DETAILED ACTION This office action is in response to the Applicant’s filing dated October 29 th , 2025 . 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 Claims Claims 14-33 are pending in the instant application. Acknowledgement is made of Applicant's remarks and amendments filed on May 10 th , 2023 . Acknowledgement is made of Applicant's cancelation of claim s 1-13; and addition of new claims 14-33 . Priority This application is a 371 of PCT/CN2021/129184 filed on November 8 th , 202 1 ; and claims benefit of foreign priority of CN202011251434.0 filed on November 10 th , 2020. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Election/Restrictions Applicant's election without traverse of Group I I in the reply filed on October 29 th , 2025 is acknowledged. Claims 14-25 and 30-33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected group. Election was made without traverse in the reply filed on October 29 th , 2025. Applicant's election of species without traverse of a polyethylene glycol-modified irinotecan as the polyethylene glycol-modified camptothecin derivative compound to be administered in the elected method of treating a tumor in the reply filed on October 29 th , 2025 is acknowledged. A prior art search was conducted for the elected species: This compound can be found in the specification on page 8 . The elected polyethylene glycol-modified irinotecan is a species of genus General Formula (I); Wherein PEG has a molecular weight of 300-60,000 Da; wherein A 1 is a glutamic acid residue ( GLU ) , specifically ; wherein A 2 is a glycine residue ( GLY ) , specifically ; wherein CPT is irinotecan; wherein n is 1 and m is 2. The applicant further elected neuroblastoma as the tumor to be treated. This search retrieved prior art. Therefore, the Examiner’s search will not be extended unnecessarily to additional species of genus Formula (I) in/for/during this Office Action. Claims 26-29 read on the elected species, and will be examined herein. Claim Rejections - 35 USC § 112 (a) 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. Claim s 26-2 9 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 treating SK-N-SH neuroblastoma tumors in mice with a polyethylene glycol-modified irinotecan as a monotherapy and in combination with temozolomide in Example 1 of the specification on pages 15-21 , does not reasonably provide enablement for the treatment of all tumors with the claimed pharmaceutical composition comprising a polyethylene glycol-modified camptothecin derivative and temozolomide . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection . To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation . In re Wright , 999 F.2d 1557, 1561 ( Fd . Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that: The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt , 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation". The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands , 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman , 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors: 1- the quantity of experimentation necessary, 2- the amount of direction or guidance provided, 3- the presence or absence of working examples, 4- the nature of the invention, 5- the state of the prior art, 6- the relative skill of those in the art, 7- the predictability of the art, and 8- the breadth of the claims These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher , 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons: 1. The nature of the invention and breadth of the claims The invention relates to a method of treating a subject having or susceptible to tumors . Claims 26-2 9 are directed to a method of treating a subject having or susceptible to a tumor comprising administering a pharmaceutical composition comprising a polyethylene glycol-modified camptothecin derivative and temozolomide . Thus, the claims are extremely broad with regards to the diseases to be treated as well as the possible compounds that can be utilized . 2. The state and predictability of the art, and relative skill of those in the art The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant’s invention would generally be a physician with a M.D. degree and several years of experience. The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher , 166 USPQ 18, at 24 (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 involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al ., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain). As illustrative of the state of the art, the examiner cites Gura et al., cited for evidentiary purposes , teaches that researchers face the problem of sifting through potential anticancer agents to find ones promising enough to justify human clinical trials. The reference further teaches that, since formal screening began in 1955, many thousands of drugs have shown activity in cell or animal models, but only 39 have actually been useful for chemotherapy (page 1041, first and second paragraphs) . With regard to unpredictability, Johnson et al., also cited for evidentiary purposes , teaches that the in vivo activity of 39 different agents in a particular histology in a tumor model did not correlate with activity in the same human cancer (page 1426, Results). Martino et al., also c ited for evidentiary purposes , teaches that there is significant inter-patient metabolic variability for the conversion of irinotecan (inactive form) to SN-38 (active form), and that dose increases of irinotecan may not lead to proportional increases in cytotoxicity (page 705, left column, first paragraph). Martino further teaches that camptothecins as a broader class are not curative, and represent one of the main causes of treatment failure; often administered near their maximum tolerated dose, thus already being close to the amounts that produce negative side effects (page 706, left column, second paragraph). “The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art” In re Fisher , 427 F.2d 833, 166 USPQ 18 (CCPA 1970) . Accordingly, the more unpredictable an area is, the more specific enablement is necessary in order t o satisfy the statutory requirements. Furthermore, the mechanism of action of anticancer agents is often unknown or highly unpredictable, and the administration of such agents is frequently accompanied by undesirable side effects. 3. The amount of direction or guidance provided and the presence or absence of working examples The specification provides data for treating SK-N-SH neuroblastoma tumors in mice with a polyethylene glycol-modified irinotecan as a monotherapy and in combination with temozolomide in Example 1 of the specification on pages 15-21 , but it is not sufficient to provide support for the full scope of compounds encompassed by the claims or for the full scope of conditions or disorders associated with all tumors , particularly in humans . The specification provides no particular direction or guidance for determining the particular administration regimens (e.g. timing, administration routes, etc ) necessary to treat all tumors encompassed by the claims, particularly in humans. At best, an "effective amount" is exemplified as a dosage sufficient to provide treatment for SK-N-SH neuroblastoma tumors in mice with a polyethylene glycol-modified irinotecan as a monotherapy and in combination with temozolomide . While experimentation is presented for treatment of SK-N-SH neuroblastoma tumors in mice with a polyethylene glycol-modified irinotecan as a monotherapy and in combination with temozolomide , there is no experimentation or mechanism or action presented or discussed in the specification regarding all tumors in a subject with a polyethylene glycol-modified camptothecin derivative and temozolomide, particularly in humans . 4. The quantity of experimentation necessary Because of the known unpredictability of the art (as discussed supra ) and in the absence of experimental evidence commensurate in scope with the claims , the skilled artisan would not accept that any pharmaceutical composition comprising a polyethylene glycol-modified camptothecin derivative and temozolomide could be predictably used as treatment for all conditions or disorders associated with tumors, particularly in humans . Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent protection' is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" (42 USPQ 2d 1001, Fed. Circuit 1997). A review of the state of the art fails to reveal the mechanism of action or experimental data regarding the use of the claimed pharmaceutical composition comprising a polyethylene glycol-modified camptothecin derivative and temozolomide to treat all known tumors . Determining if any particular claimed comp osition would treat a conditions or disorders associated with all tumors would require synthesis of the compound, formulation into a suitable dosage form of the pharmaceutical composition , and subjecting it to clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. As noted in supra , even in vitro and in vivo assays do not always correlate to efficacy in humans and are not generally predictive of clinical efficacy. This is undue experimentation given the limited guidance and direction provided by Applicants. Accordingly, the inventions of claims 26-29 do not comply with the scope of enablement requirement of 35 U.S.C 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation with no assurance of success. Claim Rejections - 35 USC § 103 In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis ( i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. 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. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows: 1. Determining the scope and contents of the prior art. 2. Ascertaining the differences between the prior art and the claims at issue. 3. Resolving the level of ordinary skill in the pertinent art. 4. Considering objective evidence present in the application indicating obviousness or nonobviousness . This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. Claims 26-29 are rejected under 35 U.S.C. 103 as being unpatentable over Ray et al (WO 2010/148163 A1) ; in view of Liu et al (Anti-tumor Pharmacy, (2011), 1(2), pages 118-120 and 132), cited in the IDS filed on October 29 th , 2025 . Regarding claims 26-29 , Ray teaches a macromolecule -anti cancer agent conjugate pharmaceutical composition ( page 14, lines 26-29 ) suitable for treating tumors . Ray teaches that this macromolecule conjugation is beneficial when treating tumors because of the Enhanced Permeability and Retention (EPR) effect, which is the passive accumulation of substances such as macromolecular conjugates inside a tumor leading to an accumulation of an anti-cancer compound more rapidly in tumor tissue than in normal tissue (page 5, lines 23-24; page 6, lines 1-4). Ray teaches a suitable macromolecule is polyethylene glycol (PEG) ranging from 1kD-200kD (page 7 , lines 1-3 and 14); and the anticancer agent can be irinotecan (page 13, line 24). MPEP § 2144.05 states : In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim , 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff , 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson , 65 USPQ2d 1379, 1382 (Fed. Cir. 2003). Ray further teaches that the macromolecule conjugate may comprise recurring amino acid derived units, disclosed as Formulas II and III (page 9, line 15); wherein the anticancer agent is indirectly bonded to the macromolecule via a linker selected from an amino acid, oligopeptide or amino acid sequence (page 10, lines 7-20; page 11, lines 11-13) wherein the linker can be glycine (page 28, line 1). Ray expressly teaches that such macromolecule-anti-cancer agent conjugates are suitable for treating tumors, including neuroblastoma (page 19, line 13). Ray further teaches that the recurring units of Formula s II and III may comprise amide linked amino acid residues, wherein A 1 /A 2 are independently oxygen or NR 3 , and R 3 is H (page 9, line 15) . Although not directly stated, Formulas II and III as taught by Ray structurally encompas s the amino acid residue of glutamic acid as shown: , as defined by the amino and carboxyl connectivity. Thus, as Ray teaches that the anti-cancer agent (irinotecan) can be indirectly bonded to the macromolecule via an amino acid (glycine), Ray teaches PEG-modified irinotecan conjugates that render the instantly claimed PEG-modified irinotecan conjugate structure obvious to a person of ordinary skill in the art. Ray does not teach a pharmaceutical composition comprising both a polyethylene glycol-modified irinotecan and temozolomide . Liu teaches combination therapy of temozolomide with irinotecan is routinely used in treatment of neuroblastoma tumors in clinical settings (page 120, right column, second paragraph). Liu further teaches that temozolomide increases tumor cell sensitivity to irinotecan by increasing the degree of methylation of the upstream promotor region of the MGMT coding gene, and reducing the expression of the MGMT gene (page 120, right column, last paragraph). “[ T ] he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395 . It would have been prima facie obvious to a person of ordinary skill in the art to administer the PEG-modified irinotecan composition taught by Ray thereby taking advantage of the EPR effect, in combination with temozolomide as taught by Liu, in order to achieve improved therapeutic efficacy in the treatment of neuroblastoma. The selection of a PEG-modified irinotecan composition as taught by Ray, for use in a known irinotecan-temozolomide combination regimen, as taught by Liu, represents a routine optimization and predictable use of prior art elements according to their established functions, with a reasonable expectation of success. Taken together, all of this would result in the methods of instant claims 26-29 with a reasonable expectation of success. Conclusion Claims 26-29 are rejected. No claim is allowed. 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