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 .
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.
Response to Amendment
The amendment filed December 10, 2025 has been entered. Claims 3-4, 6, 8, 8-16, and 18-20 have been amended, claims 1-2, 5, 7, and 17 have been cancelled, and claim 21 has been added. Applicant’s amendments to the claims have overcome the 112 rejections previously set forth in the Non-Final Office Action mailed September 12, 2025. Applicant’s cancellation of claims 1-2, 5, 7, and 17 have rendered the corresponding rejections/objections moot. As such, these rejections and objections are hereby withdrawn.
Applicant’s arguments filed December 10, 2025 were fully considered but they were not persuasive. Modified/New rejections necessitated by Applicant’s amendment and response to arguments are addressed below.
Claims 3-4, 6, 8-16, and 18-21 are pending in this application.
Priority
This application is a 371 of PCT/KR2022/013186 filed September 2, 2022 and claims foreign priority to KR10-2021-0118942 filed September 7, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Objections
Claim 20 is objected to because of the following informalities:
Claim 20 recites inter alia, “the method comprising to a subject in need thereof”, which should read, “the method comprising administering to a subject in need thereof”
Appropriate correction is required.
Claim Interpretation
Claim 19 is drawn to a method for treating cancer comprising administering to a subject a composition comprising ADP-ribose sodium salt. Claim 20 is drawn to a method for treating cancer comprising administering to a subject a composition comprising ADP-ribose sodium salt and a second anti-cancer drug. Claim 21 is drawn to a method of treating cancer comprising administering to a subject a composition comprising ADP-ribose sodium salt in combination with radiation therapy. The Examiner notes that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps (See MPEP 2111.03). Thus, usage of the phrase comprising in claim 19 encompasses methods which are combination therapies, such as those encompassed by claims 20-21. For example, if the prior art teaches or renders obvious a combination therapy that includes ADP-ribose sodium salt in the composition, this teaching would be encompassed by instant claims 19 and 20.
New Claim Rejections - 35 USC § 112 (b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 18 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 18 recites the limitation " the second anti-cancer drug" There is insufficient antecedent basis for this limitation in the claim. The Examiner notes, that had claim 18 been dependent on claim 20, which directly recites inclusion of a second anti-cancer drug, the claim would have been rejected under 112(d) for failing to further limit the claim, as the claim necessarily encompasses both of these possibilities.
Modified/New 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 3-4, 6, 19, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Shalwitz (WO 2017/143113, IDS filed April 7, 2023) in view of Pero (WO 99/12951, IDS filed April 7, 2023)
Regarding claims 3, 6, 19, and 21: Shalwitz teaches a method for treating cancer in a subject comprising administering to the subject a pharmaceutically acceptable amount of ADPR (i.e. ADP-ribose, abstract. pg.17, para. 0067). Shalwitz teaches other pharmaceutically acceptable salts are encompassed (pg. 17, para. 0067). Shalwitz teaches in a specific embodiment the ADPR compound for use in the compositions and methods provided herein is in the form of its sodium salt or lithium salt (pg. 2, para. 0007, pg. 3, para. 0008). Shalwitz teaches cancer include solid tumors, such as breast cancer, as well as cancer that is metastasized (pg. 17, para. 0069). Shalwitz teaches ADPR sodium salt exhibits minor activity in reducing specifically A549 adenocarcinoma cells at 42 mM (pg. 60, para. 00429). Shalwitz discloses that A549 cells are human alveolar adenocarcinoma cells (i.e. a solid lung cancer, pg. 60, para. 00427). Although Shalwitz teaches it exhibits minor activity and prefers the dilithium salt, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments (See MPEP 2123 (II)).
Additionally, Pero teaches a method of killing tumor cells in a subject comprising administering to the subject an amount of nicotinamide adenine dinucleotide (NAD) or its analogs effective to increase clonogenic toxicity of said cells (abstract, pg. 8, lines 28-35). Pero teaches NAD analogs include ADP-ribose (pg. 8, lines 10-14). Although ADP-Ribose is listed among several other alternatives, Pero demonstrates that ADP-ribose specifically exhibits comparable activity to NAD and induces cytotoxicity in leukemic cell lines (pg. 6, figure 4, pgs. 15-16, bridging para., Example 4). Although Pero does not teach ADP-ribose activity in solid tumors specifically, Pero teaches NAD achieves a cytotoxicity affect in human lung adenocarcinoma (H298 cells, page. 7, lines 19-26). Thus the art recognizes NAD and ADP-ribose as equivalents suitable for the same purpose, it would have been obvious to utilize ADP-ribose for this purpose (See MPEP (See MPEP 2144.06 (II)). Pero teaches NAD and its analogs sensitize conventional radiation therapies (pg. 16, lines 16-29, Example 5), thus administration of ADP-ribose necessarily improves radiation sensitivity, and it would be obvious to utilize the composition for this purpose.
Taken together, it would have been prima facie obvious to administer the ADP-Ribose sodium salt for the treatment of a solid tumor, such as solid lung cancer as taught by Shalwitz and Pero. A person of ordinary skill in the art would have the motivation to do so as its general anticancer ability has been contemplated in the prior art, and has been specifically applied to the inhibition of solid tumor cells, albeit as a non-preferred embodiment.
Regarding claim 4: Wherein it would have been obvious to administer the composition to patients with cancer, the composition necessarily results in accumulation of ADP-ribose in cancer cells. Although Shalwitz and Pero do not disclose the impact of ADP-ribose on ADP-ribose accumulation in cancer cells, wherein the prior art teaches the administration of ADP-ribose for the treatment of cancer, property naturally flows as a result of practicing the invention.
Claims 8-16, 18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Shalwitz (WO 2017/143113, IDS filed April 7, 2023) in view of Pero (WO 99/12951, IDS filed April 7, 2023) as applied to claims 3-4, 6, 19, and 21 above in view of and Paleni (WO 2020/089310, cited in previous action). The English translation of Paleni has previously been provided by the Examiner.
Regarding claims 8-16, 18, and 20: As discussed above, Shalwitz and Pero render obvious a method of administration of ADP-ribose sodium salt for the treatment of solid lung cancer. Pero teaches NAD and its analogs sensitize conventional radiation therapies (pg. 16, lines 16-29, Example 5), thus administration of ADP-ribose necessarily improves radiation sensitivity, and it would be obvious to utilize the composition for this purpose. Shalwitz teaches a method of treating cancer comprising administering to a patient having cancer a pharmaceutically effective amount of ADP-ribose (pg. 18, para. 0072). Shalwitz teaches cancers to be treated include breast cancer, lung cancer, or liver cancer (pgs. 17-18, para. 0070).
They do not teach administration with an additional anti-cancer drug, wherein the anti-cancer drug is a targeted anti-cancer drug that targets VEGF/VEGFR, EGFR, and HER2. They do not teach wherein the anti-cancer drug is an alkylator or immuno-oncology drug.
However Paleni teaches a method of administering Flavin Adenine dinucleotide (FAD) for the treatment of cancer (abstract). FAD is in a comparable class of compounds to NAD and thus ADP-ribose. Paleni teaches FAD can be combined with additional known chemotherapeutic agents including: gemcitabine (English translation, pg. 33, bottom of page section IV); a alkylator such as cisplatin (English translation, pg. 33, bottom of page section V); monoclonal antibodies bevacizumab, cetuximab, ipilimumab or trastuzumab (English translation, pg. 8, second to last para.), and bricatinib (English translation, pg. 37, second to last para.) (i.e. same time administration). According to the instant specification ipilimumab is an immune-oncology drug (pgs. 26-27, bridging para.). According to the instant specification bevacizumab is a VEGF/VEGFR inhibitor (pg. 30, lines 5-17). According to the instant specification, cetuximab is an EGFR inhibitor (pg. 24, lines 7-11). According to the instant specification trastuzumab is a HER2 inhibitor (pg. 31, lines 2-10). According to the instant specification gemcitabine is a cytotoxic anti-cancer drug (pg. 22, lines 5-6, 20-22).
Taken together, it would have been prima facie obvious to a person of ordinary skill to modify the method of Shalwitz and Pero by including the anti-cancer drugs, such as gemcitabine, cisplatin, monoclonal antibodies bevacizumab, ipilimumab or trastuzumab, and bricatinib, as taught by Paleni. A person of ordinary skill would have had the motivation to do so with a reasonable expectation of success as combination therapies with ADP-ribose and anti-cancer drugs are known in the art and Pero demonstrates ADP-ribose induces apoptosis in a pathway separate from traditional agents, in order to more effectively treat the cancer by targeting multiple pathways. Although the prior art does not teach ADP-ribose enhances sensitivity to the target anti-cancer drug, wherein the prior art suggests inclusion in combination therapies, this is an expected property of the composition. The Examiner notes the discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer (See MPEP 2112 (I)).
Response to Arguments
Applicant’s arguments filed December 10, 2025 have been fully considered but they are not persuasive.
On page 11 of Applicant’s response, Applicant argues the newly amended claims are now drawn to a method of treating solid cancer using ADP-ribose salt (para. 3). The Examiner notes that the previous claim set was drawn to a composition comprising ADP-ribose or a salt thereof, and general methods of treating/preventing cancer using compositions comprising ADP-ribose and combination therapies thereof, and did not specify solid cancers or the sodium salt of ADP-ribose. Applicant argues Pero only exhibits cytotoxicity of ADP-ribose in hematological cancer cells and not solid cancer cells (para. 4). Applicant argues that Shalwitz teaches the cytotoxicity induced by dilithium salt, rather than the sodium salt (para. 4). In short applicant argues the prior art does not teach or suggest treatment of solid cancers. On page 11 of Applicant’s response, Applicant argues that even if hematological cancers can be treated, it cannot be readily predicted it would show the same anti-cancer activity in solid cancers and cites that HDAC inhibitors can demonstrate efficacy in hematological cancers but fail to show clinically meaningful results in kidney cancer, prostate cancer, and head and neck cancer (para. 4). Applicant argues that the IC50 values of ADPR disclosed in Pero and Shalwitz are significantly lower, and it would be difficult to expect ADPR to be effective in hematological cancers, and such effects would be even less predictable in solid cancers. In short, Applicant argues that is not obvious to apply the method of treating hematological cancers to solid cancers as instantly claimed given the activity of ADP-ribose in vitro. On page 12 of Applicant’s response, Applicant argues that Shalwitz shows cytotoxic effects in solid cancer cells in Example 7, but was due to synergistic fashion between lithium and ADPR, and ADPR sodium salt only reduced cell replication at 21 mM in Example 8 and displays anticytotoxic effects in bacterial extracts and possesses measurable inhibition of TNF-a mediated toxicity. Thus Applicant states that Shalwitz demonstrates activity against cancer cell replication with ADPR sodium alone, albeit Shalwitz in meant to support synergy with lithium and ADPR. Applicant argues that Shalwitz teaches away from ADPR in that it alone is not known to reduce cell replication. On page 13, Applicant argues that the dilithium ADPR only has activity due to synergy with lithium, and ADPR alone, or the sodium salt are not known to possess anticancer activity.
However, as discussed above, Shalwitz suggests ADPR (sodium salt) exhibits, albeit small reduction, in cellular replication in A549 cells at higher doses than ADPR dilithium (pg. 60, para. 00429). Shalwitz discloses that A549 cells are human alveolar adenocarcinoma cells (i.e. a solid tumor, pg. 60, para. 00427). Given that Shalwitz teaches the purpose of inhibiting this type of cancer cells, a person of ordinary skill in the art would have the motivation to apply this to the treatment of such solid tumors, given the study of this salt directly in solid tumor models as is instantly claimed. Additionally, Pero further suggests ADP-ribose has similar response curves as NAD in leukemic cells (pg. 6, lines 23-31). Although Pero does not teach ADP-ribose activity in solid tumors specifically, Pero teaches NAD achieves a cytotoxicity affect in human lung adenocarcinoma (H298 cells, page. 7, lines 19-26). Taken together, a person of ordinary skill would recognize the therapeutic activity generally of ADP-ribose generally, and the potential of the sodium salt specifically in these cancer cells as taught by Shalwitz. Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments (See MPEP 2123 (II)).
With respect to the cited references that Applicant argues that even if hematological cancers can be treated, it cannot be readily predicted it would show the same anti-cancer activity in solid cancers and cites that HDAC inhibitors can demonstrate efficacy in hematological cancers but fail to show clinically meaningful results in kidney cancer, prostate cancer, and head and neck cancer (para. 4). However, there is no such teaching that such a result is relevant to ADP-ribose specifically in the context of anti-cancer reagents. While the art relied upon may have preferred embodiments, the art as a whole suggests the broad anti-cancer activity of ADP-ribose and its salts.
On page 13 of Applicants response, Applicant argues that the ADP-ribose sodium salt was demonstrated to be effective in several solid cancer cell lines (last para.). Applicant argues the demonstrated activity was higher compared to that of Pero and Shalwitz. On page 14 of Applicant’s response, Applicant argues that ADP-ribose alone resulted in a significant reduction in tumor volume and showed no toxicity in normal cells (paras. 1-2). Applicant argues that Pero does not disclose anything specific about the toxicity of ADP-ribose sodium salt in normal cells. On page 15 of Applicant’s response, Applicant argues the application discloses an inhibitor effect on metastasis and invasive ability of cancer cells, which would not have been predicted by Pero or Shalwitz (para. 1). Applicant points to Example 3, figures 10 and 11 which demonstrates the ADP ribose sodium salt reduces the invasion ratio to 20% of less of the invasive rate of the control group (para. 1). In summation, Applicant argues the ADP-ribose sodium salt of the invention has significant anti-cancer effects that neither disclosed or anticipated by Pero and Shalwitz.
However, throughout the instant application, the active compound is solely referred to as ADP-ribose, not the specific sodium salt. While the instant specification mentions that alternative salts can be used (See specification, pg. 7, lines 11-20), the general disclosure points to “ADP-ribose” as the active ingredient, with no specific indication that the sodium salt is being used (see specification, pg. 1, lines 1-11, pg. 62, lines 18-19, drawings figure 10 and 11, i.e. ADPR= ADP-ribose). A person of ordinary skill would understand this to mean the compound, with no specific indication of a salt being used. Thus, wherein the results cannot be directly attributed to the sodium salt, the unexpected results are found to not be persuasive.
In short Shalwitz teaches the administration of ADP-ribose sodium salt as a non-preferred embodiment for the treatment of solid tumors. Pero further recognizes the anticancer/radio-sensitization ability of ADP-ribose as well. The instant specification points to ADP-ribose as the active ingredient, with no specific indication that the sodium salt is responsible for the claimed unexpected activity.
Applicant’s reply is considered to be a bona fide attempt at a response and is being accepted as a complete response. The 35 USC § 103 rejections are maintained for reason of record and foregoing discussion.
Conclusion
No claims are allowed in this action.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/S.L.G./Examiner, Art Unit 1693
/ANDREA OLSON/Primary Examiner, Art Unit 1693
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