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. Claims 17, 20, 22, 23, 24 and 29-32 to non-elected Groups (II)-(V) are withdrawn from consideration. Claims 1-6, 8, 10, 11, 13, 14, 16, and 26 are under examination on the merits and are rejected.
Election/Restrictions
Applicant elects Group (1), 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 Claims 17, 20, 22, 23, 24 and 29-32 to non-elected Groups (II)-(V) are withdrawn from consideration pursuant to 37 CFR 1.142(b). The restriction/election requirement is made FINAL.
Applicant’s Traversal
Applicant argues that Groups I-V are unified by way of the blocking groups present in the [MzLz1]zn+ ions in each. This argument is not persuasive because Qin discloses the following ion-ligand complex NiM-3:
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Qin at page S15. Where in the above complex, Qin’s ligand L (which corresponds to claim 1 formula N-Y-N) is:
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Qin at page 16202, Fig. 1; see also pages S2-S3 (“Preparation of chiral metallo-supramolecular complexes”).
Qin’s complex meets the limitations of withdrawn claim 24 because Qin forms a complex with a macrocycle and therefore (per claim 24) capable of reversibly trapping the macrocycle. Qin at page 16202, Fig. 1.
Applicant further argues that it is a requirement of claim 1 that each Ar positioned at either end of the ion of formula [MzLz1]zn+ is optionally substituted with one or more blocking groups capable of trapping the macrocycle, with the proviso that each end of the ion comprises at least one blocking group, which distinguishes the claimed ion of formula [MzLz1]zn+ over Qin.
This argument is not found persuasive since Qin’s NiM-3 in fact traps the macrocycle, it necessarily comprises the claimed blocking groups “wherein the blocking groups are capable of reversibly trapping a macrocycle.” Note that claim 1 does not require that the blocking group is a substituent of group Ar.
In any case, the Groups (I)-(V) lack unity of invention because, as stated in the Restriction mailed on Nov. 3, 2025, the alternatives encompassed by the claim 1 Markush grouping of “a rotaxane comprising a macrocycle and an ion of formula [MzLz]zn+” do not share a common chemical structure which occupies a large portion of their structures. Here, claim 1 is directed to any macrocycle and any metal.
Where a single claim defines alternatives of a Markush group, the requirement of a technical interrelationship and the same or corresponding special technical features as defined in Rule 13.2, is considered met when the alternatives are of a similar nature. When the Markush grouping is for alternatives of chemical compounds, the alternatives are regarded as being of a similar nature where the following criteria are fulfilled:
(A) all alternatives have a common property or activity; AND
(B)(1) a common structure is present, that is, a significant structural element is shared by all of the alternatives; OR
(B)(2) in cases where the common structure cannot be the unifying criteria, all alternatives belong to a recognized class of chemical compounds in the art to which the invention pertains.
See, MPEP § 1850(III)(B); PCT INTERNATIONAL SEARCH AND PRELIMINARY EXAMINATION GUIDELINES, Chapter 10, Unity of Invention, 1 (Jul. 1, 2020) (See pages 79-80, 10.17, “Markush Practice”; see also, Examples 23 and 24, pages 85-87); MPEP § 1893.03(d).
The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity. Id.
SUMMARY OF REQUIREMENTS FOR PATENT APPLICATIONS FILED ON OR AFTER JULY 1, 2022, THAT HAVE SEQUENCE DISCLOSURES
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835.
This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.831-1.834 because it does not contain a “Sequence Listing XML” as a separate part of the disclosure. A “Sequence Listing XML” is required because the specification teaches the following three oligonucleotide sequences with10 or more specifically defined and enumerated residues
Gel electrophoresis studies were performed using following oligonucleotide sequences (from Eurofins Germany): 5'-CGGAACGGCACTCG-3' (S1), 5'CGAGTGCAGCGTGG-3' (S2), 5'-CCACGCTCGTTCCG-3' (S3).
Specification at page 43, lines 31-33. Therefore, Applicant must conform to CFR §§1.821 1.825 (see MPEP §2412).
Required response - Applicant must provide:
• A “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2.; together with
o A statement that indicates the basis for the amendment, with specific references to particular parts of the application as originally filed, as required by 37 CFR 1.835(a)(3);
o A statement that the “Sequence Listing XML” includes no new matter as required by 37 CFR 1.835(a)(4)
AND
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(a)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
o A statement that the substitute specification contains no new matter.
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
The Rotaxane of Claim 1
Claim 1 is directed to a rotaxane comprising a macrocycle and an ion of formula [MzLz1]zn+.
Rotaxanes
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:
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Xue at page 7399, Figure 1; see also specification Figure 1.
The Primary Claim 1 Structural Elements
The primary claim 1 structural elements are recited as follows:
1. A rotaxane comprising a macrocycle and an ion of formula [MzLz1]zn+, wherein
M is a metal ion or combination of ions of oxidation state n+,
z is 2 to 4,
z1 is 2 to 6 and
L is a ligand of formula (I):
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. . .
Structural interpretation of the claimed rotaxane is easier understood with reference to the disclosed species as discussed below.
The claim 1 “macrocycle”
Significantly, the “macrocycle” is structurally undefined within claim 1. 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.
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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).
Claim 1 Ligand L and [MzLz1]zn+
The specification discloses the following species of formula (I), ligand L:
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Specification at pages 32-43; Id. at Figure 2; Id at Figure 15. The specification teaches that ligands L and L’ do not comprise the claim 1 “blocking group” and interact with the macrocycle to give precursor pseudo rotaxanes. Specification at page 24, lines 12-25. That is, the specification teaches the rotaxanes are prepared by first threading compound [MzLz1]zn+ (having unblocked ligands L and L’) into the macrocycle cavity to form the unclaimed precursor pseudo rotaxanes. Id. The pseudo rotaxanes are then subsequently reacted to attach a blocking group at each end of unblocked Ligand L or L’ thereby locking the [MzLz1]zn+ within the macrocycle to form the claimed rotaxane. Id.
The claim 1 component [MzLz1]zn+ comprises ligand L. For example, in disclosed rotaxane CB10-[Ni2(L”)3][Cl]4 the [MzLz1]zn+ species [Ni2(L”)3][Cl]4, has the following structure:
Structure of [Ni2(L”)3][Cl]4 (a Disclosed Species of [MzLz1]zn+)
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Specification at page 37, line 33; Id. at Figure 7, see also, CAS Indexing of Compounds Disclosed in US 20230373962 (2023) (CAS RN 2649115-16-0).
A simpler representation of this disclosed species [Ni2(L”)3][Cl]4, where the claim 1 variables Ar and blocking group are indicated, is as follows:
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.
Here, per claim 1, “each Ar is positioned at either end of the ion of formula [MzLz1]zn . . . with the proviso that each end of the ion comprises at least one blocking group”.
The Claim 1 Rotaxane
The claim 1 rotaxane requires that the ion [MzLz1]zn+ threads into the macrocycle. The specification working examples disclose about five species of claimed rotaxane (all comprising the same “macrocycle” i.e., Cucurbit[10]uril, CAS RN 307001-50-9), where per claim 1 “each end of the ion comprises at least one blocking group”, i.e., CB10-[Ni2L"3][Cl]4; [Fe2L”3-CB10][Cl]4; [Ni2Ldmnb3-CB10][Cl]4; and [Ni2Ldnb3-CB10][Cl]4; and three species of pseudo rotaxane (where ligand L lacks the blocking group), i.e., CB10-[Fe2L3][Cl]4; CB10-[Ni2L3][Cl]4; CB10-[Ru2L3][Cl]4. Specification at pages 33-43.
Claim Rejections 35 U.S.C. 112(a) – Written Description
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.
For an originally filed claim, 35 U.S.C. 112(a) requires that the specification shall contain a written description of the invention demonstrate that the inventor was in possession of the invention that is claimed.1 MPEP § 2163(I); MPEP § 2163(II)(A)(3)(a). Possession may be shown by disclosure of drawings or structural chemical formulas that show that the invention was complete. MPEP § 2163(I).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. MPEP § 2163(II)(A)(3)(a)(ii). A "representative number of species" means that the species which are adequately described are representative of the entire genus. MPEP § 2163(II)(A)(3)(a)(ii). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. MPEP § 2163(II)(A)(3)(a)(ii) (citing AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
The § 112(a) rejection
Claims 1-6, 8, 10, 11, 13, 14, 16, and 26 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement because neither the application as filed nor the art of record discloses either: (1) sufficient species of the claim 1 “macrocycle” that structurally functions with “ion of formula [MzLz1]zn+” to form a rotaxane, where per claim:
claim 1 . . . M is a metal ion or combination of ions of oxidation state n+, z is 2 to 4, z1 is 2 to 6 and L is a ligand of formula (I):
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. . .
with the proviso that each end of the ion comprises at least one blocking group . . .
or; (2) a structure-function correlation between the claimed “macrocycle”, the ion of formula [MzLz1]zn+ such that one of skill can recognize which combinations of macrocycle/[MzLz1]zn+/blocking group function to form a claimed rotaxane, where the blocking group must be correctly selected to so as to mechanically trap the macrocycle and [MzLz1]zn+ in the rotaxane configuration.
Guidance and Predictability
What is conventional or well known to one of ordinary skill in the art need not be disclosed in detail. MPEP § (II)(A)(3)(a). Thus, the state of and predictability in the art is a relevant consideration in determining compliance with § 112(a), written description. MPEP § (II)(A)(3)(a) (citing Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1085 (Fed. Cir. 2005) ("The ‘written description’ requirement must be applied in the context of the particular invention and the state of the knowledge…. As each field evolves, the balance also evolves between what is known and what is added by each inventive contribution”).
Guidance in the Specification
The specification teaches that “[t]he inventors have found that an 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 defines “macrocycle” as follows:
A macrocycle is defined herein to be a cyclic macromolecule comprising a twelve or more membered ring. The macrocycles disclosed herein comprise a cavity in which an ion of formula [MzLz1]zn+ may reside
Specification at page 11, lines 24-26. 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.
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 unclaimed precursor pseudo rotaxanes. Specification at page 24, lines 12-25. The pseudo rotaxanes are then subsequently reacted to attach a blocking group at each end of unblocked ligand L or L’ thereby locking the [MzLz1]zn+ within the macrocycle to form the claimed rotaxane. Id. Specification at page 24, lines 14-25. 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:
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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 interact to form a pseudo rotaxane, where these species also function such that they can be subsequently converted into a claimed rotaxane via a blocking-group reaction.
The specification body provides general guidance, where one of skill must then look to the specification working examples for more specific instruction on choice of combinations of macrocycle/[MzLz1]zn+ to practice the full claim 1 scope. Other than the working examples, the specification provides very limited (insufficient) guidance with respect to which macrocycle and [MzLz1]zn+ to select such that a rotaxane is realized. As discussed above, the specification working examples disclose only one species of “macrocycle” used to form the pseudo rotaxanes and claimed rotaxanes (i.e., Cucurbit[10]uril, CAS RN 307001-50-9), which has the following structure. Specification at page 33, lines 11-17.
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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).
The specification working examples disclose about five species of claimed rotaxane (all comprising the same “macrocycle” i.e., Cucurbit[10]uril, CAS RN 307001-50-9), where per claim 1 “each end of the ion comprises at least one blocking group”, i.e., CB10-[Ni2L"3][Cl]4; [Fe2L”3-CB10][Cl]4; [Ni2Ldmnb3-CB10][Cl]4; and [Ni2Ldnb3-CB10][Cl]4; and three species of pseudo rotaxane (where ligand L lacks the blocking group), i.e., CB10-[Fe2L3][Cl]4; CB10-[Ni2L3][Cl]4; CB10-[Ru2L3][Cl]4. Specification at pages 33-43.
All working-example species of [MzLz1]zn+ comprise the following common ligand “L” core structure, where the claim 1, formula (I) key variable “Ar” is limited to imidazole only.
Working Example Common L group of of [MzLz1]zn+
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Specification at pages 33-43; see also specification Figure 2. The specification working examples of [MzLz1]zn+ are limited to only three metals Ni, Fe and Ru.
Further, the claim 1 blocking group of the working examples is limited to the following three species:
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Specification at pages 33-43; Id. at Figure 15.
The specification provides no general guidance or paradigm to predict other combinations of macrocycle/[MzLz1]zn+/blocking group that function to form a rotaxane 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”
Predictability in the Art
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. 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 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. 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 and the specification teaches only one species macrocycle (i.e., Cucurbit[10]uril, CAS RN 307001-50-9) and only a few species of [([MzLz1]zn+] (all having the same ligan L core, and limited to metals Ni, Fe, and Ru) perform the claimed function.
Claim Breadth
Claim breath is relevant to the instant § 112(a) written description rejection. The written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. MPEP § 2163(II)(A)(3)(a)(ii) (citing Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021)).
Claim 1 directed to any “macrocycle”, having any core structure and any number of undefined substituents, is very broad and encompasses an uncountable number. Further, the claim 1 “blocking group” is structurally undefined in claim 1. Still further, claim 1 encompasses any metal (in any oxidation state) on the periodic table. Also significant respecting claim breadth is that in formula (I), variable “Ar” is generically defined 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 . . .
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.
Dependent claims 2-6, 8, 10, 11, 13, 14, 16 and 26 provide no significant structural constraints on the macrocycle or blocking group. And claim 8 further functionally defines the blocking group as requiring reversibility. Claim 16 limits the macrocycle to broad classes of “cucurbituril, crown ether, cyclodextrin, calixarene, pillararene, and metallo-organic macrocycle, each of which is a vast genus. Specification at page 22.
Claim 1-6, 8, 10, 11, 13, 14, 16, and 26 Lack an Adequate Supporting Written Description
Claims 1-6, 8, 10, 11, 13, 14, 16, and 26 fail to comply with 35 U.S.C. 112(a) because neither the application as filed nor the art of record discloses either: (1) sufficient species of the claim 1 macrocycle that structurally functions with [MzLz1]zn+ to form rotaxane or macrocycle species that function with unblocked ion of formula [MzLz1]zn+ to form a pseudo rotaxane (where the pseudo rotaxane and can thereafter further function so as to be substituted with a blocking group to form the claimed rotaxane) or; (2) a structure-function correlation between the claimed macrocycle and the ion of formula [MzLz1]zn+ and their capacity, to form a rotaxane. As such that one of skill cannot recognize which combinations of macrocycle/[MzLz1]zn+/blocking group can be chosen so as to form the claimed rotaxane.
Here, Applicant is not in possession of the full claim scope because neither the specification nor the art of record provides sufficient guidance (representative species or a structure-function relationship) allowing one of skill to correctly predict those species of macrocycle/[MzLz1]zn+/blocking group that perform the claim 1 function of arranging into a rotaxane.
The specification clearly does not disclose a representative number of species of each component macrocycle/[MzLz1]zn+/blocking group chosen so as to arrive at the claimed rotaxane. The specification working examples disclose about five species of claimed rotaxane (all comprising the same “macrocycle” i.e., Cucurbit[10]uril, CAS RN 307001-50-9), where per claim 1 “each end of the ion comprises at least one blocking group”, i.e., CB10-[Ni2L"3][Cl]4; [Fe2L”3-CB10][Cl]4; [Ni2Ldmnb3-CB10][Cl]4; and [Ni2Ldnb3-CB10][Cl]4; and three species of pseudo rotaxane (where ligand L lacks the blocking group), i.e., CB10-[Fe2L3][Cl]4; CB10-[Ni2L3][Cl]4; CB10-[Ru2L3][Cl]4. Specification at pages 33-43. All working-example species of [MzLz1]zn+ comprise the following common ligand “L” core structure, where claim 1, formula (I) variable “Ar” is imidazole.
Working Example Common L group of of [MzLz1]zn+
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Specification at pages 33-43; see also specification Figure 2. Variable “Ar” as imidazole is clearly not representative of the full scope of
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 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.
And the claim 1 blocking group of the working examples is limited to the following species:
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Specification at pages 33-43; Id. at Figure 15. Further, the specification working examples of [MzLz1]zn+ are limited to metals Ni, Fe and Ru.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. MPEP § 2163(II)(A)(3)(a)(ii); see also, Idenix Pharms. LLC v. Gilead Scis. Inc., 941 F.3d 1149, 1164 (Fed. Cir. 2019) (“[a]s a result, a POSA is deprived of any meaningful guidance into what compounds beyond the examples and formulas, if any, would provide the same result”).
Here the single disclosed species of macrocycle (i.e., CB10), single disclosed species of Ar (i.e., imidazole) and three species of blocking groups that can operate as a combination to perform the claimed function, are not representative of the conceptually vast claimed genus.
Further, neither the art nor the specification shows a well-established correlation between the structure of macrocycle/[MzLz1]zn+/blocking group and the function of form 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”. Here, one of skill is limited to the specification because the art of record is devoid of guidance in this respect. MPEP § 2164.03. The claims recite no structure regarding the claimed macrocycle and blocking groups. Disclosure of function and minimal structure may be sufficient when there is a well-established correlation between structure and function. MPEP § 2163(II)(A)(3)(a)(i). In contrast, without such a correlation, the capability to recognize or understand the structure from the mere recitation of function and minimal structure is highly unlikely. MPEP § 2163(II)(A)(3)(a)(i) (citing Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406). Accordingly, a “sufficient description . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349 (Fed. Cir. 2010).
Subject matter free of the Art of Record
Claims 1-6, 8, 10, 11, 13, 14, 16, and 26 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
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which is a complex comprising the following ligand (termed “L” by Qin):
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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).
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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
Claims 1-6, 8, 10, 11, 13, 14, 16, and 26 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. One of ordinary skill does not have reasonable expectation of success in forming the rotaxane; or even if the rotaxane is formed that it will be therapeutically active. 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.
Conclusion
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ALEXANDER R. PAGANO
Examiner
Art Unit 1692
/ALEXANDER R PAGANO/Primary Examiner, Art Unit 1692
1 While there is a presumption that an adequate written description of the claimed invention is present in the specification as filed, a question as to whether a specification provides an adequate written description may arise in the context of an original claim. MPEP § 2163.03 (V) (citing In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976)). An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. MPEP § 2163.03 (V) (citing Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) ("[e]ven if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed”).