DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims 21, 23-24, and 33-36 are pending in this application.
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 1-20, 22, and 25-32 are cancelled. Claim 36 is new.
Response to Amendment
The amendments filed on 9 Jun. 2026 have been entered.
Response to Arguments
In view of Applicants amendments, the objection to claim 21 because of minor informalities is withdrawn.
In view of Applicants amendments, the rejection of claims 25-30 under 35 USC 103 as being unpatentable over Rodriguez et al. (Mitochondrion; published 2008), in view of Herrnstadt et al. (US 2003/0087858 A1; published 8 May 2003) and Madar et al. (US 2004/0033197 A1; published 19 Feb. 2004) is withdrawn.
In view of the certified translation filed on 9 Jun. 2026, the rejection of claims 21, 25-28, 30, and 34-35 under 35 USC 102(a)(1) as being anticipated by Inkster et al. (J. Nucl. Med.; published 2019) is withdrawn.
In view of the certified translation filed on 9 Jun. 2026, the rejection of claims 21, 25-30, and 33-35 under 35 USC 103 as being unpatentable over Inkster et al. (J. Nucl. Med.; published 2019), in view of Rodriguez et al. (Mitochrondrion; published 2008) and Mou et al. (Molecules; published 30 Mar. 2017) is withdrawn.
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.
Claim(s) 21, 23-24, and 33-35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rodriguez et al. (Mitochondrion; published 2008), in view of Herrnstadt et al. (US 2003/0087858 A1; published 8 May 2003) and Yuan et al. (Chem. Commun.; published 2013), in further view of Mou et al. (Molecules; published 30 Mar. 2017) for the reasons cited in the Office action filed on 12 Mar. 2026.
Applicants Arguments
Applicants assert that Yuan and Mou are similarly flawed and the combination of Rodriguez, Herrndstadt, Yuan, and Mou fails to render the claims obvious. Yuan merely mentions acridium (NAO) as a potential independent probe for mitochondria not as a validated or tested cardiac PET tracer. Mou reviews general PET tracers but does not show or suggest that acridinium cations are myocardial perfusion agents. The Dr. Wlostowska declaration demonstrates the unexpected result of selectively of the compounds described herein for the heart, allowing sufficient visualization of the heart using the claimed PET cardiovascular diagnostic method to examine the cardiovascular system of a mammal. The cited references fail to disclose or suggest a cardiotracer compound capable of rapid, selective uptake in the myocardial wall of healthy subjects, rapid plasma clearance and clear visualization of the heart within minutes and greater accumulation in the heart compared to other organs. None of the cited references, alone or in combination, disclose or suggest the claimed positron emission tomography diagnostic method, further comprising testing a myocardial perfusion of a myocardium of the mammal to quantify regional blood flow.
Applicant's arguments filed 9 Jun. 2026 have been fully considered but they are not persuasive. The Dr. Wlostowska declaration was found ineffective for the reasons cited in the Office action filed on 12 Mar. 2026. Expected beneficial results are evidence of obviousness. Rodriguez teaches that NAO as a highly specific probe for CL and teaches that all of MAO, HAO and NAO show excellent specificity for the mitochondria. At pg. 245, Rodriguez teaches using the acridine orange derivatives therein for imaging mitochondria with reasonable expectation of success. Yuan provides for selectively visualization of the heart using PET cardiovascular diagnostic methods to examine the cardiovascular system of a mammal wherein the selective visualization administers a mitochondrial targeted probe. At Fig. 3, Yuan provides scans illustrating that a mitochondrial cardiotracer compound accumulated in the healthy tissue of the patient’s heart. Visible deficits were observable. The Fig. 3 in Yuan shows clear PET imaging of the heart. At pg. 10363, Yuan provides some teaching that NAO derivatives are advantageous for imaging the mitochondria rich heart. Obviousness does not require absolute predictability. A person of ordinary skill would have reasonably expected 18F-labeled NAO derivatives to accumulate in healthy heart tissue of a patient’s heart and enable clear PET imaging of the heart since 18F-labeled NAO derivatives are taught and suggested as having excellent specificity for the mitochondria and since Yuan teaches that PET labeled mitochondria target enable clear visualization of the heart and defect areas.
Rodriguez provides for the MAO, HAO, and NAO acridine orange compounds reading in part on instant formula I differing only at the R2 group of claimed formula I that requires an atom of 18F fluorine radioisotope replacing a hydrogen atom at one of the carbon atoms and a -CH2 fragment as a terminal member of a chain. At pg. 237, Rodriguez teaches that CL has an important role in heart ischemia. At pg. 242, Rodriguez teaches that all compounds showed excellent specificity for mitochondria. Herrnstadt teaches that for in vivo imaging acridine orange can be labeled with 18F and at Fig. 4, Herrnstadt teaches modification of acridine orange at the N-alkyl substituent. Yuan teaches that mitochondrial targeted probes can be of the mitochrondrial binding, potential independent type. An example of a potential independent probe is nonyl acridine orange which binds to cardiolipin target. Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention is an exemplary rationale for obviousness. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the teaching of Rodriguez by incorporating 18F on MAO, HAO, and NAO or homologue derivative thereof to arrive at a compound of formula I and then administer that compound to a mammal in order to perform a cardiological diagnostic positron emission tomography scan on the mammal and examine the cardiovascular system as taught by Rodriguez, Herrnstadt, and Yuan because it would have been expected to advantageously enable imaging the mitochondrial rich myocardium and perfusion deficits independent of mitochondrial potential.
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 21, 23-30, and 33-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending Application No. 19/312,604, in view of Rodriguez et al. (Mitochondrion; published 2008), and Yuan et al. (Chem. Commun.; published 2013) for the reasons cited in the Office action filed on 12 Mar. 2026. This is a provisional nonstatutory double patenting rejection.
Applicants Arguments
Applicants assert that this rejection will be addressed once the claims of the present application are otherwise in condition for allowance.
Applicant's arguments filed 9 Jun. 2026 have been fully considered but they are not persuasive. The NSDP rejection is being maintained for the reasons cited in the Office action filed on 12 Mar. 2026.
New Grounds of Rejection
Claim Rejections - 35 USC § 103
Claim(s) 36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rodriguez et al. (Mitochondrion; published 2008), in view of Herrnstadt et al. (US 2003/0087858 A1; published 8 May 2003) and Yuan et al. (Chem. Commun.; published 2013).
Rodriguez et al. teach targeting of mitochondria by 10-N-alkyl acridine orange analogues: role of alkyl chain length in determining cellular uptake and localization (see title). Rodriguez et al. teach that cardiolipin CL has an important role in pathologies such as heart ischemia and Barth syndrome (see pg. 237). The fluorescent dye 10-N-nonyl-acridine orange (NAO) has been used as a highly specific probe for CL. The high binding affinity of NAO to CL has been used to determine a number of properties of CL, e.g. to image CL (see pg. 238). Rodriguez et al. teach synthesizing 3 analogues of NAO bearing C-1 (MAO), C-6-(HAO), and C-16-alkyl chains (HDAO) (Table 1; instant X=Br-) in the 10-position.
A variety of derivatives have been made for different applications. All acridine orange compounds show some selectivity for mitochondria and CL (see pg. 238). MAO and NAO have similar uptake in MCF-7c3 cells (human breast cancer cells). HAO showed the highest uptake. HAO and NAO enter the cells quicky, reaching maximum values by 30 min (see pg. 241). MAO, HAO, and NAO showed excellent specificity for mitochondria (pg. 242). The data show that a long chain alkyl chain is not essential for cellular binding. HAO appears to be a superior acridine orange derivative for imaging mitochondria, because it is useful at very low concentrations with minimal perturbation of cells (pg.245).
Rodriguez et al. do not teach the instant cardiological diagnostic method comprising administering to a mammal the instant cardiotracer compound to a mammal wherein the cardiotracer compound comprises 3,6-bis(dimethylamino)-10-(2-[18F]fluoroethyl)acridinium salt and wherein the method comprises performing cardiological diagnostic PET scan on the mammal, and examining the cardiovascular system of the mammal.
Herrnstadt et al. teach diagnostic and therapeutic compositions for Alzheimer’s disease (see title). Herrnstadt et al. teach that mitochondria carrying mutated cytochrome c oxidase genes have increased levels of cardiolipin and other negatively charged phospholipids as well as increased mitochondrial membrane potential. As a result, the mitochondria selectively accumulate acridine orange and lipophilic cations such as rhodamine 123 and JC-derivatives. In in vivo diagnosis a targeting molecule such as acridine orange is labeled with 18F as an imaging ligand. This labeled targeting molecule is introduced into the bloodstream of a patient ([0101]-[0102], [0110]-[0111]). Herrnstadt et al. teach acridine orange derivatives (see Fig. 4). Hernstadt et al. teach human disease ([0003])
Yuan et al. teach fluorescent and radiolabeled triphenylphosphonium probes for imaging mitochondria (see title). Yuan et al. teach that diverse types of lipophilic cations have been used for mitochondrial targeting and imaging mitochondria. The TPP group has been used to obtain [18F] probes to image myocardial perfusion (see pg. 10361). The TPP fluorochromes behave like many other lipophilic cations with uptake by the functional myocardium and not by perfusion deficit (pg. 10361). Yuan et al. teach imaging myocardial perfusion deficit after injection of [18F]-labelled TPP fluorochrome (Fig. 3; connotes pharmaceutically acceptable carrier formulated as a sterile solution). A perfusion deficit was observed in the lateral wall of the heart. Mitochondrial targeted probes can be either of the mitochondrial membrane potential dependent type or mitochondrial binding, potential independent type. Examples of the potential independent probes include BODIPY based OBEP and nonyl acridine orange (NOA) which binds to a cardiolipin. Substantial corrections for mitochondrial binding are essential when determining mitochondrial membrane potential (pg. 10363).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Rodriguez et al. (NAO and its homologue derivatives such as MOA, HAO that that show some selectivity to CL and show excellent specificity to mitochondria and their use for detection of mitochondria) so that the N-alkyl substituent is a [18F]fluoroethyl substituent to arrive at a 3,6-bis(dimethylamino)-10-(2-[18F]fluoroethyl)acridinium salt and then administer that compound with a pharmaceutically acceptable carrier to a mammal such as a human and perform cardiac diagnostic PET on the subject and examine the cardiovascular system of the subject as taught Herrnstadt et al., and Yuan et al. because that compound and cardiological diagnostic method would have been expected to advantageously enable imaging the mitochondrial rich myocardium and perfusion deficits independent of mitochondrial membrane potential. Homologues are prima facie obvious due to a general expectation of similar properties. See In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
Double Patenting
Claim 36 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending Application No. 19/312,604, in view of Rodriguez et al. (Mitochondrion; published 2008), and Yuan et al. (Chem. Commun.; published 2013). This is a provisional nonstatutory double patenting rejection.
Claims 1-17 of copending Application No. 19/312,604 a PET diagnostic method and compound I
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wherein X- is a pharmaceutically acceptable counterion such as mono-basic inorganic acid; n is an integer of 9; R3 and R4 combine to form a butadienyl-1,3 substituent whose terminal atoms are linked to adjacent non-nodal carbon atoms to for an aromatic C ring with the A and B ring systems; and wherein R1 may H, or amino group having 2 hydrogen atoms replaced with C1-C6 alkyl; and wherein R2 is a carbon aliphatic chain having 1-16 carbon atoms, 18F fluorine radioisotope replacing a H on one of the carbon atoms and a CH2 fragment as a terminal member of a chain wherein the chain connects to H and wherein the method administers the compound to a subject and performs a PET scan on the subject and further comprises testing myocardial perfusion of a myocardium of the subject to quantify blood flow or further comprises quantifying coronary reserve and pharmaceutical composition further comprising a pharmaceutically acceptable carrier or diluent and optionally formulated as a sterile solution
Claims 1-17 of copending Application No. 19/312,604 do not further claim the instant cardiological diagnostic method wherein the cardiotracer compound comprises 3,6-bis(dimethylamino)-10-(2-[18F]fluoroethyl)acridinium salt.
Rodriguez et al. teach as discussed above.
Yuan et al. teach as discussed above.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify claims 1-17 of copending Application No. 19/312,604 so that 2R1’s=-NMe2 and R3 and R4 combine to form an acridinium ring and so that the cardiotracer compound is 3,6-bis(dimethylamino)-10-(2-[18F]fluoroethyl)acridinium salt as taught by Rodriguez et al. and Yuan et al. because that compound and cardiological diagnostic method would have been expected to advantageously enable imaging the mitochondrial rich myocardium and perfusion deficits independent of mitochondrial membrane potential.
Conclusion
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 SEAN R DONOHUE whose telephone number is (571)270-7441. The examiner can normally be reached on Monday - Friday, 8:00 - 5:00 EST.
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/SEAN R. DONOHUE/
Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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