DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
Three information disclosure statement (IDS) submitted: One on February 15th, 2023; one on May 8th, 2023; and one on October 11th, 2023. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: “Self-Assembled Tripodal Ligand-Metal Complexes for the Treatment of Cancer.”
The section labeled as “Examples” currently, page 124, should be re-labeled “Detailed Description of the Drawings”.
Tables 1, 2, and 3 of the spec. show % values wherein the decimal places are separated by commas (e.g. 88,24; 93,33; etc.). These values should be presented with a period separating the decimal place (i.e. 88.24; 93.33; etc.)
Status of the Claims
Claims 1, 3, 5-7, 9-24, and 26 are pending in this application. Claims 2, 4, 8, and 25 have been cancelled by Applicant. Claims 1, 3, 5-7, 9-12, 14-19, and 26 are under examination herein. Claims 13 and 20-24 are withdrawn from consideration.
Claim Interpretations
Claim 1 mentions “carbocyclyl” and “heterocyclyl” groups. The specification defines “carbocyclyl” as non-aromatic, saturated or partially saturated monocyclic, fused, bridged, or spiro rings ([0046]) and “heterocyclyl” as non-aromatic, saturated or partially saturated monocyclic, fused, bridged, or spiro rings having 1-5 heteroatoms ([0047]).
Claim 15 mentions “spherical monoanions, dianionic tetrahedrial, or trianionic tetrahedral.” The specification defines these anions as halides, sulphate, and phosphate, respectively [0297].
Examiner Notes
While claims 20-24 are not under examination herein, for the purposes of compact prosecution, Examiner invites Applicant to amend the multiple-dependency issues present in these withdrawn claims and amend the scope of enablement issues consistent with the 112(a) raised herein for claim 1. See MPEP § 608.01(n) and 2164.08.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 5-7, 9-12, 14-19, and 26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the treatment of some cancers (specifically colorectal adenocarcinoma, pancreatic carcinoma, lung carcinoma, glioblastoma, and mesothelioma), does not reasonably provide enablement for the treatment of all cancers or prevention of any cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make use of the invention commensurate in scope with these claims.
The applicant’s attention is drawn to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1998), where the court set forth eight factors to considers when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the examples; and (8) the quantity of experimentation necessary.
Breadth of Claims
Claim 1 broadly encompasses the treatment and prevention (see definition of “treatment” from the instant specification below) of any proliferative disease, wherein the proliferative disease is cancer (including any cancer, such as the many cancers listed in [0029] of the specification) comprising administration of any of the ligands of Formula I, or pharmaceutically acceptable salt, hydrate, or solvate thereof, in combination with sources of M (wherein M is Zn2+, Mn2+, Cu2+, Fe2+, or Co2+) to a subject in need thereof.
The term “subject” is defined as animals, including human and non-human animals (humans, other primates, dogs, cats, squid, etc.) (see [0035]).
The term “treatment” is defined to include prophylaxis as well as the alleviation of established symptoms of a condition. "Treating" or "treatment" of a state, disorder or condition therefore includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition (see [0033]).
The term “prevent” is not defined in the specification; however, The Oxford English Dictionary (2024) defines “prevent” as to “preclude the occurrence” and thus the instant claims encompass embodiments in which the claimed compounds can preclude the many proliferative diseases, including cancer. See definition II.9.a. Obtained from oed.com [retrieved on 2025-03-05] URL:httos://www.oed.convdictionary/prevent_y?t=true).
Nature of the invention/ State of the Prior Art/ Predictability in the Art
The art provides no successful method of prevention for all cancers, as taught by Gu et al. (J. Cancer Prev. 25(3): 127-135, 2020) beyond: (i) eliminating or mitigating risk factors by adopting healthy behaviors and lifestyles, such as avoiding tobacco, alcohol, and UV radiation; (ii) screening to identify precancerous lesions and taking intervention measures to prevent disease progression to malignancy; or (iii) controlling the symptoms or morbidity caused by cancer therapy. Gu also recommends that high-risk populations take chemo-preventive agents such as selective estrogen receptor modulators for breast cancer, and non-steroidal anti-inflammatory drugs (aspirin) for colorectal cancer prevention etc. There is not one single drug that works for the prevention of all cancers.
Finally, the medical arts are also generally considered to be unpredictable making the goal of achieving prevention in this case even less likely. See Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). See also In re Fisher, 427, F. 2d 833, 166, USPQ 18 (CCPA 1970) (“In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involve.”).
Level of One of Ordinary Skill
The level of one of ordinary skill in the art would be high, likely an M.D. or Ph.D. in the medical arts (e.g., studying treatment of cancers and proliferative diseases). See Orthopedic Equip. Co. v. All Orthopedic Appliances, Inc., 707 F.2d 1376 at 1381–82 (Fed. Cir. 1983) (Factors that may be considered in determining level of ordinary skill in the art include: … type of problems encountered in the art …”).
Guidance/Working Examples
The specification provides in vitro examples of inhibition of HT29, DLD-1, HCT116 p53+/+, and HCT116 p53-/- - all of which are colorectal adenocarcinoma cell lines; PSN-1, BxPC-3 and MiaPaCa2 – pancreatic carcinoma; A549 and H460 – lung carcinoma; NP1 – a telomerase-immortalized, adult female human mesothelial cell line for the study of mesothelioma; and GBM1 – a glioblastoma cell line. Applicant also shows non-cancer cell lines ARPE-19 and MCF10A for comparison (see [0368] and Figures 8 and 15a for the relative potencies; and all Figures – descriptions starting in page 124). Applicant discloses that ligand-metal complexes [L2M3]6+ (specifically [L2Cu3]6+ and [L2Zn3]6+) were freshly formed in DMSO prior to administration to cell lines (see [0369]-[0371]) - wherein L (the only ligand tested) has the structure below:
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82
192
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Greyscale
Applicant discloses that pancreatic cancer cell lines were resistant to both complexes tested (see end of [0371]). Applicant also discloses studies of the impact of encapsulation of different anions into the complexes prior to any cell exposure (see [0374]).
Applicant also shows in ovo anti-cancer activity with 3 different cancer cell lines (H460, HT29, and HCT116) – once again, ligand and metal were premixed prior to administration (see [0391]-[0410]).
Thus, all of the examples provided required pre-formation of ligand-metal complexes prior to contacting the cells. There are no examples in the specification of administration of the ligands of Formula I in combination with a metal source (i.e administered simultaneously, without preformation of the ligand-metal complex) with any level of success against cancer cell lines tested.
The specification does not show examples to enable one of ordinary skill to make use of the invention for treatment and prevention of all cancers, as claimed.
Degree of Experimentation
To practice the invention as claimed, the skilled artisan would have to screen each of the many compounds encompassed by the genus in instant Formula I in combination with sources of M (wherein M can be Zn2+, Mn2+, Cu2+, Fe2+, or Co2+) in order to determine whether the ligands + metal source, administered “in combination” as claimed (reading on simultaneous or sequential administration), meet the functional limitations of the preformed ligan-metal complex (with L – shown above – being the only ligand tested in the instant disclosure) for the treatment and prevention of any cancer. In addition, the skilled artisan would need to determine which subjects would benefit from treatment and prevention of these diseases (humans, other primates, cats, dogs, squid, etc.) by administering the instantly claimed ligands in combination with a metal source to a statistically significant pool of subjects from each species. Prevention the aforementioned conditions would require long-term monitoring of each patient for appearance of any new cancer. Thus, the quantity of experimentation in this area would be extremely large, since there are a significant number of parameters that would have to be studied beyond the preliminary in vitro or in ovo studies provided – none of which show administration of the ligands of Formula I “in combination” with a metal source, but rather, preformation of the ligand(L – shown above)-metal complex followed by administration. Furthermore, the ultimate outcome of such experimentation is completely unpredictable.
In sum, taking into consideration the Wands factors outlined above, an undue amount of experimentation would be required here to make and use the full scope of the claimed invention.
Claims 3, 5-7, 9-12, 14-19, and 26 are rejected for depending upon the limitations of claim 1.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 11 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 11 is rejected for failing to further limit claim 1, from which it depends. Amended claim 1 states R1 cannot be aryl, however, claim 11 expands the limitations of claim 1 to encompass embodiments in which R1 is phenyl. While claim 12 depends on claim 11, claim 12 is not included in this rejection because it remedies the issues of claim 11.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to Arguments
Claims/ Claim Objections
Claim amendments are acknowledged and have been entered. No new matter has been introduced.
Applicant’s arguments, see pages 21-22, filed 03/27/2026, with respect to objections to the claims have been fully considered and are persuasive. The objections of the claims have been withdrawn. However, upon further consideration, in view of claim amendments and rejoinder of previously unexamined claims, a new ground(s) of objection is made.
Specification/ Drawings
Amendments to the specification and the drawings are acknowledged and have been entered. No new matter has been introduced.
Applicant’s arguments, see page 22, filed 03/27/2026, with respect to objections to the specification and drawings have been fully considered and are persuasive. The objections of the specification and drawings have been withdrawn.
However, upon further consideration, the title of the invention is still not descriptive, therefore, the objection to the title is reinstated. Examiner suggests the following title, which is more in line with the scope of the claims: “Self-Assembled Tripodal Ligand-Metal Complexes for the Treatment of Cancer.”
In addition, as pointed out in the last office action, the “Detailed Description of the Drawings” needs to be clearly relabeled. Currently it is labeled as “Examples” – page 124 of the spec.
Claim Rejections - 35 USC § 112(a)
In light of claim amendments, the 35 USC § 112(a) rejections of the claims have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made. This rejection was not necessitated by amendments; therefore, this action is non-final.
Claim Rejections - 35 USC § 112(b)
In light of claim amendments, the 35 USC § 112(b) rejections of the claims have been withdrawn.
Claim Rejections - 35 USC § 103
In light of claim amendments, the 35 USC § 103 rejections of the claims have been withdrawn.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JACKSON J HERNANDEZ whose telephone number is (571)272-5382. The examiner can normally be reached Mon - Thurs 7:30 to 5.
Examiner interviews are available via telephone 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, Kortney L. Klinkel can be reached at (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627
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