SUPRAMOLECULAR MOLECULES FOR THE TREATMENT OF CANCER

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 . DETAILED ACTION Claims 1-6, 8, 10, 11, 13, 14, 16, 17, 20, 22-24, 26, 29-32 of M. Hannon et al., US 18/028,238 (Sep. 28, 2021) are pending. Claim 24 to non-elected Group (IV) is withdrawn from consideration. Claims 1-6, 8, 10, 11, 13, 14, 16, 17, 20, 22-23, 26, 29-32 are under examination on the merits. Claims 1-6, 8, 10, 11, 13, 14, 16, and 26 are in condition for allowance. Claims 29-32 are rejected. Election/Restrictions Applicant elects Group (I), claims 1-6, 8, 10, 11, 13, 14, 16, and 26 drawn to a rotaxane, with traverse in the Reply to Restriction Requirement filed on December 30, 2025. Claims 17, 20, 22, 23, 24 and 29-32 to non-elected Groups (II)-(V) were previously as from consideration pursuant to 37 CFR 1.142(b). Per rejoinder below, claims 17, 20, 22, 23 and 29-32 (the inventions of Groups (II), (III) and (V)) are rejoined. The invention of Group (IV) (i.e., claim 24) is maintained as withdrawn. The restriction/election requirement is maintained as FINAL. Rejoinder Claim 1 is directed to an allowable product. In view of Applicant’s amendments and pursuant to the procedures set forth in MPEP § 821.04(b), claims 17, 20, 22, 23 and 29-32 (the inventions of Groups (II), (III) and (V)), directed to the process of making and using the allowable product of claim 1, previously withdrawn from consideration as a result of a restriction requirement, are hereby rejoined and fully examined for patentability under 37 CFR 1.104. Claim 24, directed to the invention of (IV) does not require all the limitations of an allowable product claim, and claim 24 has NOT been rejoined. Because a claimed invention previously withdrawn from consideration under 37 CFR 1.142 has been rejoined, the restriction requirement among groups (I)-(III) and (V) as set forth in the Office action mailed on November 3, 2025, is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01. 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: The sequence listing in computer readable format, filed by Applicant on 7/20/2026, was found defective. See Defection Notice issued of July 21, 2026. The Defection notice states the reason is that 18/028,238 is an international filing date before July 1, 2022, therefore, ST.25 format is required, where Applicant used ST.26 format. MPEP § 1893.02(II). Resubmission in the correct format is required. Further, the date of “July 16, 0226”, as recited in the substitute specification, filed July 20, 2026, is clearly incorrect. Claim Rejections - 35 USC § 112, First Paragraph 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 29-32 are rejected under 35 U.S.C. 112(a) because the specification, while enabling one of skill in the art to treat cancer, a viral disease, and/or a bacterial disease comprising administering a therapeutically effective amount of a rotaxane of claim 1 (amended as proposed below) to a subject: 1. A rotaxane comprising (i) cucurbit[10]uril (ii) an ion of formula [MzLz1]zn+, wherein each M is a metal ion of oxidation state n+, each independently selected from the group consisting of Fe, Ni, Ru, z is 2 z1 is 3 L is a ligand of formula (I): PNG media_image1.png 200 400 media_image1.png Greyscale wherein Y1 is independently CR1 R1 is independently selected from H, C1-C4alkyl, each Ar is positioned at either end of the ion of formula [MzLz1]zn+ and is independently imidazole or pyridyl with the proviso that the two Ar are substituted with one or more blocking groups such that each end of the ion comprises at least one blocking group, and wherein each Ar is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C1-C4alkylol, carboxy, C1-C4alkanoate, C1-C4alkyl, C1-C4alkoxy, halo, cyano, nitrite, C1-C4haloalkyl, C1-C4alkylthio, C1-C4alkyleneC1-C4alkylthio, C1-C4alkylsulfonate, diC1-C4alkylamino and C1-C4alkynyl; N-Y-N is PNG media_image2.png 200 400 media_image2.png Greyscale wherein A 2)1-4, CHR2, or CR22 Ar1 is phenyl optionally substituted one or more times with R3; Ar2 is phenyl or biphenyl optionally substituted one or more times with R3; and R2 and R3 are independently any one or a combination selected from the group consisting of H, hydroxy, C1-C4alkylol, carboxy, C1-C4alkanoate, C1-C4alkyl, halo, cyano, nitrite, C1-C4haloalkyl, C1-C4alkylthio, C1-C4alkyleneC1-C4alkylthio, C1-C4alkylsulfonate, diC1- C4alkylamino and C1-C4alkynyl. does not reasonably enable one of skill in the art to: Per claims 29 and 31 treat any disease/condition comprising administering a therapeutically effective amount of a rotaxane of claim 1 Per claims 30 and 32 treat the full scope of viral disease and/or a bacterial disease comprising administering a therapeutically effective amount of a rotaxane of claim 1 in any subject without undue experimentation. Factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue” include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. MPEP. § 2164.01(a); In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988); In re Wright, 999 F.2d 1557, 27 USPQ2d 1510 (Fed. Cir. 1993). Nature of the Invention - Structure of the Claimed Rotaxane Claims 29-32 are directed to treating diseases generally comprising administering a therapeutically effective amount of a rotaxane of claim 1 to a subject. Claim 1 is directed to a rotaxane comprising a macrocycle and an ion of formula [MzLz1]zn+. The primary claim 1 rotaxane structural elements are recited as follows: 1. A rotaxane comprising (i) a macrocycle selected from the group consisting of a cucurbituril, calixarene, pillararene, and metallo-organic macrocycle; or comprising aryl groups linked by C1-C4-alkylenes, C1-C4-ethers, C2-C4-alkenylenes and C2-C4-alkynylenes and (ii) an ion of formula [MzLz1]zn+, wherein each M is a metal ion of oxidation state n+, each independently selected from the group consisting of Fe, Ni, Ru, Co, Cu, Ag, Cd, Zn, Rh, Mn, Ir, Os, Pd, and Pt z is 2 to 4, z1 is 2 to 6 and L is a ligand of formula (I): PNG media_image1.png 200 400 media_image1.png Greyscale wherein Y1 is independently CR1 or N . . . each Ar is positioned at either end of the ion of formula [MzLz1]zn+ and is independently a C3-C9heteroaryl comprising at least one nitrogen atom, and wherein each Ar is optionally substituted with one or more blocking groups capable of trapping the macrocycle, with the proviso that at least two Ar are substituted with one or more blocking groups such that each end of the ion comprises at least one blocking group . . . Breadth of the Claims The claim 29-32 breadth of diseases/disorders are considered to encompass a large and mechanistically diverse genus of diseases/conditions. The claim 29-32 breadth of rotaxanes encompassed is vast because the claim 1 “macrocycles” encompasses five structurally divergent macrocyclic genera as follows. Claim 1 . . . (i) a macrocycle selected from the group consisting of a cucurbituril, calixarene, pillararene, and metallo-organic macrocycle; or comprising aryl groups linked by C1-C4-alkylenes, C1-C4-ethers, C2-C4-alkenylenes and C2-C4-alkynylenes . . . The specification defines “cucurbituril” as follows: A cucurbituril is a macrocyclic molecule consisting of glycoluril monomers linked by methylene groups. Specification at page 22, lines 9-10. Glycoluril has the following structure: PNG media_image3.png 200 400 media_image3.png Greyscale . See specification Fig. 2. Here the specification definition does not permit the cucurbituril to comprise other structure or substituents. The specification defines “calixarene” according to the process by which it is made: A calixarene is defined herein as a macrocycle that is a hydroxyalkylation product of a phenol and an aldehyde (such as formaldehyde). The phenol and the aldehyde may be substituted, for example with C1-C4alkyl groups. Specification at page 22, lines 15-17. Thus, a calixarene can have widely divergent structures depending upon the phenol and aldehyde reactants, including potential substituents. The specification defines “metallo-organic macrocycle” as follows: A metallo-organic macrocycle comprises aryl groups linked by metal ions alone or in combination with other organic linkers. Specification at page 22, lines 18-19. Thus a “metallo-organic macrocycle” has no definite structure. The specification does not structurally define or limit the structural meaning of “pillararene”. Pillar[n]arenes are described in the art as pillar-shaped macrocyclic hosts composed of hydroquinone structural units connected by methylene group at the 2,5-position. See e.g., F. Guo et al., 30 Supramolecular Chemistry, 81-92 (2018). Thus, the claim 1 term “pillararene”, as a class, is broadly and reasonably interpreted as permitting substituents on the hydroquinone portion. MPEP § 2111. See Guo at pages 82-83. The last member of the claim 1 macrocycle genus is “a macrocycle comprising aryl groups linked by C1-C4-alkylenes, C1-C4-ethers, C2-C4-alkenylenes and C2-C4-alkynylenes”. The underlined term “comprising” is open-ended and does not exclude addition chemical structure. MPEP § 2111.03(I). Thus, the final macrocycle genus is structurally undefined, with the only requirement that is comprises linked aryl groups. The claim 1 macrocycle genera are large because they can vary in ring size as well comprise unnamed substituents as well as the fact that the nebulous genera of calixarene, metallo-organic macrocycle, and macrocycles comprising aryl groups linked by C1-C4-alkylenes, C1-C4-ethers, C2-C4-alkenylenes and C2-C4-alkynylenes, are structurally undefined. Still further, claim 1 encompasses a listing of alternative metals (i.e., Fe, Ni, Ru, Co, Cu, Ag, Cd, Zn, Rh, Mn, Ir, Os, Pd, and Pt), where the only metal demonstrated in the working examples is nickel. Also significant respecting claim breadth is that in formula (I), variable “Ar” and the blocking group are both generically defined (where the blocking group is functionally defined as “capable of trapping the macrocycle”) as: Claim 1 . . . each Ar is positioned at either end of the ion of formula [MzLz1]zn+ and is independently a C3-C9heteroaryl comprising at least one nitrogen atom and wherein each Ar is optionally substituted with one or more blocking groups capable of trapping the macrocycle. . . Here, the structurally identity of Ar within variable L is a key aspect regarding not only whether it correctly complexes with a particular metal to provide the claimed ion [MzLz1]zn+, but also whether the so formed [MzLz1]zn+ can then thread the macrocycle to form a pseudo rotaxane, and still further whether the Ar group (now within the pseudo rotaxane) if functionally capable of reacting with the correct blocking group so as to trap the [MzLz1]zn+ in the macrocycle. In this regard, the claim 1 blocking group is also structurally undefined. Guidance in the Specification and Working Examples Specification General Teachings The specification defines “treatment” as follows: The term "treatment" defines the therapeutic treatment of a human or non-human animal, in order to impede or reduce or halt the rate of the progress of the condition, or to ameliorate or cure the condition. Specification at page 10, lines 21-23. The specification teaches that the ability to deliver a non-active self-assembled metallo-supramolecular helicate [for example, the claimed rotaxane comprising the biological active metallic ion [MzLz1]zn+, where L is formula (I) bound to a nucleic acid] and turn it into an active self-assembled metallo-supramolecular helicate at a target site could be effective in controlling the specificity of the self-assembled metallosupramolecular helicate in the body. Specification at page 2, lines 4-7. The specification teaches that the biological activity of the ion of formula [MzLz1]zn+ is switched off when the ion is comprised within a rotaxane, where the biological activity may then be switched back on by removing blocking group(s) (one or both) from the rotaxane, allowing the ion to diffuse away from the macrocycle.. Specification at page 4, lines 5-8; Id. at page 16, lines 25-32; Id. at page 27, lines 10-15. The specification teaches that removal of the blocking groups within the rotaxane causes the biologically active metallic ion of formula [MzLz1]zn+ to diffuse away from the macrocycle (for example, at the therapeutically active site of the subject). Specification at page 4, lines 10-13; Id. at page 17-19. Thus, in practice of the claim 29-32 method of treatments, the blocking groups must be removed in situ (i.e., within the subject’s body) after administration: Blocking group(s) of the rotaxane, when used as a medicament (such as for the treatment of cancer, a viral disease and/or a bacterial disease) may be removed from the rotaxane in situ. Blocking group(s) may be removed in situ by any of the methods described in relation to the first aspect of the invention. For example, blocking group(s) may be removed by reacting the rotaxane with hydrogen or a thiol, photo-irradiating the rotaxane, contacting the rotaxane with an enzyme, reacting the rotaxane with a reducing agent or reacting the rotaxane with water. Specification at page 30, lines 19-25. In this regard, Figure 10 which is discussed at specification pages 51-52, shows: Figure 10 is (a) PAGE gel showing that the [Ni2L’3]4+ and [Ni2L"3]4+ complexes stabilise DNA 3WJ but the rotaxanated [Ni2L”3•CB10]4+ cylinder does not. (b) CD and (c) LD spectra of ct-DNA (100μM DNA concentration; 10 mM sodium chloride; 1 mM sodium cacodylate) with [Ni2L”3•CB10]4+ and (d) the corresponding CD and (e) LD spectra of ct-DNA with [Ni2L”3•CB10]4+. R values represent DNA base pairs/complex. Specification at page 6, lines 11-16. The art and the specification provide sufficient guidance for one of skill to conclude that the deblocked metal ion ligand of formula [MzLz1]zn+, itself (at least where Y is N), when unlocked from within the claimed rotaxane, has a mechanistic connection to the treatment of certain cancers, certain bacterial diseases, and certain viral diseases. MPEP § 217.03.1 Rotaxanes Synthesized in the Specification Working Examples In summary, the specification discloses the four following blocked rotaxane species (CB-10-[MzLz1]zn+), all with the same macrocycle curcubit[10]uril (CB-10): (1) CB10-[Ni2L"3][Cl]4: (specification at page 38, lines 35 et seq.) (2) [Fe2L”3-CB10][Cl]4:, (specification at page 39, lines 10 et seq.); (3) [Ni2Ldmnb3-CB10][Cl]4: (specification at page 41, lines 9 et seq.); (4) [Ni2Ldnb3-CB10][Cl]4: (specification at page 42, lines 30 et seq.) Where the ligands L”, Ldnb and Ldmnb have the structures below and where L and L’ (also shown below) are unblocked and therefore form pseudo rotaxanes, e.g., CB10-[Fe2L3][Cl]4; -[Ni2L3][Cl]4; and -[Ru2L3][Cl]4. Specification at page 37, lines 1-3. PNG media_image4.png 200 400 media_image4.png Greyscale The general structure of above four rotaxanes threaded with metal complexed ligands L is shown below with respect to the imidazole type ligands. PNG media_image5.png 200 400 media_image5.png Greyscale The working examples disclose only one species of “macrocycle” used to form rotaxanes (i.e., Cucurbit[10]uril, CAS RN 307001-50-9), which has the following structure. Specification at page 33, lines 11-17. PNG media_image6.png 200 400 media_image6.png Greyscale For the structure of Cucurbit[10]uril, see, S. Liu et al., 127 Journal of the American Chemical Society, 16798-16799 (2005) (“Liu”); specification Figure 2; see also, CAS Indexing of Compounds Disclosed in US 20230373962 (2023) (CAS RN 307001-50-9). Other than the four disclosed species, the specification provides no specific guidance or paradigm to predict other combinations of macrocycle/[MzLz1]zn+/blocking group that function to form other claimed rotaxanes or a precursor pseudo rotaxane that can subsequently be converted to the claimed rotaxane where “each end of the [([MzLz1]zn+] comprises at least one blocking group” Specification Cell Biology Studies with Non-Claimed Free cylinders (i.e., [M2L3]4+) or pseudo rotaxane cylinder-CB10 (i.e., [M2L3]4+-CB-10) The specification teaches that cell biology experiments were performed using A2780 and MDA-MB-231 cancer cell lines. Specification at page 44, lines 24-25. In an MTT cell survival assays. Specification at page 44, line 32 to page 45, line 10. The specification teaches that the non-rotaxane metal complex (the ligand in isolation) of [Ni2L'3]4+ has at 72 h an IC50 for MDA-MB-231 of 163 ±10 μM and an IC50 for A2780cis of 83±6 μM. Specification at page 45, lines 9-10. Referencing Figure 62, the specification teaches that with the unblocked non-claimed pseudo rotaxane [Ni2L3•CB10]4+ the cylinder parts from the CB-10 to preferentially bind to the anionic DNA 3WJ cavity. Specification at page 49, lines 8-20; Id. at pages 49, line 33 to page 50, line 3. The specification teaches cell uptake by ICP-MS: MDA-MB-231 cells (106 in 10 ml medium previously seeded overnight in T-75 flasks) were incubated with 50 μM of compound (complexes or complex-CB10 systems only containing Ru and Ni). Specification at page 45, lines 11-13. The specification teaches that consistent with the in vitro DNA binding, when we treat cells (A2780 ovarian and MDA-MB-231 breast cancer lines) with the pseudo rotaxane cylinder•CB[10] complex, we observe very similar inhibitions of cell proliferation (as assessed by an MTT cell survival assay) to those with the corresponding free cylinder (Figure 6). Specification at page 50, lines 4-10. De-capping the Claimed Rotaxanes with Thiol The specification teaches that the rotaxane [Ni2Ldmnb3-CB10][Cl]4 was treated with 10 mM mercaptoethanol in water and the solution to remove the blocking groups (decap) and generate the free cylinder. Specification at page 53, line 30 to page 54, line 5. The specification teaches that to confirm that the released cylinder is now able to bind DNA-junctions, we investigated the binding of the [Ni2Ldmnb3-CB10][Cl]4 rotaxane in absence and in presence of mercaptoethanol to DNA 3-way junctions (3WJ) using gel electrophoresis. Specification at page 54, lines 6-16. Figure 16 shows that the intact capped rotaxane [Ni2Ldmnb3-CB10][Cl]4 does not stabilize the 3WJ, but that when treated with decapping agent mercaptoethanol, the caps are released, the cylinder can leave the CB[10] cavity and bind to the DNA 3WJ as anticipated. Specification at page 54, lines 6-16. Per Figure 17: Figure 17 shows PAGE Gel electrophoresis of DNA 3-way junction (3WJ) binding following rotaxane decapping in water/buffer with 10mM of decaping agent. The gel shows that the rotaxanated [Ni2(Ldnb)3•CB10]4+ cylinder does not stabilise DNA 3WJ but once decapped, the cylinders can be released and their 3WJ binding is enabled. Upper band is 3WJ and the lower band the individual single strands. Specification at page 7, lines 15-20. State of the Prior Art/Level of Predictability in the Art Claim 1 is directed to a rotaxane. A “rotaxane” is a compound that consists of a linear species (sometimes called the rodlike part or guest) and cyclic species (sometimes called the beadlike part or host) bound together in a threaded structure by noncovalent forces. M. Xue, 115 Chemical Reviews, 7398-7501 (2015) (see page 7399, col. 1); specification at pages 1, lines13-25. A Pseudorotaxane does not comprise bulky stoppers at the end of the axle and a pseudorotaxane with only one stopper is called semirotaxane. Id. Rotaxanes can be represented, per Xue Figure 1, as follows: PNG media_image7.png 200 400 media_image7.png Greyscale Xue at page 7399, Figure 1; see also specification Figure 1. Waeles teaches that synthetic modification of rotaxanes is challenging and linked to the fact that the mechanical bond might greatly affect the reactivity of a functionality of the encircled axle, but that the interlocked architecture needs to be preserved during the synthesis and thus the mechanical bond plays a fundamental role in the strategy employed. P. Waeles et al., 60 Angewandte Chemie, International Edition, 16778-16799 (2021) (see Abstract); Waeles at page 16780, col. 1. Waeles teaches that often in rotaxanes, the encircling macrocycle acts as a non-covalent shielding protection that decreases the reactivity of the encircled thread. The post-synthetic modification of the encircled axles functional groups may then necessitate harsher experimental conditions and become a challenging task (i.e., the instantly claimed blocking group reaction). Waeles at page 16790, col. 2. Waeles teaches that to date, the interlocking reaction of components has mostly been realized at the final stage of the synthesis. Waeles at page 16796, col. 2. Waeles evidences the challenging nature of determining which macrocycles can first form the claim 1 pseudo rotaxane and thereafter be synthetically modified in a blocking-group reaction so as to result in the claimed rotaxane. While significant research has been conducted in the art of rotaxanes, and numerous synthetic methods exist, still, one of ordinary skill must be aware of size constraints as well as intermolecular forces between the host and guest, such as hydrophilic and hydrophobic forces. H. Dardeer et al., 7 International Journal of Chemistry, 161-167 (2015) (“Dardeer”) (see page 161). The forces that affect the threading, pseudorotaxanes and rotaxanes can be classified to seven types: statistical threading, chemical conversion, hydrogen bonding, hydrophilic-hydrophobic interaction, metal-ligand complexation, π-π stacking and charge transfer. Dardeer at page 160, lines 1-5. Generally, the threading of a linear component through the macrocycle is formed thermodynamically by noncovalent bonding interactions to produce the most stable species in solution. Dardeer at page 160, lines 1-5. Thus respecting the claim 1 limitation that “each end of the ion comprises at least one blocking group”, selecting the blocking group so as to mechanically trap the macrocycle and [MzLz1]zn+ in the rotaxane configuration involves more than a simple steric/size relationship. Rather it involves an unpredictable consideration of a multitude of factors, including hydrogen bonding, hydrophilic-hydrophobic interaction, metal-ligand complexation, π-π stacking and charge transfer. In summary of above, the art rotaxanes is unpredictable. The Quantity of Experimentation Needed Is Undue In the current case, claims 29-32 are properly rejected under 35 U.S.C. § 112(a), for lack of enablement because upon balancing the above-discussed factors, the specification at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full claim scope of Per claims 29 and 31 treat any disease/condition comprising administering a therapeutically effective amount of a rotaxane of claim 1 Per claims 30 and 32 treat the full scope of viral disease and/or a bacterial disease comprising administering a therapeutically effective amount of a rotaxane of claim 1 in any subject without undue experimentation. The primary consideration is that in order to treat the claimed disease/condition one of skill must obtain a claimed rotaxane that releases the ion of formula [MzLz1]zn+ (which is the active agent), at the active site within the subject (in situ). This requires selection of the correct blocking group/macrocycle combination. In view of the breadth of macrocycles claimed and the art-recognized unpredictability regarding size constraints as well as intermolecular forces between the rotaxane host and guest, experimentation is undue. See discussion above regarding H. Dardeer et al., 7 International Journal of Chemistry, 161-167 (2015) (“Dardeer”) (see page 161). The forces that affect the threading, pseudorotaxanes and rotaxanes can be classified to seven types: statistical threading, chemical conversion, hydrogen bonding, hydrophilic-hydrophobic interaction, metal-ligand complexation, π-π stacking and charge transfer. Dardeer at page 160, lines 1-5. The specification gives only one in vitro example of rotaxane de-threading to release the therapeutically active ion [Ni2Ldmnb3] from CB10 in the rotaxane [Ni2Ldmnb3-CB10][Cl]4 in presence of mercaptoethanol whereupon the ion binds to the DNA 3-way junctions (3WJ). Specification at page 54, lines 6-16. No art of record supplements the specification regarding in-situ release of the claimed ion of formula [MzLz1]zn+ from a macrocycle in a rotaxane. MPEP § 2164.03 (citing Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) “[n]ascent technology, however, must be enabled with a ‘specific and useful teaching.’ The law requires an enabling disclosure for nascent technology because a person of ordinary skill in the art has little or no knowledge independent from the patentee’s instruction”). In the absence of such art, one of skill using the instant specification as a map has no guidance regarding correct macrocycle/[MzLz1]zn+ combinations (other than the species disclosed), that function within subject, to release the ion of formula [MzLz1]zn+ from the macrocycle so as to treat the disease/condition suffered by the subject. In view of the claim breadth and unpredictability, a prima facie case of undue experimentation is made. A secondary contribution to undue experimentation is that the rotaxanes must be synthesized in the first place. This contributes greatly to the amount of experimentation, in view of the unpredictability in rotaxane synthesis and claim breadth. The holding in Idenix Pharms. LLC v. Gilead Scis. Inc., 941 F.3d 1149, 1163 (Fed. Cir. 2019) is also relevant to the facts at issue. In idenx, the court found that in order to know whether or not they are effective against HCV. Moreover, a significant number of candidate 2'-methyl-up nucleosides would need to be synthesized before they could be screened, which increases at least the quantity of experimentation required, even if the synthesis was routine. Idenix Pharms., 941 F.3d 1163 (Fed. Cir. 2019). However, here rotaxane synthesis is not routine. Withdrawal Claim Rejections 35 U.S.C. 112(a) – Written Description Rejection of claims 1-6, 8, 10, 11, 13, 14, and 26 under 35 U.S.C. 112(a) as failing to comply with the written description requirement is withdrawn in view of Applicant’s amendment. Claim 1 is amended such that “macrocycles” is limited to five chemical structure genera as follows. Claim 1 . . . (i) a macrocycle selected from the group consisting of a cucurbituril, calixarene, pillararene, and metallo-organic macrocycle; or comprising aryl groups linked by C1-C4-alkylenes, C1-C4-ethers, C2-C4-alkenylenes and C2-C4-alkynylenes . . . “cucurbituril” The specification defines “cucurbituril” as follows: A cucurbituril is a macrocyclic molecule consisting of glycoluril monomers linked by methylene groups. Specification at page 22, lines 9-10. Glycoluril has the following structure: PNG media_image3.png 200 400 media_image3.png Greyscale . See specification Fig. 2. Here the specification definition does not permit the cucurbituril to comprise other structure or substituents. “calixarene” The specification defines “calixarene” according to the process by which it is made: A calixarene is defined herein as a macrocycle that is a hydroxyalkylation product of a phenol and an aldehyde (such as formaldehyde). The phenol and the aldehyde may be substituted, for example with C1-C4alkyl groups. Specification at page 22, lines 15-17. In the art, calixarenes are known as macrocycles consisting of phenolic units linked by methylene bridges, forming a bowl-shaped structure. A. Dondoni et al., 110 Chemical Reviews, 4949-4977; C. Wieser et al., 165 Coordination Chemistry Reviews, 93-161 (1997). “metallo-organic macrocycle” The specification defines “metallo-organic macrocycle” as follows: A metallo-organic macrocycle comprises aryl groups linked by metal ions alone or in combination with other organic linkers. For more information on metallo-organic macrocycles see: M. J. Prakash and M. S. Lah in Chem. Commun., 2009, 3326-3341 DOI: 10.1039/b902988e; Leininger, S.; Olenyuk B.; Stang, P. J. in Chem. Rev. 2000, 100,853 doi.org/10.1021/cr9601324; M. Fujita in Chem. Soc. Rev., 1998, 27, 417-425 DOI: 10.1039/A827417Z; P.J. Altmann and A. Pothig in J. Am. Chem. Soc. 2016, 138, 40, 13171-13174; Frischmann, P. D.; Maclachlan, M. J. in Chem. Soc. Rev. 2013, 42, 871. Specification at page 22, lines 18-25. The meaning of “metallo-organic macrocycle” is clear. The specification does not structurally define or limit the structural meaning of “pillararene”. Pillar[n]arenes are described in the art as pillar-shaped macrocyclic hosts composed of hydroquinone structural units connected by methylene group at the 2,5-position. See e.g., F. Guo et al., 30 Supramolecular Chemistry, 81-92 (2018). “macrocycle . . . comprising aryl groups linked by C1-C4-alkylenes, C1-C4-ethers, C2-C4-alkenylenes and C2-C4-alkynylenes” The last member of the claim 1 macrocycle genus is “a macrocycle . . . comprising aryl groups linked by C1-C4-alkylenes, C1-C4-ethers, C2-C4-alkenylenes and C2-C4-alkynylenes”. The structural meaning is clear. Reason for Rejection Withdrawal The claim 1 “rotaxane”, comprises a “macrocycle” and an “ion of formula [MzLz1]zn+” that structurally functions with a “blocking group” (i.e., macrocycle/[MzLz1]zn+/blocking group combinations) to form the claimed rotaxane, per claim 1: claim 1 . . . comprising (i) a macrocycle selected from the group consisting of a cucurbituril, calixarene, pillararene, and metallo-organic macrocycle; or comprising aryl groups linked by C1-C4-alkylenes, C1-C4-ethers, C2-C4-alkenylenes and C2-C4-alkynylenes and (ii) an ion of formula [MzLz1]zn+, wherein each M is a metal ion of oxidation state n+, each independently selected from the group consisting of Fe, Ni, Ru, Co, Cu, Ag, Cd, Zn, Rh, Mn, Ir, Os, Pd, and Pt . . . L is a ligand of formula (I): PNG media_image1.png 200 400 media_image1.png Greyscale . . . each Ar is positioned at either end of the ion of formula [MzLz1]zn+ and is independently a C3-C9heteroaryl comprising at least one nitrogen atom and wherein each Ar is optionally substituted with one or more blocking groups capable of trapping the macrocycle with the proviso that at least two Ar are substituted with one or more blocking groups such that each end of the ion comprises at least one blocking group. . . The chemical structure is fully set forth except that the structure of the blocking group is functionally defined as a group that functions to trap the ion of formula [MzLz1]zn+ within the macrocycle. With respect to claim 1 as amended, Applicant persuasively argues that the skilled person is able to assess which blocking groups are capable of trapping the macrocycle based on the teachings of the specification. Reply at page 11; (citing specification at page 12, lines 15 et seq.). The specification teaches that the ion of formula [MzLz1]zn+ may be surrounded with a macrocycle, which macrocycle may be trapped around the ion by blocking groups bound to the ion, resulting in the formation of a rotaxane”. Specification at page 2, lines 20-23. The specification further teaches that: The rotaxanes disclosed herein comprise blocking groups (at least one blocking group at each end of the ion of formula [MzLz1]zn+ capable of trapping the macrocycle (by which is meant that the movement of the macrocycle past the blocking group(s) is hindered, and the macrocycle is thus kinetically locked in place). Specification at page 11, lines 27-30. The specification further teaches that: The distance by which the blocking group must extend thus depends on the size of the internal diameter of the macrocycle used. For example, the internal diameter of cucurbit[8]uril is about 0.88 nm, thus blocking groups capable of trapping cucurbit[8]uril extend at least about 0.44 nm (measured relative to the centre of the macrocycle). The internal diameter of cucurbit[1 0]uril is 1.13-1.24 nm. Thus, blocking groups capable of trapping cucurbit[10]uril extend at least 0.57-0.62 nm (measured relative to the centre of the macrocycle). Specification at page 12, lines 15-21 (emphasis added). Most significantly, the specification teaches the claimed rotaxanes are prepared by first threading compound [MzLz1]zn+ (having unblocked ligands L and L’) into the macrocycle cavity to form the the claimed rotaxane or a an unclaimed precursor pseudo rotaxanes that can be converted to the claimed rotaxane via a blocking group reaction. Specification at page 24, lines 12-25. The Examiner represents this concept schematically as follows with respect to disclosed ligand L'[Symbol font/0xAE] L” (where L and L” are disclosed species, see Figure 2), nickel ion and a generic macrocycle: PNG media_image8.png 200 400 media_image8.png Greyscale Thus, in order to arrive at the claimed rotaxanes, one of skill must understand the structure-function relationship between unblocked [MzLz1]zn+ and the particular macrocycle, such that the they mechanically function/interact to form the claimed rotaxane or a pseudo rotaxane that can be converted into a claimed rotaxane via a blocking-group reaction. Here, Applicant is in possession of the claimed genus of rotaxane because one of skill would recognize that the claimed genera of macrocycle and ion of formula [MzLz1]zn+ are sufficient structurally defined such that there is a written description of the claimed genus of rotaxane. MPEP § 2163(I). APPLICANT’S ADDITIONAL ARGUMENT Argument in the Reply (i) Applicant Argument Applicant argues that density functional theory and molecular dynamics simulations disclosed on pages 46 and 47 of the application, where simulations show that curcubituril [10] is a suitable macrocycle to use together with [Ni2L"3]4+ to form a rotaxane, in line with experimental observations. Reply at pages 11-12. Applicant argues that such simulations may be employed by one of ordinary skill in the art to determine which macrocycles and which sizes of macrocycle are suitable to be used with specific ions comprising specific blocking groups to synthesize the claimed rotaxanes. Reply at page 12. As cited by Applicant, the specification teaches that Density Functional Theory optimization was carried out at the SSBD-D3/LANL2-DZ and SSBD-D3/DEF2-SVP, with the corresponding ECP basis for the metal, using NwChem 6.8.1 software on Bluebear HPC cores, and additional software and parameters. Specification at page 47, lines 1-6. The specification teaches that to evaluate the energy penalty of CB10 deformation, DFT optimisation as described above on the CB10 and the deformed CB10 under the same parameters were performed to calculate CB[10 DFT energy and deformed energy, and their difference. Specification at page 47, lines 10-14. The specification then goes on to conduct physical experiments verifying that CB[10] is suitable macrocycle for particular species of ligands. Specification at pages 48-50. (ii) Examiner Response This argument is given some weight. However, the main reason for rejection withdrawal is that Applicant is in possession of the claimed genus of rotaxane because one of skill would recognize that the claimed genera of macrocycle and ion of formula [MzLz1]zn+ are sufficiently structurally defined such that there is a written description of the claimed genus of rotaxane. MPEP § 2163(I). (iii) Applicant Argument -- Macrocycle Applicant argues that given that the purpose of the macrocycle is simply to encircle the ion, any macrocycle containing a central cavity that is capable of encapsulating organic containing molecules in its cavity would be expected to function in the same way as the exemplified cucurbituril. Reply at page 13. Thus, one of ordinary skill in the art would have no reason to suspect that the macrocycles specified in the claims would not function in the same way as the cucurbituril exemplified in the application. Therefore, the scope of the macrocycle defined in the claims is commensurate with the exemplified rotaxanes. Id. (iv) Examiner Response This argument is persuasive to the extent that Applicant has amended the genus of “macrocycle”. (v) Applicant Argument -- Ar Group Applicant argues that claim 1 defines Ar as: Claim 1 . . . wherein each Ar is optionally substituted with one or more substituents selected from the group consisting of hydroxy, C1-C4alkylol, carboxy, C1-C4alkanoate, C1-C4alkyl, C1-C4alkoxy, halo, cyano, nitrite, C1-C4haloalkyl, C1-C4alkylthio, C1-C4alkyleneC1-C4alkylthio, C1-C4alkylsulfonate, diC1-C4alkylamino and C1-C4alkynyl . . . and, per claim 1, claim 1 . . . each Ar is positioned at either end of the ion of formula [MzLz1]zn+ and is independently a C3-C9heteroaryl comprising at least one nitrogen atom, and wherein each Ar is optionally substituted with one or more blocking groups capable of trapping the macrocycle, with the proviso that at least two Ar are substituted with one or more blocking groups such that each end of the ion comprises at least one blocking group . . . Reply at pages 13-14. Applicant argues that two Ar groups are disclosed in the specification, i.e., imidazole and pyridine, each having a free nitrogen to bond to the metal and another atom to react with a blocking group. Id. Applicant argues that Thus, the inventors have shown that both C3 and C5 heteroaryls comprising a nitrogen atom, effectively bind to M to form an ion that can be threaded through a macrocycle. Reply at page 14. Applicant argues that support for the suitability of larger heteroaryls as Ar groups is provided by Zhou and Sun, in Chem. Commun. (2015) 51 (94): 16767-16770 (“Zhou”).3 Applicant argues that Zhou teaches benzimidazole groups bind act analogously to the Ar groups of the ligands of formula (I) defined in the claims and are shown to effectively bind to palladium ions to form M2L4 cages, where M is the palladium ion and L is the ligand comprising the benzimidazole. Reply at page 14. Applicant concludes that provided the heteroaryl comprises a heteroatom, such as a nitrogen atom, that is capable of binding to a metal ion, it would be expected to function in the same way as the exemplified Ar groups. Reply at page 14. (vi) Examiner Response This argument is given weight to the extent that the specification demonstrates two Ar groups, i.e., imidazole and pyridine, each having a free nitrogen to bond to the metal and another atom to react with a blocking group, function with the macrocycle CB[10] to form a rotaxane. Note that Zhou and Sun, in Chem. Commun. (2015) 51 (94): 16767-16770 (“Zhou”), cited by Applicant, teaches that A M2L4 cage with D4 symmetry was self-assembled from four anthracene-bridged benzimidazole ligands and two PdII ions. Zhou at page 16768 (Fig. 1, compound 2). Zhou’s cage formation does not appear to be related, in any way, to the claimed rotaxanes. However, the main reason for rejection withdrawal is that Applicant is in possession of the claimed genus of rotaxane because one of skill would recognize that the claimed genera of macrocycle and ion of formula [MzLz1]zn+ are sufficiently structurally defined such that there is a written description of the claimed genus of rotaxane. MPEP § 2163(I). (vii) Applicant Argument – Blocking Group Applicant argue that to assess whether blocking groups prevent de-threading of the macrocycle from the rotaxane, one of ordinary skill in the art could have employed computational simulations, such as steered Molecular Dynamics computational simulations, e.g. those described by Suan and Khanh in Curr. Bioinform., 2012, 7, 342-351, enclosed in Appendix A. Reply at page 15. (viii) Examiner Response This argument is addressed below in the analysis of the Declaration of Dr. Michael Hannon Under 37 C.F.R. § 1.132. (ix) Applicant Argument – Metal Ions Applicant argues that the ligand L, with the structure set out below, is known to form [M2L3]4+ complexes with Fe(II), Ru(II), Zn(II), Ni(II), Co(II) and Cu(II) and ligand L" complexes with Mn(II), Co(II), Ni(II), and Fe(II), each with the same 3D structure that is very similar to that of the [M2L3]4+. Reply at pages 16-17. PNG media_image9.png 200 400 media_image9.png Greyscale Applicant argues that support for the suitability of Pd metal ions is provided by Zhou and Sun, in Chem. Commun. (2015) 51 (94): 16767-16770 (supra). In this paper, ligands that act analogously to the ligands of formula (I) defined in the claims, are shown to effectively bind to palladium ions to form M2L4 cages, where M is the palladium ion and Lis the ligand comprising the benzimidazole. Applicant argues that in view of the large number of metal ions shown in the application as filed and the literature to successfully form [MzLz1]zn+ ions with ligands of or similar to the type claimed, one of skill in the art would have no reason to suspect that the metal ions defined in the claims would not function in the same way as the Ni, Fe and Ru ions exemplified in the application. Reply at page 17. Applicant concludes, therefore, the scope of the metal ions defined in the claims is commensurate with the exemplified rotaxanes. Id. (x) Examiner Response Applicant’s above points are noted. However, the main reason for rejection withdrawal is that Applicant is in possession of the claimed genus of rotaxane because one of skill would recognize that the claimed genera of macrocycle and ion of formula [MzLz1]zn+ are sufficiently structurally defined such that there is a written description of the claimed genus of rotaxane. MPEP § 2163(I). Declaration of Dr. Michael Hannon UNDER 37 C.F.R. § 1.132 Applicant submits the Declaration of Dr. Michael Hannon UNDER 37 C.F.R. § 1.132 (July 18, 2026) (the “Hannon Declaration”). As discussed in more detail below, the Hannon Declaration is not given weight regarding rejection withdrawal. The rejection is withdrawn the reasons given above. (i) Proffered Compounds The Hannon Declaration avers additional support for the claimed rotaxanes, and specifically for the Ar variable, additional rotaxanes of the type [Ni2L3(CB-10)]4+ have been prepared where L is La, Lb or Lc from the diagram and CB-10 is curcubit[10]uril. Hannon Declaration at ¶ 4. The Hannon Declaration proffers the synthesis of rotaxanes [Ni2La3(CB-10)]4+, [Ni2Lb3(CB-10)]4+, and [Ni2Lc3(CB-10)]4+. Hannon Declaration at pages 1-5, ¶ 4. These rotaxanes have the following structures PNG media_image10.png 200 400 media_image10.png Greyscale [Ni2La3(CB-10)]4+: R1 is NO2, R3 is NO2, R2, R4, and R5 are H; [Ni2Lb3(CB-10)]4+: R1 is NO2, R2 - R5 are H; [Ni2Lc3(CB-10)]4+: R2 is NO2, R1 and R3 - R5 are H; [Ni2Ld3•CB10]Cl4: R1 is H, R2 and R3 are methoxy, R4 is H, R5 is NO2. The Hannon Declaration further proffers the synthesis of rotaxane [Ni2(Le)3•CB10]Cl4. Hannon Declaration at pages 5-6, ¶ 4. Rotaxane [Ni2(Le)3•CB10]Cl4 has the following structure. PNG media_image11.png 200 400 media_image11.png Greyscale [Ni2La3(CB-10)]4+ is the same rotaxane disclosed in the specification at page 42 “Synthesis of DNB capped rotaxane [Ni2(Ldnb)3 • CB10]Cl4”. [Ni2Ld3•CB10]Cl4 is the same rotaxane disclosed in the specification at page 41, “Synthesis of DMNB capped Ni rotaxane [Ni2Ldmnb3•CB10][Cl]4”. But each of of [Ni2Lb3(CB-10)]4+; [Ni2Lc3(CB-10)]4+, and [Ni2(Le)3•CB10]Cl4 appear to be post-filing date evidence. (ii) Steered molecular dynamics simulations The Hannon Declaration avers that the steered molecular dynamics simulations (SMD) described by Mai Suan Li et al, 7 Current Bioinformatics, 342-351 (2012) (“Suan and Khanh”) were used to simulate pulling the ion or thread away from the macrocycle in compounds of type [Ni2La3(CB-10)]4+, in which the imidazole Ar group contained varying numbers of the dinitrobenzene blocking groups. The relative forces required to remove the ions from the CB-10 macrocycles were compared. Hannon Declaration at pages 7-8.4 The Hannon Declaration mathematical experiments appear to apply the concept/equations of Susan Khanh to estimate the force required to remove the ligand from the Cucurbit[10]uril in the proffered compounds. In this regard, the Hannon Declaration avers that in the simulations were performed by applying a pulling rate of 0.01 nm per ps between the centres of mass of the CB10 macrocycle and the ion with a spring force constant of 1000 kJ mo1-1 nm-1. Hannon Declaration at page 7. The Hannon Declaration determined that with 3 blocking groups at each ligand end, a very large forces and major deformations were required to remove the ion, while two blocking groups at each end also required strong forces to remove the ion, but decreasing forces were required in the presence of one to zero blocking groups at each end. Hannon Declaration at page 7, referencing the Figure. (iii) Summary of Proffered Results The Hannon Declaration summarizes that rotaxanes with various Ar groups were prepared, specifically with groups such as pyridine, which comprises a single free nitrogen. Hannon Declaration at ¶ 5. The Hannon Declaration avers that pyridine Ar groups are suitable for rotaxanes and that both C3 and C5 heteroaryls comprising a nitrogen atom effectively bind to M to form an ion that can be threaded through a macrocycle and are able to trap the macrocycle and form rotaxanes. Hannon Declaration at ¶ 5. (iv) The Proffered Results Are Not Persuasive The proffered results are not persuasive because the § 112(a) analysis is conducted based one the knowledge of one of skill as of the filing date. MPEP § 2163 (II)(3)(a)(ii) (such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date”, citing AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)). The specification provides no disclosure regarding Mai Suan Li et al, 7 Current Bioinformatics, 342-351 (2012) (“Suan and Khanh”) or steered molecular dynamics simulations (SMD), let alone that SMD can be applied to predict the force required to remove a rotaxane ligand from its macrocycle. And Applicant has not cited any evidence that, as of the effective filing date, one of skill would be know that the SMD could be so applied. Subject matter free of the Art of Record Subject to the § 112(a) rejection, claims 1-6, 8, 10, 11, 13, 14, 16, 17, 20, 22-23, 26, 29-32 are free of the art of record. The closest art of record is H. Qin et al, 139 Journal of the American Chemical Society, 16201-16209 (2017) (“Qin”). Qin discloses the following ion-ligand species [Ni2L3]4+ as a mixture of enantiomers Ni-M and Ni-P PNG media_image12.png 200 400 media_image12.png Greyscale which is a complex comprising the following ligand (termed “L” by Qin): PNG media_image13.png 200 400 media_image13.png Greyscale and which arguably, in view of the claim 1 functionally language defining “blocking group, falls within the claim 1 genus of an ion of formula [MzLz]zn+. See Qin at page 16202, Fig. 1(B); see also pages S2-S3 (“Preparation of chiral metallo-supramolecular complexes”). Qin discloses that the enantiomer [Ni2L3]4+-P, as a telomeric G-quadruplex-targeting ligand, can preferentially reduce cell growth in breast CSCs compared to the bulk cancer cells. Qin at Abstract. Differences between Qin and Claim 1 Assuming Qin meets the blocking group limitation of claim 1, Qin’s differs from claim 1 because this reference does not teach or suggest threading [Ni2L3]4+ into a macrocycle to form a claimed rotaxane. M. Sojka et al., 58 Inorganic Chemistry, 10861-10870 (2019) (“Sojka”) Sojka teaches coupling of Ru(II) units with cucurbit[6/7]uril-based pseudorotaxane ligands to obtain rotaxanes RuC-1@CB6 and RuC-1@CB7. Sojka at page 10862, col. 2 (see Figure 2). PNG media_image14.png 200 400 media_image14.png Greyscale Sojka at page 10862, col. 2 (see Figure 2). Sojka teaches that cucurbiturils have been reported as carriers enhancing the water solubility and transport of guest molecules across the cell membrane while simultaneously protecting them from degradation in biological environments. Sojka at page 10861, col. 2. Sojka teaches that RuC-1@CB6 and RuC-1@CB7 are active against breast cancer cell lines. Sojka at page 10864, col. 1, Table 1. Sojka teaches the concept of incorporating ruthenium ion complexes within cucurbituril macrocycles to arrive at potential chemotherapeutic rotaxanes. The Claims Art not Obvious over Qin Claim 1 and its dependent claims 2-6, 8, 10, 11, 13, 14, 16, 17, 20, 22-23, 26, 29-32 are not obvious over Qin because one of ordinary skill is not motivated to apply Sojka’s concept by threading Qin’s chemotherapeutically active [Ni2L3]4+ into a macrocycle (for example into a cucurbituril as taught by Sojka) so as to arrive at the instantly claimed rotaxanes of claim 1. One of ordinary skill does not have reasonable expectation of success in forming the rotaxane. MPEP § 2143.02(I). Here, as discussed above, the art of rotaxane formation is unpredictable. Significantly, no secondary art of record even teaches how to insert Qin’s [Ni2L3]4+ into a macrocycle, let alone Applicant’s procedure of first threading the smaller, unblocked ion into the macrocycle to form a pseudo rotaxane followed by capping with a blocking group to lock the so formed [Ni2L3]4+ into a rotaxane structure. In this regard, Applicant teaches that that trapping the ion [MzLz1]zn+ in the rotaxane configuration switches off the ion’s biological activity and that biological activity may then be switched back on by removing the blocking group from the rotaxane allowing the ion to de-thread (diffuse away from the macrocycle). Specification at page 2, lines 24-28. Claim 17 necessarily produce the rotaxanes of claim 1 by contacting a macrocycle (where “macrocycle” is defined in claim 17 the same as in claim 1) with an ion [MzLz1]zn+ (“as defined in claim 1”, but with the proviso that each Ar is not substituted with one or more blocking groups capable of trapping the macrocycle). Claims 17 and 20 are therefore free of the art for the same reasons as the rotaxane of claim 1. Claim 20 is free of the art of record for the same reasons as claim 17. Claims 22, 23 and 29-32 are free of the art of record because they include, as a claim element, the novel, non-obvious rotaxane of claim 1. Conclusion 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. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDER R PAGANO whose telephone number is (571)270-3764. The examiner can normally be reached 8:00 AM through 5:00 PM. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Goon can be reached at 571-270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. ALEXANDER R. PAGANO Examiner Art Unit 1692 /ALEXANDER R PAGANO/Primary Examiner, Art Unit 1692 1 The specification teaches that nucleic acid junction structures are targets found both in biology and nucleic acid nanoscience. Junction-binding self-assembled metallo-supramolecular helicates arrest the proliferation of cancer cells, bacteria and viruses. The specification teaches that as described above, ions of formula [MzLz1]zn+ have been shown to bind to the heart of DNA and RNA 3-way junction structures, and other junctions and bulges, and arrest the proliferation of cancer cells and microbes including the HIV virus and coronavirus. Specification at page 30, lines 10-18 (citing L. Cardi et al, 8 Scientific Reports, 1-7 (2018) (teaching that metal (Fe, Ni, Ru) complex of bis-pyridylimine ligand L binds to TAR bulge motif of HIV-1 and inhibit the formation of TAR-TAT complexes, where the TAT-TAR complex provides an interesting target for anti-retroviral therapy); A. Richards et al., 33 International Journal of Antimicrobial Agents, 469-472 (2009) (teaching that synthetic metallomolecules [Fe2L3]4+ and [Cu2(L’)2]2+, where L is a bis-pyridylimine ligand, is bactericidal for Bacillus subtilis and Escherichia coli); (grafting arginine residues onto the cylinder of Fe2(L2)3]10+ and [Fe2(L3)3]10+, where L is a bis-pyridylimine ligand, dramatically affects the cylinder core and significantly enhances the DNA binding and activity); A. Holtz et al., 15 Chemistry & Biology, 1258-1267 (2008) (at page 1259 teaching that the supramolecular cylinder [Fe2L3]Cl4, where L is a bis-pyridylimine ligand, is a potent inhibitor of cellular proliferation in a panel of tumor cells); and H. Qin et al, 139 Journal of the American Chemical Society, 16201-16209 (2017) (“Qin”) (teaching that [Ni2L3]4+, where L is a bis-pyridylimine ligand, can repress cancer stem cell properties and induce apoptosis in breast cancer stem cells)). 2 Figure 6 is (a) PAGE gel showing that the [Ni2L3•CB10]4+ complex stabilises DNA 3WJ in the same way as [M2L3]4+ cylinders alone. (b) CD and (c) LD spectra of ct-DNA (100μM DNA concentration; 10 mM sodium chloride; 1 mM sodium cacodylate) with [Ni2L3•CB10]4+. R values represent DNA base pairs/complex. Specification at page 5, lines 24-27. 3 The asserted reference, Zhou and Sun, in Chem. Commun. (2015) 51 (94): 16767-16770, is not present in Appendix A nor submitted by Applicant in an Information Disclosure Statement. 4 Mai Suan Li et al, 7 Current Bioinformatics, 342-351 (2012) (“Suan and Khanh”) teaches that steered molecular dynamics (SMD) may be used in predicting ligand binding affinity to a surface. Suan and Khanh at Abstract. Suan and Khanh teaches that the breaking of hydrogen bonds (HB) requires a force around [Symbol font/0x65]H/[Symbol font/0x61] and assuming the hydrogen bond energy [Symbol font/0x65]H [Symbol font/0xBB] 1 kcal/mol and typical distance between two atoms [Symbol font/0x61] [Symbol font/0xBB] 0.4 nm one needs force f around 10 pN or a pulling rate v around 100 nm/s to break a hydrogen bond within one tenth of second using cantilever with k = 10 pN/nm. Suan and Khanh at page 343, col. 1. Suan and Khanh Schematic plot for pulling ligand from a receptor by applying the force F via the cantilever with the spring constant k. Suan and Khanh at page 344, Fig. 1.