DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Acknowledgement of Receipt
Applicant’s Response, filed 6/25/2026 in reply to the Office Action mailed 2/25/2026, is acknowledged and has been entered. Claims 32 and 79 have been amended. Claims 32, 33, 35-37, 39-42, 72-83 are pending, of which claims 73, 74, 78 and 82 are withdrawn from consideration at this time as being drawn to a non-elected invention. Claims 32, 33, 35-37, 39-42, 72, 75-77, 79-81 and 83 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 Any rejection not reiterated herein has been withdrawn.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 previous rejection has been modified, necessitated by claim amendment. The Examiner’s response to Applicant’s arguments is 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 32, 33, 35-37, 39-42, 71-72, 75-77, 79-81 and 83 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 11,592,396, for reasons set forth in the previous Office Action.
Claims 32, 33, 35-37, 39-42, 71-72, 75-77, 79-81 and 83 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 9,155,471 in view of U.S. Patent Publication No. 2003/0044353 to Weissleder, for reasons set forth in the previous Office Action.
Response to arguments
Applicant argues that as the scope of the instant claims may change during prosecution, Applicant asserts that the double patenting rejections should be held in abeyance until allowable subject matter has been reached.
Applicant's arguments have been fully considered. The rejections are maintained at this time as terminal disclaimers have not been received.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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 32, 33, 35-37, 39-42, 71-72, 75-77, 79-81 and 83 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Rajopadhye (US 2009/0220430).
Rajopadhye teaches intramolecularly quenched imaging agents for use in both in vivo and in vitro imaging that contain at least one enzymatically cleavable oligopeptide and two fluorophores or a fluorophore and a quencher. When subjected to proteolytic cleavage, at least one fluorophore is unquenched and becomes capable of producing a fluorescent signal upon excitation with light of an appropriate wavelength. Also provided are in vivo and in vitro imaging methods using such imaging agents (abstract).
In one aspect, the invention provides an intramolecularly-quenched imaging agent. The agent comprises (a) an enzymatically cleavable oligopeptide comprising from about 2 to about 30 amino acid residues; (b) an optional biological modifier chemically linked to the enzymatically cleavable oligopeptide; and (c) either two fluorophores or one fluorophore and one quencher, each covalently linked, directly or indirectly, to the oligopeptide or to the optional biological modifier, wherein one fluorophore quenches the other fluorophore or the quencher quenches the fluorophore and upon enzymatic cleavage of the oligopeptide, at least one fluorophore becomes unquenched and is capable of producing a greater fluorescent signal when excited by electromagnetic radiation than before enzymatic cleavage of the oligopeptide (paragraph 0008).
An exemplary imaging agent is: Acetyl-Phe-Arg-Lys(F5)-Gly-Gly-Arg-Lys(F5)-[OH] (Table 6).
An exemplary imaging agent is pentynoyl-Phe-Arg-Lys-(F5)-Gly-Gly-Arg-Lys(F5) (Table 7).
As used in Table 6, F5 is the fluorochrome as depicted above in agent Q77, F6 is the fluorochrome as depicted above in agent Q88, MPEG is methoxypolyethylene glycol of a specified molecular weight (for example, mPEG20K is a 20 kDa methoxypolyethylene glycol). Ahx is aminohexanoic acid, Orn is ornithine, and DAP is 2,3-diaminopropionic acid (paragraph 0267).
Further, it is taught that an oligopeptide may be:
Phe-Arg-Lys-Gly-Gly-Arg-Lys-Ahx (Table 4, oligopeptide 27).
As with all the imaging agents discussed herein, the two fluorophores or the fluorophore and the quencher are located within the intact imaging agent at fluorescent-quenching interaction permissive positions. In other words, a first fluorophore is located close enough in the intact imaging agent to a second fluophore (or quencher) to permit them to interact photochemically with one another so that the second fluorophore (or quencher) quenches the signal from the first fluorophore. In the case of the imaging agents with two fluorophores, one fluorophore preferably quenches the other fluorophore (paragraph 0202).
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(paragraph 0264).
Claim 1 is directed to an intramolecularly-quenched imaging agent comprising: (a) an enzymatically cleavable oligopeptide comprising from about 2 to about 30 amino acid residues; (b) an optional biological modifier chemically linked to the enzymatically cleavable oligopeptide; and (c) either two fluorophores or one fluorophore and one quencher, each covalently linked, directly or indirectly, to the oligopeptide or to the optional biological modifier, wherein one fluorophore quenches the other fluorophore or the quencher quenches the fluorophore and upon enzymatic cleavage of the oligopeptide, at least one fluorophore becomes unquenched and is capable of producing a greater fluorescent signal when excited by electromagnetic radiation than before enzymatic cleavage of the oligopeptide.
In claim 4, the agent of claim 1 is represented by:
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Further, it is taught that L may comprise a moiety selected from the group consisting of an amido bond, amino-polyethylene glycol-carboxylic acid, amino-polyethylene glycol azide, diaminoPEG, cysteic acid, glutamic acid, aminocaproic acid, ethylenediamine, propylenediamine, spermidine, spermine, hexanediamine, and a diamine-amino acid (claim 21).
With regard to claim 33, enzymatic cleavage by cathepsin is taught (paragraph 0256 and Examples).
With regard to claim 35, various useful, exemplary fluorophores are commercially available and include, for example: Cy5.5, Cy5 and Cy7; AlexaFlour660, AlexaFlour680, AlexaFluor750, and AlexaFluor790; VivoTag680, VivoTag-S680, and VivoTag-S750; Dy677, etc. (paragraph 0160).
With regard to claim 36 and 37, a number of quenchers are available and known to those skilled in the art including, but not limited to 4-{[4-(dimethylamino)-phenyl]-azo}-benzoic acid (DABCYL), QSY-7 (9-[2-[(4-carboxy-1-piperidinyl)sulfonyl]phenyl]-3,6-bis(methylphenylamin- o)-xanthylium chloride, QSY-33, etc. (paragraph 0200).
With regard to claim 39, optical imaging in the visible spectrum can be used (paragraph 0004).
With regarding claims 40-41, the in vivo half-life of the agent can be designed to be at least about 10 minutes, but more preferably 30 minutes to several hours (paragraph 0257). Further, the exemplified structures disclosed by Rajopadhye contain the structural elements of the instant claims. Accordingly, the imaging agents would be capable of the same functional properties. A composition and its properties are inseparable. See MPEP 2112.
With regard to claims 42 and 75-76, pharmacokinetic modifiers, spacers and linkers are taught, see paragraph 0267, e.g. aminohexanoic acid, as well as paragraph 0214, which teaches that linkers or spacer moieties can be used to covalently link one or more fluorophores, quenchers, biological modifiers and non-fluorescent reporters to an enzymatically cleavable oligopeptide or to an optional biological modifier, as well as aminocaproic acid, etc. in claim 21.
Accordingly, Rajopadhye does not specifically exemplify an imaging probe comprising at least one visible light fluorochrome and at least one or more quenchers separated by an enzyme cleavage site and a spacer, wherein the enzyme cleavage site is an amino acid sequence selected from the group consisting of GGRK and GRKL and the spacer is aminohexanoic acid.
However, it would have been obvious to one of ordinary skill in the art at the time of the invention to provide an imaging probe comprising at least one visible light fluorochrome and at least one or more quenchers separated by an enzyme cleavage site and a spacer, wherein the enzyme cleavage site is an amino acid sequence selected from the group consisting of GGRK and GRKL and the spacer is aminohexanoic acid in view of the broader teaching of Rajopadhye. For example, Rajopadhye teaches an exemplary imaging agent is: Acetyl-Phe-Arg-Lys(F5)-Gly-Gly-Arg-Lys(F5)-[OH] (Table 6), or an exemplary imaging agent is pentynoyl-Phe-Arg-Lys-(F5)-Gly-Gly-Arg-Lys(F5) (Table 7). While the exemplary imaging agents do not specifically recite an Ahx spacer, it would have been obvious to provide an aminohexanoic acid spacer, with a reasonable expectation of success, because Rajopadhye teaches aminocaproic acid, which is synonymous with aminohexanoic acid, as one of a few suitable linkers positioned between an enzymatically cleavable peptide and fluorophore and quencher, see claims 4 and 21. Further, Phe-Arg-Lys-Gly-Gly-Arg-Lys-Ahx is taught to be a suitable oligopeptide in Table 4. With regard to claims 75 and 76, directed to further spacers, it is noted that the linkers in claims 4 and 21 of Rajopadhye may be selected independently, as such more than one spacer/linker may be present, including aminocaproic acid, which is synonymous with aminohexanoic acid.
With regard to the amended limitation wherein the spacer is chemically linked to a glycine residue of the enzyme cleavage site, is noted that Rajopadhye teaches that a linker, including aminocaproic acid/aminohexanoic acid, may be present on either end of the enzymatically cleavable oligopeptide, see variables K, which may be N-L and G, which may be F-L, of an agent having the structure
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.
Response to arguments
Applicant argues that claim 32 has been amended to recite, "wherein the spacer is chemically linked to a glycine residue of the enzyme cleavage site." Applicant asserts that Rajopadhye does not inherently or expressly disclose, nor does it render obvious, the above referenced feature. As noted on page 7 of the Office Action, the Patent Office alleges that Rajopadhye teaches a GRKL enzyme cleavage site chemically linked to an aminohexanoic acid spacer. However, Table 4, oligopeptide 27 of Rajopadhye, which was cited in the Office Action, shows aminohexanoic acid chemically linked to a lysine residue of a GRKL oligopeptide. In contrast, claim 32 specifies the spacer is chemically linked to a glycine residue of a GGRK and/or GRKL cleavage site.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that while the exemplary imaging agents set forth in Rajopadhye do not specifically recite an Ahx spacer in the stated position, with regard to the amended limitation wherein the spacer is chemically linked to a glycine residue of the enzyme cleavage site, is noted that Rajopadhye teaches that a linker, including aminocaproic acid/aminohexanoic acid, may be present on either end of the enzymatically cleavable oligopeptide, see variables K, which may be N-L, and G, which may be F-L, of an agent having the structure
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. According to MPEP § 2123, prior art documents are relevant for all that they contain, including alternative embodiments, nonpreferred options, and broader teachings. Applicant’s arguments have been fully considered but the rejection is maintained.
Conclusion
No claims are allowed at this time.
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 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
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