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 .
Status of the Claims
Claims 1-6, 8-18, 32, 47, and 65 are pending in the present application.
Election/Restrictions
Applicant’s election without traverse of Group I, , drawn to a method of increasing sensitivity of a cell to treatment with an anti-neoplastic drug or antimicrobial drug comprising administering to the cell a conjugate of Formula (I) (depicted below), in the reply filed on May 29, 2026 is acknowledged.
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Applicant’s election without traverse of the following species of Formula (I) in the reply filed on May 29, 2026 is acknowledged. For shorthand, this compound will be referred to as Compound 4SP65 in accordance with the specification (see e.g. p. 129, para. [0364]).
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Compound 4SP65 is a conjugate of Formula (I) wherein:
Core is
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(neopentyl);
Linker is a repeating unit of PEG;
R1, R2, and R3 are all H;
m is 4;
n is 3; and
each p is independently 1 to 2500.
Additionally, Applicant’s election of an anti-neoplastic drug and cisplatin as said anti-neoplastic drug is acknowledged.
Claims 18, 32, 47, and 65 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 29, 2026.
Claims 4, 8-10, 14, and 17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 29, 2026.
Claims 1-3, 5-7, 11-13, and 15-16 are currently under examination as they relate to the elected invention of Group I and elected species of Compound I.
Priority
This application claims priority to U.S. Provisional Application No. 63/237,937, filed August 27, 2021, and is a 371 of PCT/US2022/041687, filed August 26, 2022.
Information Disclosure Statement
Applicant should note that the extremely large number of references in the attached IDS have been considered by the examiner in the same manner as other documents in Office search files are considered by the examiner while conducting a search of the prior art in a proper field of search. See MPEP 609.05(b). Applicant is requested to point out any particular references in the IDS which they believe may be of particular relevance to the instant claimed invention in response to this office action.
Drawings
The drawings entered Feb. 26, 2024 have been considered and accepted by the examiner.
Claim Objections
Claim 1 is objected to because it is missing a comma between “antimicrobial drug” and “said method comprising” and should read “A method of increasing sensitivity of a cell to treatment with an anti-neoplastic drug or antimicrobial drug, said method comprising[…]”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
112(a) – Scope of Enablement
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, 11-13, and 15-16 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 a method of administering a compound of Formula (I) wherein Core is neopentyl or 4-star polyethylene glycol polymer and Linker is polyethylene glycol, does not reasonably provide enablement for Core to be any atom, any molecule, or any macromolecule, Linker to be any polymer, any copolymer, or any branch of a dendrimer, nor for the administration of polymorphs of compounds of Formula (I). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Nature of the invention:
The invention is drawn to administering conjugates of the Formula (I) or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof to neoplastic cells, microbial cell, or cell infected with a microbe.
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Breadth of the invention:
The scope of the claimed invention is very broad in terms of compounds administered and cells to be treated. For example, Core of formula (I) can be any atom, any molecule, or any macromolecule, which would encompass any atom or moiety under sun and may include a protein, a polymer, or any organic or inorganic molecule. Furthermore, Linker can be any polymer or section or arm thereof, arm of any copolymer, or any branch of any dendrimer. Moreover, the method encompasses the treatment of any neoplastic cell, microbial cell, or cell infected with a microbe.
State of the prior art and predictability in the art:
The invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F. 2d 833, 839, 166, USPQ 18, 24 (CCPA 1970).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F. 2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F. 2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F. 2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Tautermann (Quantum Mechanics in Drug Discover, Humana Press, 2020, Chapter 1, pp. 1-17), cited for evidentiary purposes, teaches drug discovery is a very challenging, cost-intensive, and in terms of investment risky endeavor; on average, it takes 10–15 years and an investment of more than 2.5 billion dollars to get a new drug to the Market; especially the clinical phases cause extremely high costs and late-stage failures, especially in phase II studies, are quite common (page 1, 1st paragraph). Tautermann teaches the largest attrition in clinical phases is observed in phase II studies; the main goal is the assessment of the efficacy of the compound yielding a clinical proof of concept; a recent analysis from four major pharma companies revealed that the cause for attrition in phase II is mainly caused by lack of efficacy followed by safety issues; efficacy for a certain indication is usually preclinically tested in animal models; however, the translatability from animal models to the human situation is not always given; there are several reasons for this; often the disease condition cannot adequately be induced in animals (page 3, last paragraph). Tautermann teaches small molecules have several advantages, such as being cell and brain permeable, the lower cost of goods in their production, and oral administration; however, they are not always the easiest path forward for challenging targets; especially in the case of difficult or so far undruggable targets, new design strategies are required to be successful (page 5, last paragraph). Thus, Tautermann further establishes that the state of the art of drug design is highly unpredictable.
Level of ordinary skill in the art:
An ordinary artisan in the area of drug development would have experience in synthesizing chemical compounds for particular activities. The synthesis of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can be employed, developing a therapeutic method, as claimed, prior to synthesizing and testing compounds is generally not well-known or routine, given the complexity of certain biological systems.
The amount of direction provided and working examples:
The instant specification describes the synthesis and administration of Compound 4SP65 to neoplastic cells, where Core is neopentyl or alternatively, 4-star PEG (polyethylene glycol) polymer and linker is PEG (p. 129, para. [0364]). However, a single compound with only two possible cores and one linker is insufficient to reasonably enable the use of any atom, molecule, or macromolecule for the core nor any polymer, section of polymer, arm of polymer, or branch of dendrimer as recited in the instant claims. These definitions are vastly too broad.
Furthermore, because a polymorph is solid crystalline form, it is unclear how Applicant intends to administer said solid form of a conjugate to a cell. The specification does not provide any examples of crystalline forms of conjugates, let alone any methods of using said crystalline forms. For example, it is unclear whether Applicant intends to administer a solid powder form or a crystalline form that has then been dissolved into a solution to be administered.
Within the specification, “specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula.” See MPEP 608.01(p).
MPEP § 2164.01 (a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above 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 scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here that Applicant is not enabled for making these compounds.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-3, 5-7, 11-13, and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Walker (WO 2017/087668 A1, cited in the IDS filed March 25, 2024).
Walker teaches 4SP65 is the trifluoroacetic acid salt of WR-1065 conjugated by a disulfide bond to 4-arm star PEG (para. [0035]). The structure of WR-1065 is given below (Figure 1, p. 1/5, p. 78 overall).
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Walker teaches an aminothiol conjugate depicted below (p. 71, lines 1-5). This is WR1065 conjugated to 4-star PEG, and is thus 4SP65 per the definition of Walker. This is also the same compound as instant Compound 4SP65.
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Walker teaches the administration to and efficacy of 4SP65 against breast cancer, lung cancer, melanoma, leukemia, and ovarian cancer cells (para. [0183]).
In addition, Walker teaches amifostine, another prodrug of WR-1065, enhances the cytotoxic effects of cisplatin (p. 52, lines 13-14; definition of amifostine given on p. 5, para. [0024]).
Finally, Walker teaches administering aminothiol conjugates including Compound 4SP65 to a subject (claim 15; 4SP65 is recited in claim 5), and to a subject suffering from a neoplastic condition in particular (claim 22).
Walker does not explicitly teach the selection of a cell, the administration of Compound 4SP65 to increase sensitivity to cisplatin, nor the administration to in vivo cells.
Regarding claims 1-3, 12, and 16, although Walker does not teach selecting a neoplastic cell and administering Compound 4SP65, it would have been obvious to select a neoplastic cell and administer Compound 4SP65 to said cell since Walker teaches 4SP65 is effective against a range of neoplastic cell lines (cancer, melanoma, leukemia, and ovarian cancer).
The prior art is silent regarding “increasing sensitivity of a cell to treatment with an anti-neoplastic drug”. However: “increasing sensitivity of a cell to treatment with an anti-neoplastic drug” will naturally flow from the teachings of (or method made obvious by) the prior art, since the same compound (Compound 4SP65) is being administered to the same cells (neoplastic cells, in particular breast cancer, lung cancer, melanoma, leukemia, and ovarian cancer cells). In other words, products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances.
In other words, even though the prior art is silent regarding “increasing sensitivity of a cell to treatment with an anti-neoplastic drug”, by practicing the method suggested by the prior art: “selecting a neoplastic cell, and administering Compound 4SP65 to said cell” one will also be “increasing sensitivity of a cell to treatment with an anti-neoplastic drug”, even though the prior art was not aware of it.
Apparently, Applicant has discovered a new property or advantage “increasing sensitivity of a cell to treatment with an anti-neoplastic drug” of the method in the prior art (the selecting of breast cancer, lung cancer, melanoma, leukemia, and ovarian cancer cells and subsequent administration of Compound 4SP65 to said cells).
MPEP 2145 II states: "The fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious". Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f)).
Regarding claims 5-6, 12 and 15, it would have been obvious to one of ordinary skill in the art prior to the filing of the invention to administer Compound 4SP65 to a cell to increase sensitivity to cisplatin since Walker teaches Compound 4SP65, a conjugate of WR-1065, treats neoplastic cells and since Walker teaches amifostine, a prodrug of the same WR-1065 enhances the cytotoxic effects of cisplatin. Because both amifostine and Compound 4SP65 are prodrugs of the same active WR-1065 and because Walker teaches amifostine increases sensitivity of neoplastic cells to cisplatin, one would have been motivated and had a reasonable expectation of success in administering Compound 4SP65 to increase sensitivity to cisplatin since Walker teaches another prodrug of the same active WR-1065 increases sensitivity to cisplatin.
Regarding claim 11, the courts have recognized that combining equivalents known for the same purpose supports a prima facie case of obviousness. See MPEP 2144.06: "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
In the instant case, it would have been obvious to administer Compound 4SP65 and cisplatin together since both Compound 4SP65 and cisplatin are anti-neoplastic drugs. One would have had a reasonable expectation of success in doing so based on the teaching of the prior art that each agent works individually to treat neoplastic cells and thus there is an expectation that the combination would as well.
Regarding claim 13, it would have been obvious to administer Compound 4SP65 to increase sensitivity of a cell in vivo to an antineoplastic drug since Walker suggests Compound 4SP65 will increase the sensitivity of a neoplastic cell to cisplatin and since Walker teaches the administration of Compound 4SP65 to a subject. One would have been motivated and had a reasonable expectation of success to do so given Walker teaches it is safe and effective to administer Compound 4SP65 in vivo.
Taken together, all this would result in the invention of claims 1-3, 5-7, and 11-16 with a reasonable expectation of success.
Conclusion
Claims 1-3, 5-7, 11-13, and 15-16 are rejected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OLIVER D. HEES whose telephone number is (571)272-9840. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, AMY L. CLARK can be reached at (571) 272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/O.D.H./Examiner, Art Unit 1628
/Rayna Rodriguez/Primary Examiner, Art Unit 1628
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