DETAILED ACTION
Claims 1-24, submitted on March 8, 2024, are pending in the application and are rejected for the reasons set forth below. No claim is allowed.
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 .
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.
Claims 1-24 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for the following:
CB[7] and CB[8] as the cucurbituril and
Cys-Gly-Phe or Cys-Gly-Gly-Gly-Phe as the peptide,
does not reasonably provide enablement for the full scope of the claims. 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 and use the invention commensurate in scope with these claims.
This application is predicated upon the assumption that all cucurbituril (“CB” or “Q”) macrocycles and all peptides having the following structure will function in the same manner:
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106
292
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each AA is an amino acid of a peptide;
AA¹ is an amino acid bound to a platinum metal center;
AAˣ is a terminal amino acid of the peptide;
x is from 2 to 5000; and
Q₁ and Q₂ are independently either non-existent or at least one additional amino acid of the peptide
This assumption, however, is not supported by the prior art. On the contrary, the prior art raises substantial questions about the challenges known to exist in this technology area. The following references1 are representative of the state of the prior art:
Yin et al., “Challenges and Opportunities of Functionalized Cucurbiturils for Biomedical Applications,” JACS Au 2023, 3, 2356-77.
Armstrong et al., “Molecular recognition of peptides and proteins by cucurbit[n]urils: systems and applications,” Chem. Soc. Rev., 2024, 53, 11519-56.
Barrow et al., “Cucurbituril-Based Molecular Recognition,” Chem. Rev. 2015, 115, 12320-406.
Yin discloses that “functionalized CB[7] has rarely been interfaced with metal-ligand complexes” (p. 2372). Yin also discloses that “functionalized CB[8] are still quite exotic compounds, CB[8] being very hard to functionalize, and also relatively weakly soluble” (p. 2372). Yin further states that a “small number of derivatives used in biological applications illustrates quite well the daunting task of functionalizing CB[8]” (p. 2372). While Yin hypothesizes that “there are no doubts about the number of possibilities remaining to be explored if the CB[8] functionalization can be unlocked” (p. 2373), the reference nevertheless would clearly inform the skilled artisan that the use of CB[7] and CB[8] involves a high level of unpredictability, with substantial problems remaining to be solved.
With respect to protein and peptide binding of CB[7] and CB[8] (also known as “Q7” and “Q8”), Armstrong discloses that these macrocycles have “site-specific binding of cucurbit[n]urils, particularly Q7 and Q8, to peptides and proteins” (p. 11539). One observed type of sequence-specificity has been shown by “the addition of Q7 to protein samples following peptic digestion,” which “increases mass spectrometric signal abundance and sequence coverage for peptides containing N-terminal Phe” (p. 11541). Note that the two peptides of applicant’s working examples (discussed below) include an N-terminal phenylalanine (Phe). One would be skeptical, however, that other peptides would have similar affinity for CB[7]. This raises further questions about the enablement of the claimed invention. Other known problems with the affinity of cucurbituril macrocycles with various peptides is illustrated in Fig. 24 in the reference and the discussion thereof (p. 11543). Armstrong provides details of the following experiment, which illustrates the sequence specificity of the cucurbituril-peptide interaction:
Excited by the discovery that Q8 can bind peptides via inclusion of the side chains of neighboring residues, we considered that the additional complexity of a dipeptide binding site should allow us to identify other possible sequences that bind Q8 with high affinity. The additional binding interface enabled by pair-inclusion should allow inclusion of nonaromatic residues. To this end, we synthe-sized and screened a series of 144 peptides of sequence H-Var1-Var2-Ala-NH2 (Var1 = Tyr, Phe, Ile, Leu, Met, Pro, Arg, Lys, and Var2 = all 20 amino acids except Trp and Cys). The peptides were synthesized using parallel solid-phase synthesis, and the relative extent of binding to Q8-MBBI was analyzed indirectly by comparing the relative change in the fluorescence of Q8-MBBI in the presence vs. absence of peptide. The patterns of fluorescence suggested that certain peptides with N-terminal Met bind tightly to Q8. A detailed structure-activity investigation by ITC and NMR yielded several determinants for sub-micromolar binding via the pair-inclusion motif (Fig. 12) (Table 4). Specifically, when the first resi-due is Met, then the second residue should be Leu, Tyr, Phe, Lys, or Arg; the first two resides can be reversed in sequence; and the third residue should be Gly or Ala. Therefore, the pair-inclusion motif allowed for targeting N-terminal Met, which is found in all newly translated eukaryotic proteins, as well as entirely nonaromatic binding sites.
According to this passage in Armstrong, “the first residue” should be one particular amino acid, “the second residue” should be selected from four different specific amino acids, although “the first two resides can be reversed in sequence,” and the “third residue” should be another specific amino acid. One of skill in the art would appreciate that this sequence specificity was discovered through extensive experimentation and that not every peptide or protein would have equivalent affinity for every cucurbituril macrocycle.
Barrow describes similar observations about the sequence specificity the peptide. In one experiment, “tripeptides consisting of 2 glycine residues and a single tryptophan or phenylalanine were investigated, and it was again found that the distance of the aromatic residue from the C-terminus had a large effect on binding affinity” (p. 12391). Barrow further explains that “[o]ther aromatic amino acid residues were investigated (tyrosine, histidine); however, binding to CB[8] was not observed for these derivatives” (p. 12391). This raises further questions about the premise of the claimed invention, namely, that essentially any peptide or protein would form a cucurbituril complex.
It is implicit that one of ordinary skill in the art is a person who can read and understand these references, as well as applicant’s own specification. Such a person would have advanced training or significant professional experience in peptide chemistry, organic chemistry, or a related technical discipline. With the known challenges in this technology area in mind, one of skill in the art would look to applicant’s own specification to see how the invention is made and used in actual practice. In applicant’s drawings, and the accompanying written description in the specification, examples are presented of Cys-Gly-Phe (see Figs. 1 and 10) and Cys-Gly-Gly-Gly-Phe (see Figs. 2-5, 7, and 9) as the peptide. Complexes of these peptides are with CB[7] and CB[8] as the cucurbituril. There is no evidence in applicant’s specification that any other peptide or cucurbituril has been reduced to practice. Even the subject matter of instant claims 20 and 24, which relate to a protein found in SARS-CoV-2, is speculative (see applicant’s specification at p. 28). The examiner therefore concludes that one of skill in the art would be burdened with undue experimentation when attempting to make and use the invention commensurate with the full scope of the claimed subject matter.
Background Prior Art
The prior art made of record (see attached form PTO-892) and not relied upon is consid-ered pertinent to applicant’s disclosure. Bray et al., Aust. J. Chem. 43, 629-34 (1990) discloses platinum-terpyridine-peptides, although it does not specifically disclose cucurbituril complexes.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Theodore R. Howell whose telephone number is (571)270-5993. The examiner can normally be reached Monday - Thursday, 8:00 am - 7:00 pm (Eastern Time). Exam-iner 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, Amy L. Clark can be reached at (571)272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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THEODORE R. HOWELL
Primary Examiner
Art Unit 1628
/THEODORE R. HOWELL/Primary Examiner, Art Unit 1628
February 5, 2026
1 Internal citations in the quotations of the references in this Office action have been omitted to improve readability.