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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 6, 2026, has been entered.
Response to Arguments
Applicant has amended the claims require a hydrobromide or dihydrobromide salt form. Applicant has also added that the cancer to be treated overexpresses IDO, TDO, or both. The examiner responds to these amendments and reiterates positions already of record, where applicable.
With respect to a hydrobromide or dihydrobromide salt for being claims, the examiner notes that Cadieux teaches numerous examples of acid addition salt forms, including dihydrochloride and dihydrobromide embodiments. Further, acid addition salts including those formed with hydrobromic acid are taught. See par. 71.
Cadieux also teaches inhibiting DMT1 to mitigate excess iron in subjects with conditions associated therewith including cancer. The examiner cites the following new prior art and evidentiary references in response to Applicant’s amendments to the claims.
Xue et al., Iron Uptake via DMT1 Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis, Cell Metab. 2016 Aug 18;24(3):447–461.
Xue teaches systemic iron balance is implicated in colorectal cancer. DMT1 is highly expressed in CRC and inhibiting DMT1 disrupted colon tumor models in mice. A pharmacological inhibitor of DMT1 antagonized the ability of iron to promote tumor growth in a CRC mouse model and a patient-derived CRC enteroid orthotopic model. Xue further explains that DMT1 is responsible for intracellular iron accumulation in colorectal cancer and iron activates CDK1-JAK1-STAT3 to support tumor cell proliferation. Thus, in view of Xue, there is a mechanistic basis to think that those DMT1 inhibitors taught by Cadieux will treat colorectal cancer.
With regard to claim 43, the examiner cites the following evidentiary references.
As evidenced by Zhao et al., “TDO2 knockdown inhibits colorectal cancer progression via TDO2–KYNU–AhR pathway,” Gene 792 (2021) March 2021: “Moreover, 30 CRC tissue samples that contained both tumor tissue and corresponding normal tissues were used to detect the TDO2 expression levels between tumor and normal tissues via qRT-PCR. TDO2 expression was found to be significantly higher in tumor tissues than in normal tissues (Fig. 2B).” TDO2 was also noted to be highly expressed in most tumors. See p8, 3rd par.
As evidenced by Yang et al., “IDO1 inhibitors are synergistic with CXCL10 agonists in inhibiting colon cancer growth,” Biomedicine & Pharmacotherapy 179 (2024), “IDO1 is highly expressed in colon cancer patients and is associated with poor prognosis [21], demonstrating the potential of IDO1 inhibitors for the treatment of colon cancer.” See p2, 3rd full par.
As such, compounds taught by Cadieux include the claimed compound. Salt forms including dihydrobromide salt forms are provided in examples and hydrobromic acid is taught for use as an acid addition salt. A POSA would immediately envisage the claimed slat forms. Further, one particular salt form, absent evidence to the contrary, is not patentably distinguishing in view of the prior art.
Cadieux teaches treating conditions including cancer by inhibiting DMT1. Xue teaches that inhibiting and disrupting DMT1 will treat colon and colorectal cancer cells. Xue teaches system iron balance is implicated in colorectal cancer and that DMT1 is highly expressed in CRC and notes that a pharmacological inhibitor of DMT1 was shown to antagonize the ability of iron to promote tumor growth in a CRC mouse model and a patient-derived CRC enteroid orthotopic model.
Thus, there is a reasonable expectation that the claimed compounds will inhibit DMT1 and antagonize the ability of iron to grow colon and colorectal cancer. Zhao evidences TDO2 expression was found to be significantly higher in CRC tumor tissues than in normal tissues and Yang evidenced IDO1 as highly expressed in colon cancer patients.
The examiner notes that the instant claims include the following compounds as specific compounds claimed within a more generic formula of independent claim 34:
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. The examiner notes that a mono-substituted compound with one halogen is also claimed wherein halogen is bromine or chlorine.
The prior art teaches:
The following two compounds constitute the closest prior art embodiments.
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, wherein the sole difference is a single fluorine atom. Further, the prior art teaches the following core formula:
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and provides for the substituents to include the following limited listing:
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Even further, examples are provided in which R3a-R3d include 2 chlorine atoms in the claimed positions, as shown below.
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The instant Specification includes many compounds that are not halogenated, including the compound above shown on pages 343-355 of the Specification. It would be inconsistent to provide a Specification directed to compounds that include no halogen atoms and provide unexpected results compared to the closest prior art wherein halogen atoms are required.
Patani teaches the substitution of a fluorine for a hydrogen is one of the most commonly employed bioisosteric substitutions. See p3149, 4th full par. Numerous examples are provided in which a fluorine is substituted for a hydrogen in antineoplastic drugs and they show efficacy, including for the drug 5-fluorouracil (5-FU). Overall, “the ability of fluorine to replace hydrogen is an effective method of exploring the affinity of an agent to the target site (receptor or enzyme) by virtue of its greater electronegativity while other parameters such as steric size and lipophilicity are maintained.” See p3150, 2nd par.
The examiner provides two independent and specific rationales for establishing a prima facie showing. The first is the replacement of a single fluorine for a hydrogen. The second is that the prior art teaches the claimed core structural scaffold as well as similar embodiments wherein two chlorine atoms are in the claimed positions and substituted for variable substituents among a limited list. No showing of unexpected results has been established because any data must provide a comparison to the closest prior art. Such comparison has not been made of record.
With respect to Applicant’s allegations of unexpected results the examiner responds.
The results show percentages in different assays. It is not clear there is a statistically significant difference between the compound 1, which is taught by the art and the other halogenated forms. Here is why.
No statistical significance is shown. It is also not clear what the confidence intervals of the comparisons are. More importantly, the IDO and TDO cell-based assays (which are the most important assays for simulating in vivo conditions) do not show superiority for the breadth of compounds claimed. Claim 1 is a compound taught by the prior art with no halogen. For compound 1 IDO and TDO percentages in the cell-based assays are 11% and -3%, respectively. For compound 2 which comprises a fluorine atom, the percentages are 7% and 7%, respectively. It is not clear that this 4% and 10% distinction constitutes a statistically significant advantage.
Moreover, compound 7 has a single chlorine atom (i.e., is halogenated) and has values of 0% and -1% for IDO and TDO assays, respectively. Compound 6 has 4 fluorine atoms with an IDO value well above 11%; and compounds 2, 7, and 10 (which are each halogenated) have values for IDO that are well below 11%. For TDO, compound 1 has a value of -3% while compounds 7 and 10 have values of -1% and 2%. Compound 36 (which has 2 chlorine atoms) has a TDO value of -15%.
Overall, the values of compounds that are halogenated are not clearly better than compound 1 nor are they shown to be statistically different. In each column of the IDO and TDO cell-based assays, compounds that are halogenated as compared to a non-halogenated compound taught by the prior art are inclusive of higher and lower percentages. It is not clear how this is a showing of a statistically significant advantage as compared to the closest prior art.
As such, no claim is allowed.
Status of the Claims
Claims 34, 37-43, and 46-48 are pending and examined.
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 34, 37-43, and 46-48 are rejected under 35 U.S.C. 103 as being obvious over Cadieux et al., (US2010/0240713), in view of Patani et al., “Bioisosterism: A Rational Approach in Drug Design,” Chem. Rev. 1996, 96, 3147-3176, and in view of Xue et al., Iron Uptake via DMT1 Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis, Cell Metab. 2016 Aug 18;24(3):447–461, as evidenced by Zhao et al., “TDO2 knockdown inhibits colorectal cancer progression via TDO2–KYNU–AhR pathway,” Gene 792 (2021) March 2021, and as evidenced by Yang et al., “IDO1 inhibitors are synergistic with CXCL10 agonists in inhibiting colon cancer growth,” Biomedicine & Pharmacotherapy 179 (2024).
Cadieux teaches a generic formula wherein each substituent on a benzene, e.g., can be at any location. The formula below is the most generic formula that provides for substituents to be acceptable at any position on a benzene ring.
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Cadieux also teaches Examples in which the substituents are on adjacent positions of a claimed cyclic structure. See both structures below wherein the ring is benzene or naphthalene in Examples 3.15 and 3.20. Thus, the claimed molecule as shown below is preferred, with the exception of a halogen substituent.
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Cadieux also provides examples in which isomers of these include compounds with a claimed ring structure (i.e., a thiophene), include halogens at claimed positions. See Example 9, below.
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.
Even further, Cadieux teaches isomers and mixtures thereof. Cadieux also teaches specific core formula structures wherein the undefined variables include R3a, R3b, and R3e.
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See par. 442.
Compounds of formula Ib-1 can be prepared by those methods known in the art. See par. 443.
The above generic formula is a claimed formula wherein R3a, R3b, R3c, and R3d are halo. They are defined to not only include halogen, but halogen is preferred as it is shown among a limited list of potential substituents. See paragraph 196, below wherein R3a-R3e include halogen among only 6 options.
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Thus, in view of Formula (Ib-1), a POSA would understand and immediately envisage a halo at the position of 3a-3e on a benzene ring. This is the sole distinction between the instant claims and Cadieux. Moreover, the halogens above include chlorine in two positions.
Applicant also claims the below compound.
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the sole difference between these compounds is the substitution of a hydrogen for a fluorine at a single position. Cadieux teaches using acid addition salts, provides examples of dihydrobromide salts, and teaches using hydrobromic acid. See par. 71.
Moreover, Patani teaches the substitution of a fluorine for a hydrogen is one of the most commonly employed bioisosteric substitutions. See p3149, 4th full par. Numerous examples are provided in which a fluorine was substituted for a hydrogen in antineoplastic drugs and it worked, including for the drug 5-fluorouracil (5-FU). Overall, “the ability of fluorine to replace hydrogen is an effective method of exploring the affinity of an agent to the target site (receptor or enzyme) by virtue of its greater electronegativity while other parameters such as steric size and lipophilicity are maintained.” See p3150, 2nd par.
Applicant has claimed compounds that fall within the scope of Cadieux. Applicant has not provided an allegation of unexpected results and as such the examiner is determining if a prima facie showing is established in view of the cited prior art. Cadieux is a POSA that would almost certainly recognize the claimed compounds as those that would have efficacy of the compounds taught by Cadieux.
Carriers and excipients can be included with the claimed compound. See par. 388. It is taught to treat cancer. See par.’s 357 and 365. The compound can be used in combination with one or more additional therapeutic agents. See Example 3.2, among others. Compounds can be used as a prodrug, with an excipients, and/or a salt form can be used. See p4, lines 6-16. A carrier can be used. See p15, line 13.
The structurally similar and overlapping compounds taught by Cadieux to treat cancer do so by inhibiting DMT1 to treat iron disorders.
Xue teaches DMT1 is highly expressed in CRC and inhibiting DMT1 disrupted colon tumor models in mice. A pharmacological inhibitor of DMT1 antagonized the ability of iron to promote tumor growth in a CRC mouse model and a patient-derived CRC enteroid orthotopic model.
As evidenced by Zhao et al., with respect to colorectal cancer cells TDO2 expression was found to be significantly higher in tumor tissues than in normal tissues (Fig. 2B).” TDO2 was also noted to be highly expressed in most tumors. See p8, 3rd par.
As evidenced by Yang et al., “IDO1 is highly expressed in colon cancer patients and is associated with poor prognosis [21], demonstrating the potential of IDO1 inhibitors for the treatment of colon cancer.” See p2, 3rd full par.
It would have been prima facie obvious prior to the filing of the instant application to arrive at the claimed compounds and methods in view of the cited prior art. One would be motivated to do so because Cadieux teaches similar compounds, including a generic core formula that is identical to compounds claimed with the exception of specifying halogen substituents on the benzene ring. Additionally, halogens are among a limited list of substituents taught to be included at the claimed positions. As such a POSA would understand that the claimed compounds can be used to inhibit DMT1 thereby treating iron excess in those subjects with cancer. Xue teaches that DMT1 is elevated in colon and colorectal cancers and inhibiting DMT1 as taught by Cadieux will treat CRC cells. Zhao and Yang evidence the elevated expression of TDO and IDO in CRC and colon cancer cells. As such, a POSA would be motivated to administer the claimed compound with a reasonable and predictable expectation of success that it would function as a DMT1 inhibiting for treating iron disorders, including cancer. This is further supported because DMT1 inhibitors have been shown to treat colorectal cancer by antagonizing the effect of iron in facilitating tumor growth. Moreover, many cancer cells lines have increased TDO and IDO, including colon and colorectal cancer cell lines when compared to normal controls. As such, the administration of a compound that is expected to inhibit DMT1 and is taught to treat cancer has a reasonable expectation of success in doing so when administered to a subject with colon and CRC because such cancers are known to overexpress DMT1, which yields excess iron and promotes the growth of those tumors. Merely claiming a salt form of an obvious compound without a showing that such salt form is not merely an equivalent salt form does not obviate the prior art of record.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 34, 37-43, and 46-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 7-9, 11, 13-17, 20, 29, and 31 of copending Application No. 18/942,152, in view of Cadieux et al., (US2010/0240713), in view of Patani et al., “Bioisosterism: A Rational Approach in Drug Design,” Chem. Rev. 1996, 96, 3147-3176, and in view of Xue et al., Iron Uptake via DMT1 Integrates Cell Cycle with JAK-STAT3 Signaling to Promote Colorectal Tumorigenesis, Cell Metab. 2016 Aug 18;24(3):447–461, as evidenced by Zhao et al., “TDO2 knockdown inhibits colorectal cancer progression via TDO2–KYNU–AhR pathway,” Gene 792 (2021) March 2021, and as evidenced by Yang et al., “IDO1 inhibitors are synergistic with CXCL10 agonists in inhibiting colon cancer growth,” Biomedicine & Pharmacotherapy 179 (2024).
The claims of the ‘152 application include compounds and methods of treating cancer with compounds and IDO/TOD inhibitors presently claimed and those rendered obvious in view of the cited prior art. Claim 7 of the ‘152 application is directed to the same core formula presently claimed. In view of the overlapping compounds and methods of use, including for those reasons set forth above, the claims are provisionally rejected for those same reasons and rationale set forth above with respect to the claims in this application.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy Clark can be reached on 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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/JARED BARSKY/Primary Examiner, Art Unit 1628
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