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 .
Acknowledgement of Receipt
Applicant’s Response, filed 11/12/2025, in reply to the Office Action mailed 8/12/2025, is acknowledged and has been entered. Claims 2, 11, 14-16, 18, 26, 27, 31, 47, 55, 56, 67, 70, 77, 87 and 88 have been amended. Claims 2, 3, 8, 11, 14-16, 18, 26-28, 31, 47, 55, 56, 67, 70, 77, 87 and 88 are pending, of which claims 3, 16, 28, 31, 47, 55, 56, 67, 77, 87 and 88 are withdrawn from consideration at this time as being drawn to a non-elected invention. Claims 2, 8, 11, 14, 15, 18, 26, 27 and 70 encompass the elected invention and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. Any rejection not reiterated herein has been withdrawn. The Examiner’s response to Applicant’s arguments is incorporated below.
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.
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.
Claim(s) 2, 8, 11, 14, 15, 18, 26, 27 and 70 are rejected under 35 U.S.C. 103 as being unpatentable over Van Leeuwen et al. (WO 20/074705) in view of Perrin et al. (WO 20/124237), for reasons set forth in the previous Office Action.
Response to arguments
Applicant argues that a skilled artisan reading the publications of Van Leeuwen and Perrin would not find that the description within these publications, individually or collectively, would be able to reach the subject matter of claim 2, which includes a fluorine atom-carrying moiety, a chelating ligand moiety, an optical probe moiety, and a biological targeting moiety. Applicant notes that the Van Leeuwen publication does not describe a compound comprising a fluorine atom-carrying moiety; and that the Perrin publication does not meet the requirement of description and enablement to yield a compound as claimed in claim 2 because it does not provide an example of or provide enabling description of a compound with an optical probe moiety or of any product yielded by the intermediate DOTA-Bn-NH-Lys-(AMBF3)-NHFmoc. Applicant asserts that combining the synthesis protocols taught within Van Leeuwen and within Perrin would not successfully yield a product as alleged within the Office Action. Applicant argues that a compound of claim 2 comprises four complex chemical functionalities (i.e., the FCM, CL, OP, and BT) that require sequential synthesis to yield a singular compound. The synthesis process is difficult, especially considering one of the moieties is an optical probe that is required to remain within the dark to maintain its optical probe qualities. Applicant asserts that many of the steps of the synthesis process require precise control over reaction sequences and conditions. Furthermore, many of the intermediate products are purified by HPLC, resulting in significant losses of yield during several steps along the way. Accordingly, compounds comprising four complex chemical moieties, such as the compounds described within the claims, are distinctively more difficult synthesize than the compounds described in the Van Leeuwen publication and the Perrin publication. In fact, the difficulty of synthesis of three chemical functionalities is noted within the cited references. Applicant argues that the synthesis of compounds with the complex chemical functionalities as claimed is described within the Specification; noting that discussion of synthesis within paragraphs 234-244 highlight the difficulties of synthesizing such compounds.
Applicant’s arguments have been fully considered but are not found to be persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It is further noted that the arguments are not commensurate in scope with the claims. For example, the claims are extremely broad directed to a compound comprising: (i) a fluorine atom-carrying moiety (FCM); (ii) a chelating ligand moiety (CL); (iii) an optical probe moiety (OP); and (iv) a biological targeting moiety (BT), wherein one or more of the moieties of (i) to (iv) are affixed, bound, or connected by one or more linkers selected from L¹, L², L³, L⁴, L⁵, L⁶ and L⁷, e.g. wherein the linker may be e.g. a bond. The components may be conjoined in any manner and are not limited to any particular arrangement. As such, any asserted difficulties associated with synthesis of specific compounds arranged in a specific manner are not commensurate in scope with the claims. Further, Perrin specifically exemplifies compounds comprising a fluorine carrying moiety, a chelate and a biological targeting moiety, see e.g. Figures 2, 57, etc. among others, and teaches that the compound or molecular complex further comprises a fluorophore or other light emitting moiety, such as (but without limitation) Cy3, Cy5, Cy7, other near- IR dyes, or fluoresceine at paragraph 0161. Accordingly, it is considered that one of ordinary skill in the art would have been capable of providing a compound comprising the claimed components as suggested by Perrin with a reasonable expectation of success.
Applicant further argues that a skilled artisan would not find that the Perrin et al. publication describes and enables compounds with an optical probe or that the DOTA-Bn-NH-Lys-(AMBF3)-NHFmoc intermediate can yield a product compound. Applicant asserts that Perrin mentions fluorophores (and synonymous terms such as fluorescent molecules) twice within the Detailed Description, once in the Summary, and once in the Claims and that there is no further supporting description or enablement within these citations. Applicant argues that the only location within Perrin that provided more than a conclusory statement on compounds with a fluorophore was in paragraph 00342, however, as explained in the following paragraph, this paragraph is also lacking description and enablement to be considered prior art. Within paragraph 00342, Perrin alleges: "[i]t is further appreciated to those trained in the art, that the above DOTA-Lys(AMBF3) could be further conjugated to a fluorescent molecule. An example of such is provided below as one of many that could be considered by those trained in the art of multimodal imaging applications. Such an example would not be limited to DOTA, Cy7 or LysAMBF3 to be found to be practicable." The paragraph also contains an image of synthesis protocol that allegedly yields a product: DOTA-Lys(AMBF₃)-Cy7. Applicant argues that reading this paragraph and looking at the synthesis protocol, a skilled artisan would find the text and synthesis protocol is speculative and lacking any data to support that the synthesis protocol works to yield the product. Notably, every synthesis protocol within Perrin, except for the synthesis protocol within paragraph 00342, included description of the protocol steps and characterization data on the product. Without any description of the synthesis steps or data on the product, a skilled artisan would find that this synthesis protocol lacks the description and enablement to yield the DOTA- Lys(AMBF₃)-Cy7 product. Another critical issue with the Perrin et al. publication is that a key intermediate was not used in any of the other synthesis protocols. The synthesis protocol alleges the intermediate DOTA-Bn-NH-Lys-(AMBF3)-NHFmoc can be combined with Cy7-NHS to yield the DOTA-Lys(AMBF₃)-Cy7 product. Applicant asserts that no tangible products were derived from using the DOTA-Bn-NH-Lys-(AMBF3)-NHFmoc intermediate.
Applicant’s arguments have been fully considered but are not found to be persuasive. With regard to the assertion that the Perrin does not describe and enable compounds with an optical probe or that the DOTA-Bn-NH-Lys-(AMBF3)-NHFmoc intermediate can yield a product compound, it is respectfully submitted that a reference is not limited to what is taught by the examples, see MPEP 2123. Patents are relevant as prior art for all they contain. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)).
A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v.Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. “The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.”).
In the instant case it is considered that one of ordinary skill in synthetic organic chemistry desiring to incorporate a BF3 moiety on the compounds taught by Van Leeuwen comprising a DOTA chelate, fluorescent dye and PSMA targeting ligand, e.g. as set forth in the previous Office Action would have been capable of doing so by using the precursor of Perrin using standard NHS/amine coupling chemistry between chelate and a fluorescent dye, as shown by both Van Leeuwen (Fig. 1) and Perrin (paragraph 0342).
Applicant further argues that the combination of Van Leeuwen and Perrin does not yield a feasible product. Applicant asserts that there is no practical means to combine the synthesis protocols within Van Leeuwen and Perrin to yield a product with a fluorine atom-carrying moiety, a chelating moiety, an optical probe moiety, and biological targeting moiety and that the combination of Van Leeuwen and Perrin does not yield a working product. Applicant argues that the Office Action suggests that the DOTA-trifluoroborate pendant moiety yielded by Perrin protocol that yields an intermediate of DOTA-Bn-NH-Lys-(AMBF3)-NHFmoc can be combined with the Cy3 dye conjugated to a PSMA targeting ligand (Office Action, pp. 8-9). For this combination to make sense in light of the description within these references, the DOTA-Bn-NH-Lys-(AMBF3)-NHFmoc intermediate of Perrin would need to be combined with the Amine-Cy7-EuK(OtBu)3 intermediate of Van Leeuwen. Applicant notes that as within the analysis of the Perrin publication, the DOTA-Bn-NH-Lys-(AMBF3)-NHFmoc intermediate was not utilized within any synthesis protocol to yield a tangible product with supporting data, and that even for the sake of argument, the DOTA-Bn-NH-Lys-(AMBF3)-NHFmoc was not merely a speculative intermediate, the Perrin synthesis protocol deprotects DOTA-Bn-NH-Lys-(AMBF3)-NHFmoc to yield a free amine. The Van Leeuwen protocol also deprotects Amine-Cy7-EuK(OtBu)₃ to yield a free amine. Applicant argues that the two intermediates will not react to yield a product with an optical probe moiety, a chelating ligand moiety, and fluorine-atom carrying moiety. Accordingly, a skilled artisan combining the synthesis protocols of Van Leeuwen and Perrin would not have a reasonable expectation of successfully yielding a working product.
Applicant’s arguments have been fully considered but are not found to be persuasive. As set forth above, a patent is not limited to what is taught by the examples. It is noted that Van Leeuwen teaches in Example 1, directed to synthesis of exemplary compounds, that compounds were synthesized in accordance with the reaction scheme illustrated in Figure 1. In this reaction scheme, phthalimide-containing cyanine fluorophores in 1) the amine liberation resulted in 2) amine-containing cyanine fluorophores. Conjugation with EuK leads to 3) fluorescence-only targeting precursors. Subsequent addition of an MAS3-NHS chelate resulted in 4) hybrid tracer precursors that contained both a fluorescent and a chelate for radiolabelling. 5) Deprotection of the EuK moiety leads to activation of the targeting EuK. a-g provide an overview of the different indole substituents for the dyes used within the matrix. While this synthesis is demonstrated for the probe EuK and chelate MAS3, as the skilled person will appreciate, the synthesis may be readily adapted to other probes (e.g. EuAF or EuPG) and other chelates (e.g. MAG3, DOTA-GA, DOTA, DTPA) (paragraph 0115).
Additional synthetic strategies including DOTAG A (0tBu)4(S03)-Cy5-EuK(0tBu)3 are further taught, paragraph 0143+.
Perrin teaches an intermediate DOTA-Bn-NH-Lys-(AMBF3) amine-bearing precursor that is reacted with a NHS-bearing fluorescent dye, see page 96.
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Perrin further teaches in paragraph 0153-4: in some embodiments, the metal chelator attaches to the linker or to the cell-targeting domain by forming an amide bond (between an amino group and a carboxylic acid group) or a 1 ,2,3- triazole (reaction between an azide and an alkyne), or by reaction between a maleimide and a thiol group.
In some embodiments, the chelator is attached (with or without a linker) to the N- terminus of a peptide/polypeptide/protein cell-targeting domain and the BF3-containing moiety (or precursor) is attached (with or without a linker) to the C-terminus of the cell-targeting domain. In some embodiments, the chelator is attached (with or without a linker) to the C-terminus of a peptide/polypeptide/protein cell-targeting domain and the BF3-containing moiety (or precursor) is attached (with or without a linker) to the N-terminus of the cell-targeting domain. In some embodiments, the chelator is attached (with or without a linker) to the N-terminus of a peptide/polypeptide/protein cell-targeting domain and the BF3-containing moiety (or precursor) is attached (with or without a linker) to a side chain of the cell-targeting domain. In some embodiments, the chelator is attached (with or without a linker) to the C-terminus of a peptide/polypeptide/protein cell-targeting domain and the BF3-containing moiety (or precursor) is attached (with or without a linker) to a side chain of the cell-targeting domain. In some embodiments, both the chelator and the BF3-containing moiety are attached (with or without linkers) to separate side chains of a peptide/polypeptide/protein cell-targeting domain. In some embodiments, the chelator is attached to the N-terminus or the C-terminus of a peptide/polypeptide/protein cell-targeting domain via a linker and the BF3-containing moiety (or precursor) is attached to the linker. In some embodiments, the chelator is attached to a side chain of a peptide/polypeptide/protein cell-targeting domain via a linker and the BF3-containing moiety (or precursor) is attached to the linker. For illustrative purposes, Figure 1 shows various non-limiting configurations of the compound or complex.
Accordingly, Perrin teaches a variety of suitable linking chemistry and one of ordinary skill in the art would have been capable of modifying the linking chemistry between the chelate and rest of the conjugate molecule (fluorophore), such as by the presence of NHS or amine on either of the chelate or fluophore for the purpose of covalent linkage of the components as functionally equivalent means to link the components. One would have had a reasonable expectation of success in doing so because Van Leeuwen teaches directionality of amide bond in various linkers may include e.g. -C(O)-R13-NH-, where R13 is a bond, or a substituted or unsubstituted alkyl; for example L.sub.2 may be a bond, a residue of lysine, a residue of ornithine, a residue of aspartic acid, a residue of glutamic acid, or -NH-(CO-C7alkyl)-C(O)- (paragraph 0008).
Conclusion
No claims are allowed at this time.
THIS ACTION IS MADE FINAL. 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 LEAH H SCHLIENTZ whose telephone number is (571)272-9928. The examiner can normally be reached Monday-Friday, 8:30am - 12:30pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL HARTLEY can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618