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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3/24/2026 has been entered.
Status of Claims
Claims 1 and 32 have been amended. Claims 1, 4, 6-8, 10, 12-14, 16, 17, 19, 20, 22-25 and 30-32 are pending, of which claims 4, 6, 8, 10, 12-14, 16, 17, 19 and 20 are withdrawn from consideration at this time as being drawn to a non-elected invention. Claims 1, 7, 22-25 and 30-32 encompass the elected invention and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. The previous rejections have been modified to address claim amendment. The Examiner’s response to Applicant’s arguments are incorporated below.
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 1, 7, 22-25 and 30-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23+ and 37+ of copending Application No. 18/641,097 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are directed to an imaging dye agent… including KUE-ZW-800-1 in claim 1, and a method of imaging and treating cancer cells, as well as an imaging agent dye comprising a charge-balanced imaging agent conjugated to a targeting vector (TV), wherein the targeting vector is cRGD, dPSMA-617, KUE, a FAP binding vector, a bombesin receptor binding vector, or a somatostatin receptor binding vector; wherein the charge-balanced imaging agent is ZW-800-1, ZW-830-1, or ZW-700-1-Forte; wherein the charge-balanced imaging agent is conjugated to the targeting vector via a linking group; and wherein the linking group is a PEG-moiety having 2 to 6 carbon atoms, wherein the PEG- moiety is bound to the charge-balanced imaging agent through an ester group, etc. The claims of the ‘097 Application are directed to a method for increasing the tumor-to-background ratio of a charge- balanced imaging administered to a patient agent for the purpose of detecting and diagnosing cancer, comprising: conjugating a targeting vector to the charge-balanced imaging agent via a linking group, wherein the linking group is a PEG-moiety having 2 to 6 carbon atoms and is bound to the charge- balanced imaging agent through an ester group. See in particular claim 42 including KUE-ZW-800-1. Accordingly, the claims of the ‘097 encompass the instantly claimed compounds and methods and the claims are obvious variants of one another. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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) 1, 7, 22-25 and 30-32 are rejected under 35 U.S.C. 103 as being unpatentable over Bao et al. (Chem. Comm., 2017, 53(10), p. 1611-1614) in view of Frangioni (US 2015/0209451).
Bao teaches KUE-conjugated NIR fluorophores were synthesized and their PSMA binding was tested in terms of net charges, spacer length, hydrophobicity, and polarity. Since the size of KUE is smaller than that of effector domain, we hypothesized that the targeting efficiency as well as biodistribution and clearance patterns of KUE conjugates would be strongly governed by the conjugated NIR fluorophores. To systematically compare the influence of physicochemical properties of fluorophores on PSMA targeting efficiency, as shown in Fig. 1, a serious of polymethine fluorophores were selected and conjugated with various length of polyethylene glycol (PEG): a pentamethine cyanine (i.e., Cy5.5) and 800 nm heptamethine fluorophores (i.e., Cy7, ZW800+3C, ZW800-1, and ZW800-3C) (page 2).
KUE-PEG2-ZW800-1 is shown in the Supplementary materials, page 7.
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To investigate the influence of linker space on PSMA binding, different lengths of PEGx (x = 0, 2, 4, 12, or 24) were applied between KUE and ZW800+3C. PEG spacers can provide sufficient flexibility for a targeting ligand to overcome spatial limitations in order to effectively interact with a corresponding target protein or receptor.28,29 As shown in Fig. 3b, in vitro PSMA targeting efficiency revealed that PEG2 (10 atoms, ≈11 Å) and PEG4 (16 atoms, ≈18 Å) provided an optimum length for keeping the potent PSMA specificity of KUE (page 3).
Accordingly, Bao does not specifically exemplify a compound KUE-ZW800-1, wherein the linking group is a PEG-moiety having 2 to 6 carbon atoms and is bound to a charge balanced imaging agent through an ester. It is noted that the PEG-moiety linker in Bao’s KUE-PEG2-ZW800-1 compound amounts to a linker comprising an amine-PEG2 moiety which comprises 7 carbon atoms.
Frangioni teaches compositions for and methods of optically imaging tissues or cells using imaging agents having desirable in vivo properties that result in improved signal-to-background ratio (abstract).
The invention provides methods of imaging tissue or cells, the methods including (a) contacting the tissue or cells with an imaging agent comprising a dye or conjugate thereof, the conjugate comprising a targeting ligand attached to the dye, wherein the dye or conjugate has a net charge of +1, 0, or -1 and comprises one or more ionic groups; (b) irradiating the tissue or cells at a wavelength absorbed by the dye or conjugate; (c) detecting an optical signal from the irradiated tissue or cells, wherein the signal-to-background ratio of the detected optical signal is at least about 1.1, thereby imaging the tissue or cells.
The invention further provides methods of preparing a dye for imaging tissue or cells, the method including (a) selecting a dye having peak absorption at about 500 nm to about 850 nm and peak fluorescent emission at about 550 nm to about 875 nm; (b) optionally modifying the dye to include a linking group; and (c) modifying the dye, and optionally the linking group, to include one or more ionic groups to achieve a solubility of the dye of at least about 10 .mu.M in 10 mM HEPES solution at pH 7.4; wherein the one or more ionic groups are selected so that the net charge of the dye is +1, 0, or -1, and wherein the signal-to-background ratio of fluorescent emission detected from the dye compound while imaging is at least about 1.1 (paragraph 0005-8).
A conjugate may have the following formula:
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An example of a targeting ligand is KUE (paragraph 0031).
The dye may be of formula X (paragraph 0105).
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As used herein, the phrase "non-ionic oligomeric or polymeric solubilizing groups" refers to soluble polymers such as, for example, polyethylene glycol, polypropylene glycol, polyethylene oxide and propylene oxide copolymer. The point of attachment can be, e.g., a carbon-carbon bond, a carbon-oxygen bond, or a nitrogen-carbon bond. The attachment group can be, e.g., an ester group, a carbonate group, a ether group, a sulfide group, an amino group, an alkylene group, an amide group, a carbonyl group, or a phosphate group (paragraph 0141).
Some examples of solubilizing groups include polyethylene glycols, such as --(CH2CH2O)a--H, --OC(=O)O(CH2CH2O)aH, --OC(--O)O(CH2CH2O)aCH3, --O(CH2CH2O)aCH3, and --S(CH2CH2O)aCH3, "a" being an integer between about 2 and about 250 (paragraph 0142).
The solubilizing moiety can have an absolute molecular weight of from about 500 amu to about 100,000 amu (paragraph 0143).
The conjugates described herein can be used for, e.g., optical tomographic, endoscopic, photoacoustic, and sonofluorescent applications for the detection, imaging, and treatment of tumors and other abnormalities. The conjugates can also be used for localized therapy. This can be accomplished, e.g., by attaching a porphyrin or other photodynamic therapy agent to a conjugate; directing the conjugates to a desired target site, or allowing the conjugates to accumulate selectively in the target site; shining light of an appropriate wavelength to activate the agent. Thus, the new conjugates can be used to detect, image, and treat a section of tissue, e.g., a tumor (paragraph 0187).
It would have been obvious to one of ordinary skill in the art at the time of the invention to modify the linking chemistry between ZW800-1 and KUE in the compounds of Bao, such as KUE-PEG2-ZW800-1 comprising amide linker chemistry when the teaching of Bao is taken in view of Frangioni for use in preparation of a targeting ligand dye conjugate for imaging or treatment. For example, each of Bao and Frangioni are directed to a dye linked to a targeting agent, including ZW800-1 and Kue via a PEG containing linker. Frangioni readily teaches that a linker may comprise an oligomeric or polymeric moiety including polyethylene glycol such as (CH2CH2O)a wherein a may range from 2-250 and various points of attachment to include a carbon-carbon bond, a carbon-oxygen bond, or a nitrogen-carbon bond and can be, e.g., an ester group, a carbonate group, a ether group, .. an alkylene group, an amide group, a carbonyl group, etc.
With regard to the limitation wherein the PEG- moiety is bound to the charge-balanced imaging agent through an ester group, one could have substituted one known point of attachment between ZW800-1 and KUE at either end of the linker, such as substitution of an ester, ether, or carbon-carbon or carbon-oxygen bond for amide linker as a functionally equivalent linking group or slightly modified the linker length among the range set forth in Frangioni to obtain a compound according to the instant claims. See MPEP 2144. A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. “An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties.” In rePayne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In rePapesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963).
With regard to claim 32, wherein the linking group is a PEG-moiety having 2 to 6 carbon atoms, wherein the PEG- moiety linking group is bound to the charged balanced imaging agent before preparation of preparation of the imaging agent dye moiety, or the PEG-moiety linking group is bound to the targeting vector before preparation of preparation of the imaging agent dye moiety, it is noted that such a limitation is considered to be a product-by-process limitation. See MPEP 2113. Product-by-process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985).
Response to arguments
Applicant argues that Bao et al. discloses KUE-PEGx-ZW800-1 conjugates where X = 2, 4, 12, or 24. Applicant asserts that the linker structures disclosed in Bao contain nitrogen atoms as part of the amine-PEG linkage chemistry. Specifically, Bao's conjugates utilize an amine-containing linker to connect the KUE targeting ligand to the ZW800-1 fluorophore, and that the conjugation chemistry results in amide bonds containing nitrogen atoms within the linker structure. Applicant asserts that the limitation "wherein the PEG-moiety is bound to the charge-balanced imaging agent through an ester group" as recited by claim 1, as amended, explicitly excludes nitrogen-containing linkages such as those present in Bao's amine-PEG linker structures. Indeed, Applicants assert that nothing in Bao teaches or suggest a linking group that comprises only carbon and oxygen atoms. Furthermore, Bao et al specifically states that the optimal spacing for their compounds require 11-16 atoms to maintain PSMA specificity. (Page 3, lines 30-32) This reads on PEG moieties having at least 7 carbon atoms - in addition to the nitrogen and oxygen atoms required in the PEG structure. As such, Applicants assert that there would have been no reason for one of ordinary skill in the art to modify Bao et al. to use the claimed number of carbon atoms in addition to excluding the amide linkage without resorting to undue experimentation. Applicant further argues that Frangioni defines "reactive linking group" as including "at least one reactive group selected from a carboxylic acid group or anhydride or ester thereof, as well as an isothio-cyanate group." Frangioni, paragraph [0147]. Applicants note that the isothiocyanate group contains nitrogen, and the typical conjugation chemistry described would result in nitrogen- containing linkages. Frangioni further describes that "R21 can be H, to form the carboxy group which is reactive with amines or other nucleophiles" and that "R21 can also represent carboxyl activating substituents such as N-succidimidyl [sic] (NHS) which can facilitate conjugation." Frangioni, paragraph [0155]. Such NHS-mediated conjugation results in amide bonds containing nitrogen atoms. Applicant contends that while Frangioni discloses various attachment modes, nothing in Frangioni specifically teaches or suggests a linking group that comprises only carbon and oxygen atoms to the exclusion of nitrogen atoms. Indeed, Applicants assert that one of ordinary skill in the art would readily understand that the use of an ester linkage VS an amide linkage would have different reactivities in the bloodstream such that stability of the molecule, cleavage rates, clearance rates, and fluorescent activity would all be expected to differ between ester and amide linkages. As such, Applicants assert that nothing in Bao nor Frangioni, alone or in combination, teaches or suggests a linking group that binds a PEG moiety to the imaging agent (i.e., the dye) using an ester group, as recited by claim 1.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that while the PEG-moiety linker in Bao's KUE-PEG2-ZW800-1 compound amounts to a linker comprising an amine-PEG2 moiety which comprises 7 carbon atoms, it is known from Frangioni that points of attachment between the linker and targeting ligand or dye may include include a carbon-carbon bond, a carbon-oxygen bond, or a nitrogen-carbon bond and can be, e.g., an ester group, a carbonate group, a ether group, an alkylene group, an amide group, a carbonyl group, etc. One could have substituted one known point of attachment between ZW800-1 and KUE at either end of the linker, such as substitution of an ester, ether, or carbon-carbon or carbon-oxygen bond for amide linker as a functionally equivalent linking group without undue experimentation as a means of selection of a disclosed bond, or slightly modified the linker length among the range set forth in Frangioni to obtain a compound according to the instant claims. See MPEP 2144.09. A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963). Applicant's arguments have been fully considered but the rejection is maintained.
Conclusion
No claims are allowed at this time.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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