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 .
DETAILED ACTION
This Office Action is in response to Applicant’s Arguments and Amendment filed, 10/15/2025, wherein the Amendment amended claims 15 and 19-20.
Claims 1-3, 7-16, and 19-24 are pending.
Priority
This application claims the following priority:
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Election/Restrictions
Applicant elected Group I and
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as the THAD Derivative (FIII) species, in the reply filed on 01/08/2024.
In the course of the search, the entire scope of instant claim 1 was searched. As such, the election of species requirement over these compounds is hereby withdrawn.
In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 7-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-3 and 19-24 are examined on the merits herein.
WITHDRAWN REJECTIONS
The status for each rejection and/or objection in the previous Office Action is set out below.
Claim Objections
Applicant’s amendment to claim 19 is partially sufficient to overcome this objection.
35 U.S.C. § 112(d)
Applicant’s amendments to claims 19 and 20 are sufficient to overcome this rejection.
35 U.S.C. § 112(a)
The declaration under 37 CFR 1.132 filed 10/15/2025, is sufficient to overcome the rejection of claims 1-3 and 19-24 based upon 35 U.S.C. § 112(a).
Declarant persuasively argues that the HMCD moiety is what imparts the tumor-targeting function (i.e., homing function) to the compounds, and that since the HMCD moiety is part of the core structure of all of the instantly claimed compounds, the instant claims are described in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.
Specifically, Declarant states “although the HMCD moiety may be substituted at the R1 and R2 positions, such substitutions do not alter its tumor-targeting or homing function. This is because the halogen atom, available for Michael addition with serum albumin, remains accessible for conjugation and albumin binding.”
This is confirmed by Shi (Heptamethine carbocyanine dye mediated near-infrared imaging of canine and human cancers through the HIF-1alpha/OATPs signaling axis, Oncotarget, published 2014, PTO-892) on pg. 10114 1st full paragraph; pg. 10117, Col. 1, last full paragraph; and abstract.
Double Patenting over co-pending Application No. 18/123,236
Applicant’s arguments that neither Chung 1 nor ‘236 teaches or suggests a conjugate with two identical moieties combined with the amendment to ‘236 that limits the anticancer drug to paclitaxel or docetaxel, is sufficient to overcome this rejection.
REJECTIONS-MAINTAINED/MODIFIED
Applicant’s amendments to the claims have resulted in the below slightly modified prior art rejection. The same prior art references continue to be relied upon.
Claim Interpretation
-In claim 19, in view of the THAD structures of claim 1, “the THAD conjugate of a dye residue conjugated to a dihydroartemisinin (DHA residue)” is interpreted as the compounds of FI, FII, FIII, and FIV, since these structures contain a tumor-homing dihydroartemisinin derivative conjugated to a dye residue.
-In claim 19, DHA is interpreted as artemisinin or dihydroarteminisinin ([0001], Specification). HMCD is interpreted as heptamethine carbocyanine dye ([0001], Specification). DZ1a and DZ1c are interpreted as
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([0051], Specification).
-In claim 19, in “a),” “DZ1a-DHA-ether, DZ1a, bis-DHA-ether” limits the structures of FI and FII, when n is 6 and R3 of FI is C6 alkyl.
-In claim 19, in “c),” “DZ1c-bis-DHA-carbamate, DZ1c-bis-DHA-thiocarbamate” limits the structure of FIV, when n is 6 and Y is O or S.
-In claim 20, the F identifiers and DZ identifiers are interpreted as alternative identifiers for the individual species. See for example, pgs. 13-14 of the instant specification. FVIII (DZ3d) is a compound of FII, as recited in claim 1. FVX (DZ3f) and FXII (DZ3h) are compounds of FIV, as recited in claim 1.
Claim Objections
(Maintained/New) Claim 19 is objected to because of the following informalities:
-(New) In claim 19, the phrase “wherein the THAD conjugate of a dye residue conjugated to a dihydroartemisinin (DHA) residue” should be deleted. This phrase is superfluous since the generic THAD conjugates of a dye residue conjugated to a DHA residue are fully defined in claim 1, and lines 1-5 of claim 19 are directed toward the further limiting of just the dye reside of the THAD of claim 1, and then lines 6-15, of claim 19 are further limiting the THAD of claim 1 (i.e., compounds of Formulas FI-FIV), which is the THAD conjugate.
-(Maintained) Claim 19 recites the acronym HMCD without defining it. Since this is the first iteration of this acronym, it should be amended to recite “heptamethine carbocyanine dye (HMCD).”
Appropriate correction is required.
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 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.
(Modified) Claims 1, 3, and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/075996 to Chung (published 04/26/2018, IDS of 06/15/2023) in view of WO 2016/106324 to Chung (published 2016, PTO-892 of 04/01/2024).
Chung ’996 (Chung 1) teaches a method of treating cancer by administering dye-therapeutic conjugates [00153]-[00156], [00159], [00164], [00166], [00179]-[00181; pg. 89, claim 10).
The dyes are compounds of formula I:,
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(pgs. 19-20; pg. 85, claim 1).
In some embodiments R3 and R4 are the same ([0093]).
Chung 1 specifically teaches that:
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(paragraph 97).
Chung 1 exemplifies the following dye-therapeutic moiety conjugate:
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(pg. 86, claim 2; pg. 88, claim 6; pg. 89, claim 13)
Regarding instant claim 1, while Chung teaches ‘996 teaches
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, it differs from that of the instantly claimed compound of FIII in that it does not depict
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at
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.
Chung 1 additionally teaches dye-artemisinin conjugates as greatly enhancing the tumor growth inhibitory effects and cytotoxic effects of artemisinin in tumors, such as tumor spheroids, B-cell lymphoma, castration-resistant prostate cancer, and renal cancer, as represented by their IC50s ([0037]-[0038]; Figs. 28). Chung 1 teaches artemisinin as having superior effects in comparison to puromycin and doxorubicin (Fig. 30).
Chung ‘324 (Chung 2) teaches a method of treating cancer by administering dye-drug conjugates (abstract; pg. 8, 1st paragraph; pgs. 30-31, claims 8-11).
Chung 2 specifically teaches the dye-drug conjugate as:
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(pg. 7), wherein the drug-dye conjugate is represented by:
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(pg. 9).
Chung 2 teaches the following symmetrical species:
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(pgs. 12-13; pgs. 27-29, claim 8).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to modify
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of Chung 1 by substituting
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at the circled position, to arrive at the instantly claimed compound of FIII. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-both Chung 1 and Chung 2 are directed toward cyanine dye-drug conjugates for the treatment of cancer,
-Chung 1 teaches that its R3 and R4 moieties,
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, can be the same,
-Chung 2 teaches heptamethine cyanine dye molecules of
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, wherein the molecules can be symmetrical and R3 and R4 are therapeutic agents,
-Chung 2 exemplifies three symmetrical species,
-Chung 2 teaches that embodiments of its heptamethine cyanine dye-drug conjugates have several advantages, including “a single cyanine dye can be conjugated with multiple equivalent of drugs to further amplify the effectiveness of chemotherapy” (pg. 8, 1st paragraph), and
-Chung 1 teaches
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as greatly enhancing the tumor growth inhibitory effects and cytotoxic effects of artemisinin in tumors, and as having superior effects in comparison to puromycin and doxorubicin, as measured by IC50 values.
As such, an artisan having ordinary skill in the art would have been motivated to make such a modification to predictably arrive at a therapeutically effective conjugate that more potently treats cancer and amplifies the effectiveness of chemotherapy
Regarding claim 3, Chung 1 teaches pharmaceutical compositions comprising these dye-therapeutic conjugates and at least one pharmaceutically acceptable carrier (pg. 88, claim 8).
Regarding claim 21, the combination of Chung 1 and 2 teach compound FIII.
Regarding claims 22 and 23, the combination of Chung 1 and 2 teach compound FIII, wherein X is Cl and R1 and R2 are H.
Thus, claims 1, 3, and 21-23 are rendered obvious.
Response to Arguments
On pg. 14, Remarks, Applicant argues that compound 9 does not represent the most promising lead compound.
This argument has been fully considered. Chung 1 specifically exemplifies “Compound 9,”
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, as a preferred compound.
Regarding lead compounds, MPEP 2143, Example 9, references Eisai Co. Ltd. V. Dr. Reddy’s Labs. This example teaches that a) any known compound might serve as a lead compound; b) “In the field of pharmaceutical chemistry, the term ‘lead compound’ has been defined variously as a ‘chemical compound that has pharmacological or biological activity and whose chemical structure is used as a starting point for chemical modifications in order to improved potency, selectivity, or pharmacokinetic parameters; and c) “any known compound might possible serve as a lead compound: ‘Obviousness based on structural similarity thus can be proved by identification of some motivation that would have led one of ordinary skill in the art to select and then modify a known compound (i.e. a lead compound) in a particular way to achieve the claimed compound.” And in the case of Eisai Co. Ltd. v. Dr. Reddy’s Labs, the proposed modification to the compound of the prior art (lansoprazole) to arrive at the claimed compound (rabeprazole) reduced the lipophilicity of the compound. “Thus the prior art created the expectation that the rabeprazole would be less useful than the lansoprazole as a drug for treating stomach ulcers and related disorders because the proposed modification would have destroyed an advantageous property of the prior art compound.”
Eisai v. Dr. Reddy is in contrast to the above rejection which properly identifies the lead compound,
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, and provides motivation to modify the lead compound to arrive at the instantly claimed compound, a compound with superior properties.
As discussed above:
-Chung 2 teaches that embodiments of its heptamethine cyanine dye-drug conjugates have several advantages, including “a single cyanine dye can be conjugated with multiple equivalent of drugs to further amplify the effectiveness of chemotherapy (pg. 8, 1st paragraph), and
-Chung 1 teaches dye-artemisinin conjugates as greatly enhancing the tumor growth inhibitory effects and cytotoxic effects of artemisinin in tumors, and as having superior effects in comparison to puromycin and doxorubicin, as measured by IC50 values.
As such, an artisan of ordinary skill would have been motivated to make such a modification to predictably arrive at a therapeutically effective conjugate that more potently treats cancer and amplifies the effectiveness of chemotherapy
On pgs. 14-15, Remarks, Applicant argues that Chung 1 discloses that its compounds may be modified in multiple regions, and that the breath of these variable substituents encompass hundreds of thousands of potential structural permutations within Chung 1, alone.
This argument has been fully considered, but is not found persuasive. The instant rejection does not modify multiple regions of
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, but modifies
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of Chung 1 by substituting
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at the circled position, to arrive at the instantly claimed compound of FIII, i.e., a single modification and not a modification of “multiple regions.” And as discussed in detail in the above rejection, there is motivation to make such a modification.
On pgs. 15-16, Remarks, Applicant argues that Chung II encompasses a vast number of potential modifications and that the Office Action has not identified any rationale or motivation to single out a particular symmetrical structure from Chung II for modification, and that none of the anticancer conjugates of Chung II are structurally similar to DHA.
This argument has been fully considered, but is not found persuasive. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-both Chung 1 and Chung 2 are directed toward cyanine dye-drug conjugates for the treatment of cancer,
-Chung 1 teaches that its R3 and R4 moieties,
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, can be the same,
-Chung 2 teaches heptamethine cyanine dye molecules of
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, wherein the molecules can be symmetrical and R3 and R4 are therapeutic agents,
-Chung 2 exemplifies three symmetrical species,
-Chung 2 teaches that embodiments of its heptamethine cyanine dye-drug conjugates have several advantages, including “a single cyanine dye can be conjugated with multiple equivalent of drugs to further amplify the effectiveness of chemotherapy” (pg. 8, 1st paragraph), and
-Chung 1 teaches
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as greatly enhancing the tumor growth inhibitory effects and cytotoxic effects of artemisinin in tumors, and as having superior effects in comparison to puromycin and doxorubicin, as measured by IC50 values.
As such, an artisan having ordinary skill in the art would have been motivated to make such a modification to predictably arrive at a therapeutically effective conjugate that more potently treats cancer and amplifies the effectiveness of chemotherapy
On pg. 16, Remarks, Applicant argues that only conjugates containing a single drug moiety were selected for preclinical investigation in Chung II, indicating that conjugates incorporating two identical or different drug components were considered less favorable for further development.
This argument has been fully considered, but is not found persuasive. Applicant is respectfully reminded that the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor. See MPEP 716.01(c). Applicant has provided no evidence that “only conjugates containing a single drug moiety. . .were selected for preclinical investigation.”
Moreover, Applicant is reminded that patents are relevant as prior art for all they contain and “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments (In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971), MPEP 2123). As discussed in the above rejection, Chung II clearly claims and exemplifies compounds comprising symmetrical linkers and drugs attached to the HMCD dye, (pgs. 27-28, claim 7; pgs. 11-12), and clearly teaches:
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On pg. 17, Remarks, Applicant argues that a bis-DHA conjugate of F-
III exhibits markedly superior potency compared to its mono-DHA counterpart, and points to Figure 2A, wherein compound DZ3b is 17-fold more potent than compound DZ3a. Applicant concludes by stating that these results underscore the unexpected nature of the structure-activity relationship, illustrating that the effect of conjugating tow DHA moieties to an HMCD dye could not have been reasonable predicted from the cited art.
This argument has been fully considered, but is not found persuasive. DZ3b has the following structure:
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, while DZ3a, the compound of Chung 1, has the following structure:
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.
While the examiner agrees that the IC50 values for cancer cell lines Caki-1 and MDVR of DZ3b are unexpectedly lower than those of DZ3a, this result is not commensurate in scope with instant claim 1 which recites THAD compounds of FI, FII, FIII, and FIV. And while DZ3a is a species of instant generic compound FIII, the unexpected results of DZ3a are also not commensurate in scope with generic compound FIII since R1 and R2 are defined as
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, “A” is any pharmaceutically acceptable negatively charged anion, and n is 2-20.
Applicant is reminded that unexpected results a) are greater than expected results, b) show superiority of a property shared with the prior art, c) exhibit the presence of an unexpected property, and/or d) exhibit the absence of an expected property. MPEP 716.02 additionally states that unexpected results must be commensurate in scope with the claimed invention and provide a comparison with the closest prior art.
For these reasons the arguments are not persuasive to overcome the instant rejection.
Free of the Prior Art & Allowable Subject Matter
Claims 2, 19-20, and 24 are free of the prior art. Claims 2, 19-20 and 24 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The closest prior art is WO 2018/075996 to Chung (published 04/26/2018, IDS of 06/15/2023).
Chung ’996 teaches a method of treating cancer by administering dye-therapeutic conjugates [00153]-[00156], [00159], [00164], [00166], [00179]-[00181; pg. 89, claim 10).
The dyes are compounds of formula I:,
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(pgs. 19-20; pg. 85, claim 1).
In some embodiments R3 and R4 are the same (paragraph 93).
Specifically exemplified is:
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(paragraph 97).
The following dye-therapeutic moiety conjugate is exemplified:
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(pg. 86, claim 2; pg. 88, claim 6; pg. 89, claim 13).
However, the reference does not teach or render obvious the linkers as having identical alkyl ether groups, identical alkylNHC(O)O- groups, alkylNHC(S)O- groups, or an alkylsulfonate group and an alkylC(O)O- group, which are distinct features of instant FI, FII, FIV and the compounds of instant claims 19-20 and 24.
As such, these claims are free of the prior art.
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN WELLS whose telephone number is (571)272-7316. The examiner can normally be reached M-F 7:00-4:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Jim) Alstrum-Acevedo can be reached on 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LAUREN WELLS/Examiner, Art Unit 1622