integrated into a practical application because the claims are drafted such that there is no difference in substance from the sequence claim to a naturally occurring (1) cyclotide backbone and (2) PG-1. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional claim elements do not integrate the judicial exceptions into something more than the judicial exception. Therefore, claims 10-11 recite a judicial exception (i.e., natural phenomenon/product of nature). Thus, the answer to step 2A, Prong One is YES.
a compound of cyclotide and PG-1 linked together:
Claims 10-11 recite that an antimicrobial comprising a cyclotide backbone and a protegrin PG- 1 polypeptide (PG-1). Regarding cyclotide backbone, the closest counterpart to the nature-based product are fascinating micro-proteins (~30 residues long) present in plants from different families including Violaceae, Rubiaceae, Cucurbitaceae, and Fabaceae families, among others (see instant specification [0030]). Regarding PG-1, the closest counterpart to the nature-based product is an 18-amino-acid long peptide, is a prototypic antimicrobial cationic peptide of the protegrin family isolated from porcine leukocytes (see instant specification [0004]). has a different structural characteristic than the natural peptides, i.e., however, each claimed peptides are otherwise structurally identical to the natural peptide, e.g., it has the same peptide backbone and amino acid sequence as cyclotide backbone amino acid sequence and PG-1 amino acid sequence in nature. This difference is not a marked difference in view of MPEP § 2106.04(c)(II)(C)(2) and the Supreme Court decision in Myriad. See, e.g., Myriad, 569 U.S. at 585, 106 USPQ2d at 1977. As specified, the cyclotide backbone polypeptide maintains a cystine-knot scaffold and head-to-tail cyclization (see instant specification [0007]) and the PG-1 has it’s characteristic of a native beta-hairpin fold (see instant specification [0159], FIG.7). In sum, the claimed peptide is different, but not markedly different, from its naturally occurring counterparts, and thus is a natural phenomenon exception.
Step 2A, Prong 2: Claims 10-11 only recite the peptide, which is a natural phenomenon exception. Because there are no additional claim elements besides the judicial exception, the judicial exception is not integrated into a practical application (MPEP § 2106.04(d)(III)).
Step 2B: Claims 10-11 only recites the peptide, which is a natural phenomenon exception. Because there are no additional claim elements besides the judicial exception, the claim does not amount to significantly more than the judicial exception (MPEP § 2106.05).
Therefore, claims 10-11 are patent ineligible.
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 1-7 and 10-11 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 claims contain 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.
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 inventor was in possession of the claimed genus.
Scope of the claims
The claims are drawn to peptides comprising a cyclotide backbone and a protegrin PG- 1 polypeptide (PG-1).
Actual Reduction to Practice
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. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In the instant case, several embodiments of the invention were reduced to practice: see Tables 6, 3, and FIGs 11A and 11B.
The specification states that in some embodiments, the cyclotide backbone is derived from, comprises, or alternatively consists essentially of one or more of the sequences listed in Table 6 (SEQ ID NOS: 10 to 290). In some aspects, residue X in the amino acid sequences of Table 6 represents one or more unnatural amino acids (see [0107]). Although these variations are allowed by the claims, they are not represented in the reduction to practice. In addition, the specification fails to include a reduction to practice of a peptidomimetic; all of the species are peptides.
Therefore, the instant specification has failed to meet the written description requirement by actual reduction to practice of a representative number of species alone.
Sufficient relevant identifying characteristic
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 thereof.
i. Complete structure
As stated above, the complete structure of the peptides in Tables 3 are disclosed.
ii. Partial structure:
The specification states that as a partial structure the peptides must comprise PG-1. Table 6 discloses numerous peptides that meet this requirement but that in one embodiment, the cyclotide incorporates one or more unnatural amino acids. "Unnatural amino acids" are non-proteinogenic amino acids that either occur naturally or are chemically synthesized. While unnatural amino acids are not on the standard 20-amino acid list, they can be incorporated into a protein sequence (see [0108]. Therefore, it is unclear from the partial structure which additional elements are necessary to meet all of the claimed properties of the genus.
iii. Physical and/or chemical properties:
The data presented in the specification raise more questions about the physical properties of the genus than they answer. The data do not suggest the physical basis for the peptide derivatives and therefore do not describe which substitutions, deletions or additions could be made while preserving this conformation. Understanding the physical basis for having antimicrobial activity is critical to determining which of the sequences that meet the sequence requirements of the genus also meet this additional functional requirement of the genus.
iv. Functional characteristics when coupled with a known or disclosed correlation between function and structure:
The specification does not describe a general correlation between sequence and structural coordinates for the claimed genus. As a result, it is impossible to predict, based on the specification, how changing any position will affect the antimicrobial activity relative to cell toxicity.
v. Method of making the claim invention
Solid state peptide synthesis and the cloning, recombinant expression and purification of proteins is well-known in the art. It is not disputed that one of ordinary skill in the art could isolate, albeit with route experimentation and optimization, a peptide of a given sequence provided that the sequence is known. Where the specification fails to provide description is in the structure of the peptide to make. For all of the reasons presented above, one of ordinary skill in the art would not know which of the countless peptides that meet the sequence requirements of the claims would also have specific structural conformation with expected antimicrobial activity. In other words, the specification does not describe which peptides to make.
Conclusion
For these reasons, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 - 14 are rejected under 35 U.S.C. 103 as being unpatentable over Veer et. al. (“Cyclotides: From Structure to Function”; Simon J. de Veer, Meng-Wei Kan, and David J. Craik; Chem. Rev. 2019, 119, page 12375−12421, published December 12, 2019) in view of US 20040014669 (published on January 1, 2004).
Veer et. al. provides an elaborate review of the plant-derived macrocyclic peptides called cyclotides which are characterized by their head-to-tail cyclic backbone and cystine knot motif, which render them to be exceptionally stable, with resistance to thermal or enzymatic degradation (see Abstract). Cyclotides are naturally occurring macrocyclic peptides found in plants that are defined by their unique cyclic cystine knot (CCK) structural motif, comprises a head-to-tail cyclic backbone that is cross-braced with a cystine knot formed by six conserved Cys residues (see Introduction, 1st paragraph, page 12375). Veer et. al. teaches the placement of Cys residues shows strong conservation among cyclotides and the cystine knot has a dominant effect on their structure, other cyclotide structures are very similar to that of kalata B1, with just minor variations in the sizes and conformations of the backbone loops between
Cys residues (see Table 2 lists the PDB ID codes for the cyclotide structures including grafted cyclotides, page 12385-12386). The cyclotide sequences are similar to the instantly claimed cyclotide sequences. For example Sequences of selected cyclotides like kalata B1, cycloviolacin O2 (cyO2), and Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II) are shown by Veer et. al.(see sequence alignment, Figure 5, page 12379). Veer et. al. also teaches that trypsin inhibitors in the seeds of Momordica plants identified two cyclotides, MCoTI-I and MCoTI-II, produced by M. cochinchinensis (see 6.1 Functions of Native Cyclotides, 1st paragraph, page 12399). Veer et. al. discloses the key features of the sequences include the six conserved Cys residues (numbered I-VI) and the six backbone loops (loops 1-6) (see Figure 5, page 12379).
Veer et. al. explains purification of cyclotide variants were performed in aqueous buffer conditions (see 2.1 Peptide-Based Discovery, 1st paragraph, page 12380); cyclization via intramolecular native chemical ligation proceeded in aqueous buffer (pH 7.4) containing TCEP, and oxidative folding was carried out in one step by dissolving the reduced, cyclic peptide in 0.1 M ammonium bicarbonate (pH 8.5) containing 1 mM GSH. Adding 50% (v/v) 2-propanol in the reaction buffer improved the yield of correctly folded cyclotide, for e.g., kalata B1 (see 5.1. Peptide α-Thioesters Produced via Boc Chemistry, page 12394-12395). Veer et. al. further discloses, Boc chemistry was successfully used to synthesize a range of non-native cyclotides, including cyclotide with chimeric sequences and libraries carrying point mutations at each non-Cys residue, and it continues to be used today, particularly for sequences that are challenging to assemble (see 5.1. Peptide α-Thioesters Produced via Boc Chemistry, page 12396).
Regarding the structure of the cyclotides, Veer et. al. teaches, MCoTI-II bound to trypsin, reflecting the exceptional rigidity brought about by the highly cross-braced CCK motif. This rigidity is one of the key features of cyclotides that makes them favorable peptide scaffolds for drug design applications in which bioactive epitopes can be grafted into their sequence (see 3.2 Secondary and Tertiary (3D) Structure, last paragraph, page 12388).
Veer et. al. teaches, the unique structures and diverse functions of cyclotides have paved the way for ongoing studies that are investigating the potential of cyclotides as novel pharmaceuticals or agricultural commodities (see 7.1. Applications Based on Natural Function, 1st paragraph, page 12405). Veer et. al. illustrates several of the substitutions that have been carried out in engineered MCoTI variants. This range of substitutions highlights the flexible nature of the framework, which has been expanded even further by modifications introduced in grafting studies (see Figure 22, 7.2. Applications Based on Redirected Function, 3rd paragraph, page 12406). Veer et. al. further teaches, the main approach for equipping cyclotides with new biological activities has involved inserting an epitope from a bioactive peptide or protein into the cyclotide framework. This process is termed “grafting” (see 7.3. Applications Based on Grafting To Introduce New Functions, 1st paragraph, page 12407). Schematic diagram illustrating the concept of grafting an epitope into a cyclotide scaffold showing - A bioactive epitope, shown as a small helix, with desired bioactivity (discovered using screening, computational design, or phage display or derived from a larger protein) is inserted into a stable cyclotide framework, resulting in a new grafted peptide that has the desired bioactivity as well as stability (see 7.3. Applications Based on Grafting To Introduce New Functions, Figure 23, page 12406). Veer et. al. further discusses application of grafted cyclotides that has attracted significant interest is their ability to deliver cargoes inside cells. Although many proteins have limited access to the intracellular space when added exogenously, several cyclotides, including kalata B1, MCoTI-I, and MCoTI-II, have been shown to be internalized by cells. Therefore, grafting epitopes into certain cyclotide frameworks can serve to not only stabilize the bioactive epitope but also enable delivery across membranes (see 7.3. Applications Based on Grafting To Introduce New Functions, 2nd paragraph, page 12407).
Veer et. al. do not specifically mention the use of protegrin PG- 1 polypeptide (PG-1) as the epitope within the cyclotide structure.
US’669 teaches about theta defensin analogs having antimicrobial activity (see [0010]).
US’669 teaches a theta defensin analog selected from the analogs referenced as SEQ ID NOS:13-31 (claim 1). US’669 further shows the amino acid sequences of theta-defensins, protegrin PG-1, and analogs (see [0015], FIG. 5A). Exemplary theta defensin analogs include the analogs shown in Table 1 and referenced as SEQ ID NOS:12-31.
SEQ ID NO: 13 of US’669 have exact same amino acid sequence as instantly claimed SEQ ID NO: 6.
US’669 describes membranolytic activity of theta-defensins and protegrin analogs (see Example III, [0146]) and theta defensin analogs having antimicrobial activity (see Examples I-III) and PG-1 permeabilized the cytoplasmic membranes of both bacterial cells and human erythrocytes (see [0169]). US’669 discloses the microbicidal activities of some of the theta-defensin and PG-1 analogs were analyzed by determining the minimum microbicidal concentrations for all twenty peptides against S. aureus, E. coli, and C. albicans. US’669 teaches all peptide activities were analyzed in 10 mM PIPES, 5 mM glucose, pH 7.4 (see [0124]) and/or concentrations of salt (145 mM NaCl), divalent cations (1-2 mM CaCl2 and MgCl2), and in 10% normal human serum (see [0125]).
It would have been obvious to combine the teaching of Veer et. al. and US’669 before the effective filing date of the claimed invention by considering cyclotides as an effective and stable peptide scaffolds into which antimicrobial epitopes/peptides like PG-1 in the instantly claimed invention can be grafted into the sequence. One of ordinary skill in the art would have been motivated to utilize the pharmaceutical grafting studies taught by Veer et. al. as potent antimicrobial polypeptide modified for improved activity with a reasonable expectation of success because US’669 teaches that peptide analogs can be used to reduce or inhibit the growth or survival of a microorganism (see Detailed Description of Invention) in addition to reducing peptide cytotoxicity without significantly affecting microbicidal activity (see [0165]). Thus, one skilled in the art can adjust the dosage of the theta defensin analog (which is PG-1 in the instant claim) so that the combination of the analog and other antimicrobial therapy is optimally effective for inhibiting the growth or survival of a microorganism in an environment (see [0080]).
Regarding claims 1-7, 10, 11, 13, and 14, US’669 discloses PG-1 sequence SEQ ID NO:13 as 100% sequence match with the instantly claimed SEQ ID NO:6.
Regarding claims 1, , Veer et. al. teaches cyclotides’ unique structure with exceptional stability, their natural functions as plant defense peptides, and their wide range of applications as bioactive molecules in medicine (see Introduction, page 12377). Cyclotides achieve exceptional stabilization and favorable biophysical properties via their CCK motif so that no further modifications are required (see 1st paragraph, page 12409). Veer et. al. teaches cyclotides are macrocyclic peptides are around 30 amino acids in size and are characterized by their head-to-tail cyclic backbone and cystine knot motif (see Abstract). The sequence features six Cys residues (conserved in all cyclotides and numbered (I−VI) linked in a I−IV, II−V, and III−VI connectivity that forms a cystine knot. In this motif, two disulfide bonds and their connecting backbone segments form a ring that is threaded by the third disulfide bond. The backbone segments between the Cys residues are referred to as “loops” and are numbered 1−6 (see Figure 1, page 12376). The β-sheet is conserved in most cyclotides and is
intimately connected to the cystine knot at the core of cyclotide structures (see Figure 9, 3.2 Secondary and Tertiary (3D) Structure). Veer et. al. further teaches that the grafted cyclotides were designed by inserting a previously identified α-helical peptide into loop 6 of MCoTI-I. This scaffold was selected because trypsin inhibitor cyclotides are internalized by cells in a nontoxic manner that does not cause membrane disruption. NMR experiments indicated that the 17-amino-acid grafted epitope did not markedly alter the structure of the MCoTI-I scaffold (loops 1−5) and was not detrimental to oxidative folding to form the cystine knot (see 7.3. Applications Based on Grafting To Introduce New Functions, 2nd paragraph, page 12407). Veer et. al, teaches about the mutagenesis studies that systematically introduced point mutations into cyclotide (kalata B1) with the aim of identifying residues that were essential for function. Initially, an Ala scan was performed using a library of 23 kalata B1 variants, where each non-Cys residue was individually mutated to Ala. Cys residues were not mutated to preserve the cystine knot (see 6.2 Linking Structure to Function, 4th paragraph, page 12400).
Regarding claim 8, Veer et. al. cyclotide−intein fusion proteins were expressed in E. coli BL21 (DE3) cells, and the desired products were isolated from cell lysates using either an intein pulldown or affinity chromatography with immobilized trypsin (see 5.3. Recombinant Expression, 3rd paragraph, page 12387). Also, aqueous acetonitrile, or aqueous buffer, followed by purification on a C18 reverse-phase column was performed (see 2.1. Peptide-Based Discovery, 1st paragraph, page 12379). Veer et. al. further detailed the production of labeled cyclotides by the conjugation of a biotin or Alexa Fluor 488 tag (see 6.2. Linking Structure to Function, 3rd paragraph, page 12400); fluorescently labeled cyclotides (see 6.3. Defining the Mode of Action for Membrane-Active Cyclotides, 5th paragraph, page 12403); and the production of a radiolabeled bioimaging probe (see 7.3. Applications Based on Grafting To Introduce New Functions, 6th paragraph, page 12408).
Regarding claims 9 and 12, US’669 teaches use as a therapeutic agent, the theta defensin or theta defensin analog can be formulated with a pharmaceutically acceptable carrier to produce a pharmaceutical composition, which can be administered to the individual, which can be a human or other mammal. A pharmaceutically acceptable carrier can be, for example, water, sodium phosphate buffer, phosphate buffered saline, normal saline or Ringer's solution or other physiologically buffered saline (see [0074]). Further teaches [0075] A pharmaceutically acceptable carrier can contain physiologically acceptable compounds that act, for example, to stabilize or increase the absorption of the theta defensin or analog thereof. Such physiologically acceptable compounds include, for example, carbohydrates such as glucose, sucrose or dextrans; antioxidants such as ascorbic acid or glutathione; chelating agents such as ethylenediamine tetraacetic acid (EDTA), which disrupts microbial membranes; divalent metal ions such as calcium or magnesium; low molecular weight proteins; or other stabilizers or excipients. One skilled in the art would know that the choice of a pharmaceutically acceptable carrier, including a physiologically acceptable compound, depends, for example, on the route of administration of the composition (see [0075]).
Regarding claims 10 and 11, Veer et. al. teaches the sequence optimization of MCoTI-II (i.e., plant-derived native cyclotides), has been carried out on a broader scale using genetically encoded sequence diverse libraries. This is a particularly powerful approach because it provides access to a much broader range of unique sequences than can be practically obtained using chemical synthesis (see 7.2. Applications Based on Redirected Function, 6th paragraph, page 12406).
Regarding claims 13 and 14, US’669 teaches [0080] Furthermore, the effective amount of a theta defensin analog to be administered to an individual can be adjusted if the theta defensin is administered in combination with another antimicrobial compound such as an antibiotic (see [0080]).
Claims 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Veer et. al. (“Cyclotides: From Structure to Function”; Simon J. de Veer, Meng-Wei Kan, and David J. Craik; Chem. Rev. 2019, 119, page 12375−12421, published December 12, 2019) in view of Gould et. al. (“Cyclotides, a novel ultrastable polypeptide scaffold for drug discovery”; Andrew Gould, Yanbin Ji, Teshome L. Aboye, and Julio A. Camarero; Curr Pharm Des.; 17(38): 4294–4307; published April 20, 2012).
The teachings of Veer et. al. are discussed above. Veer et. al. does not teach about the “hypermutation of essentially all residues is permitted with the exception of the strictly conserved cysteines that comprise the knot”.
Gould et. al. teaches despite the sequence diversity, all cyclotides share the same CCK motif (see Figs.1 and 2). Hence, these micro-proteins can be considered natural combinatorial peptide libraries structurally constrained by the cystine-knot scaffold and head-to-tail cyclization but in which hypermutation of most of the residues may be tolerated with the exception of the strictly conserved cysteines that comprise the knot (see page 2, 3rd paragraph).
It would have been obvious to combine the teachings of Veer et. al., and Gould et. al., before the effective filing date of the claimed invention utilizing cyclotides as an effective and stable peptide scaffolds into which antimicrobial epitopes/peptides like PG-1 can be grafted into the sequence. One of ordinary skill in the art would have been motivated to do so with an expectation to succeed in preparing potent antimicrobial compounds. Therefore, the presently claimed invention was prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
Conclusion
No claim is allowed.
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/KOYELI BANERJEE/Examiner, Art Unit 1658
/Melissa L Fisher/Supervisory Patent Examiner, Art Unit 1658
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