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, 21, and 22 which read on the elected species has been considered. Claims 1-14, 21, and 22 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Claims 15-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1-22 are pending. Claims 15-17 are cancelled and claims 18-20 are withdrawn for further consideration. Claims 1-14 are amended and claims 21 and 22 are newly added.
Claims 1-14, 21, and 22 are currently examined on the merits herein.
Objections/Rejections Withdrawn
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied, and constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103 (maintained and modified)
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,1-5, 8-14, 21, and 22 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 1-5, 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 21 and 22, Veer et. al. discloses the sequence Modi 1 as 100% sequence match with the instantly claimed cyclotide MCo sequence.
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]).
Response to Arguments
Applicant's arguments filed 7/13/2026 have been fully considered but they are not persuasive in view of the modified grounds of rejected necessitated by amendment.
Applicant argues the combination of cited references fails because neither reference supplies the central feature of the claimed invention, grafting protegrin PG-1 into a loop of a cyclotide scaffold, and the Examiner has supplied that feature only by using the application as a roadmap. – In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, the Examiner would like to bring to Applicant’s notice inventive concept presented by Veer et. al., shown below is the schematic diagram illustrating the concept of grafting an epitope into a cyclotide scaffold (see page 12406, Figure 23).
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Applicant argues, First, the rejection rests on impermissible hindsight. The Office Action concedes that Veer "do[es] not specifically mention the use of protegrin PG-1 polypeptide (PG-1) as the epitope within the cyclotide structure," and the Examiner's stated rationale expressly reaches the result by grafting an epitope "like PG-1 in the instantly claimed invention," thereby
reconstructing the invention from Applicant's own disclosure rather than from the prior art (MPEP § 2143.01). - It must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, 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]).
Applicant argues, second, US '669 contributes only the PG-1 sequence; it is directed to Θ-defensins and protegrin analogs (US '669, paragraphs [0010] and [0015]) and contains no teaching of a cystine-knot cyclotide scaffold or of grafting a peptide epitope into a cyclotide loop. The "cyclic" PG-1 of US '669 (cPG-1) is an end-to-end backbone-cyclized 9-defensin-protegrin hybrid prepared by EDC/HOBt cyclization of acyclic PG-1 (US '669, paragraphs [0117] and [0134]), structurally distinct from the grafted cyclotide of the claims, so US '669 provides no
suggestion to arrive at the claimed construct. – The Examiner would like to remind the Applicant that the rejection of record was that it would be obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings 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.
Applicant argues, third, and most significantly, US '669 teaches away from any reasonable expectation of success on the very property the claimed peptide improves. - Examiner reminds the Applicant that "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).
Applicant argues the claimed construct produces unexpected results that rebut any prima facie case of obviousness (MPEP § 716.02). – The Examiner would like to remind the Applicant that "A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue." In re Corkill, 771 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). In Corkhill, the claimed combination showed an additive result when a diminished result would have been expected. This result was persuasive of nonobviousness even though the result was equal to that of one component alone. Evidence of a greater than expected result may also be shown by demonstrating an effect which is greater than the sum of each of the effects taken separately (i.e., demonstrating "synergism"). Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). However, a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991). It is known in the art about that cyclotides are ultra-stable peptides characterized by their head-to-tail cyclic backbone and cystine knot, and have exceptional stability and tolerance to sequence substitutions (see Craik et. al. Table 2 for results). In the instantly claimed invention, the results table itself is not sufficient enough to convince the superiority of results achieved. Applicants who allege the inventor discovered the source of a problem must provide evidence substantiating the allegation, either by way of affidavits or declarations, or by way of a clear and persuasive assertion in the specification. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979) (unsubstantiated statement of counsel was insufficient to show appellants discovered source of the problem); In re Kaslow, 707 F.2d 1366, 217 USPQ 1089 (Fed. Cir. 1983).
Prior Art of Record: The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Craik et. al. (“Cyclotides as drug design scaffolds”; David J Craik and Junqiao Du; Current Opinion in Chemical Biology 2017, 38:8–16; published February 27, 2017).
Claim Rejections - 35 USC § 103 (maintained and modified)
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 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 US 20040014669 (published on January 1, 2004), as applied to claims 1-5, 8-14, 21, and 22 above, and further 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. and US’669 are discussed above.
Additionally, Veer et. al. teaches that cyclotides are naturally occurring macrocyclic peptides found in plants that are defined by their unique cyclic cystine knot (CCK) structural motif, for the prototypic cyclotide kalata B1; the CCK motif comprises a head-to-tail cyclic backbone that is cross-braced with a cystine knot formed by six conserved Cys residues (see Introduction, paragraph 1; and illustrated in Figure 1 shown below with 3 disulfide bonds).
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Veer et. al. elucidates the cyclotide sequence features with six Cys residues (conserved in all cyclotides and numbered here 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 (see Figure 1).
However, Veer et. al. and US’669 do 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).
Gould et. al. also teaches regarding cyclotide variants that cyclotides are a unique and growing family of backbone cyclized peptides that also contain a cystine knot motif built from six conserved cysteine residues; this unique circular backbone topology and knotted arrangement of three disulfide bonds make them exceptionally stable to thermal, chemical, and enzymatic degradation compared to other peptides of similar size; aside from the conserved residues forming the cystine knot, cyclotides have been shown to have high variability in their sequence (see Abstract); and they all share a unique head-to tail circular knotted topology of three disulfide bridges (see Introduction paragraph 1).
It would have been obvious to combine the teachings of Veer et. al., US’669, and Gould et. al., before the effective filing date of the claimed invention utilizing cyclotides as an effective and stable peptide scaffolds, that are remarkably stable due to the cyclic cystine knot (see Gould et. al. page 2, paragraph 7), 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.
Response to Arguments
Applicant's arguments filed 7/13/2026 have been fully considered but they are not persuasive.
Applicant argues the Veer/Gould combination inherits the same hindsight and expectation-of-success deficiencies. – The motivation to combine the teachings of Veer et. al. and Gould et. al. are discussed above. It must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, it would have been obvious to combine the teachings of Veer et. al., US’669, and Gould et. al., before the effective filing date of the claimed invention utilizing cyclotides as an effective and stable peptide scaffolds, that are remarkably stable due to the cyclic cystine knot (see Gould et. al. page 2, paragraph 7), 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.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KOYELI BANERJEE/ Examiner, Art Unit 1658
/Melissa L Fisher/ Supervisory Patent Examiner, Art Unit 1658
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