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
Status of Application, Amendments, and/or Claims
The Information Disclosure Statement (IDS) filed 13 July 2023 has been entered. Applicant’s amendment of the claims filed 10 April 2026 has been entered.
Election/Restriction
Applicant’s election, without traverse, of Group I, claims 1-16, in the reply filed on 10 April 2026 is acknowledged.
Claims 1-17 are pending. Claim 17 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1-16 are under examination.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Sequence Rules Compliance
The instant application is not fully compliant with the sequence rules, 37 CFR 1.821-1,825, because each disclosure of a sequence embraced by the definitions set forth in the rules is not accompanied by the required reference to the relevant sequence identifier (i.e., SEQ ID NO). This occurs in the specification at page 7, line 28 through page 8, line 6. Compliance with the sequence rules is required.
Claim Objections
The following claims are objected to because of the informalities:
It is suggested to use the term “A urokinase Plasminogen Activator Receptor (uPAR)-targeting conjugate” in claim 1, and then use the term “the uPAR-targeting conjugate” thereafter.
In claim 1, the phrase “said linker group either being part of the molecule binding to the receptor or being a separate component of the urokinase Plasminogen Activator Receptor- targeting conjugate” should be “said linker group either being part of the molecule binding to the receptor or being a separate component”.
In claims 1-2, 7 and 13, the term “tumor-to-background ratio TBR” should be “tumor-to-background ratio (TBR)”.
In claim 4, “a biological half-life in a human” should be “a half-life in a human”.
In claim 5, it is suggested to amend the claim to recite: “The urokinase Plasminogen Activator Receptor-targeting conjugate according to claim 1, wherein the urokinase Plasminogen Activator Receptor-targeting conjugate has a maximum plasma half-life of 75 hours.”
In claim 7, it is suggested to amend the claim to recite: “The urokinase Plasminogen Activator Receptor-targeting conjugate according to claim 1, wherein a peak animal tumor-to-background ratio (TBR) after administration is at least 3.”
In claim 8, it is suggested to amend the claim to recite: “The urokinase Plasminogen Activator Receptor-targeting conjugate according to claim 1, wherein the binding of the urokinase Plasminogen Activator Receptor-targeting conjugate to an urokinase Plasminogen Activator Receptor has a binding constant KD at a maximum of 2,500 nM.”
In claim 9, it is suggested to amend the claim to recite: “The urokinase Plasminogen Activator Receptor-targeting conjugate according to claim 1, wherein the binding of the urokinase Plasminogen Activator Receptor-targeting conjugate to an urokinase Plasminogen Activator Receptor has an on-rate (Kon) >1 x 103 M-1s-1 and/or an off-rate (Koff) < 1 x 10-1s-1.”
In claim 10, it is suggested to amend the claim to recite: “The urokinase Plasminogen Activator Receptor-targeting conjugate according to claim 9, wherein the urokinase Plasminogen Activator Receptor-targeting conjugate has a Kon that is equal to or higher than the Kon of a natural urokinase Plasminogen Activator (uPA), and the Kon of the urokinase Plasminogen Activator Receptor-targeting conjugate is ≥ 4.6 x 106 M-1s-1.”
In claim 11, it is suggested to amend the claim to recite: “The urokinase Plasminogen Activator Receptor-targeting conjugate according to claim 1, wherein the urokinase Plasminogen Activator Receptor-targeting conjugate displaces a natural urokinase Plasminogen Activator binding to an urokinase Plasminogen Activator Receptor with IC50 at a maximum value of 1,000 nM.”
In claim 13, it is suggested to amend the claim to recite: “…wherein the urokinase Plasminogen Activator Receptor-targeting conjugate has a maximum plasma half-life of 15 hours, wherein the urokinase Plasminogen Activator Receptor-targeting conjugate has a Kon that is equal to or higher than the Kon of a natural urokinase Plasminogen Activator (uPA), and the Kon of the urokinase Plasminogen Activator Receptor-targeting conjugate is ≥ 4.6 x 106 M-1s-1…”.
In claim 16, “human urokinase Plasminogen Activator Receptor uPAR” should be “human urokinase Plasminogen Activator Receptor”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 10 and 13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 10 and 13 use the word “implying”, which renders the claims indefinite because it is unclear whether the limitation(s) following the “implying” are part of the claimed invention.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 1 recites “A urokinase Plasminogen Activator Receptor-targeting conjugate comprising: a fluorophore; a molecule binding to the receptor; and a linker group which covalently links the fluorophore to the molecule binding to the receptor, said linker group either being part of the molecule binding to the receptor or being a separate component of the urokinase Plasminogen Activator Receptor-targeting conjugate; wherein the urokinase Plasminogen Activator Receptor-targeting conjugate has a pharmacokinetic profile where a human tumor-to-background ratio TBR of at least 1.1 is reached within 3.5 hours post administration and where the human tumor-to-background ratio TBR of at least 1.5 is maintained at least 30 minutes before decreasing below 1.5, and wherein the urokinase Plasminogen Activator Receptor-targeting conjugate is a human urokinase Plasminogen Activator Receptor-targeting conjugate.” Depending claims further require that the urokinase Plasminogen Activator Receptor-targeting conjugate exhibits various properties, including molecular weight, in vivo half-life, KD, Kon, Koff, IC50, and in vivo sensitivity for detection of cancer tissue.
The claims encompass a genus of urokinase Plasminogen Activator Receptor (uPAR)-targeting conjugates; however, the specification fails to provide adequate written description and evidence of possession of these conjugate molecules that exhibit the properties as recited in the claims. What Applicant has described in the specification are the fluorophore ICG-conjugated uPAR-targeting peptide AE105 (compound example 1), and the fluorophore IRDye800CW-conjugated uPAR-targeting peptide AE344 (compound example 2). The specification discloses that both compounds exhibit a pharmacokinetic profile as recited in the claims. The specification, however, does not teach the structural characteristics of the genus of uPAR-targeting conjugates that exhibit the pharmacokinetic profile required by the claims. The claims, as written, encompass uPAR-targeting conjugates made from a combination of any uPAR-targeting moiety (e.g., an antibody, a protein, a peptide, a small molecule, etc.), any fluorophore, and any linker group. The specification does not show evidence that the broadly claimed uPAR-targeting conjugates would exhibit the pharmacokinetic profile, such as reaching a tumor-to-background ratio (TBR) of 1.1 within 3.5 hours post administration and maintaining TBR at least 1.5 for at least 30 minutes. Mateusiak et al. (Adv. Sci., 2024, Vol. 11:2400700) teaches generation of pan-cancer anti-uPAR nanobodies (Nbs) labeled with a fluorophore (s775z) via amine-reactive conjugation for use in image-guided surgery. Mateusiak et al. teaches that the Nbs showed dramatically difference in binding affinities (see, e.g., Figure 1). Mateusiak et al. teaches that extensive in vitro characterization and in vivo testing were conducted to assess their pharmacokinetics and select lead compounds (see Abstract). It is unpredictable what properties and pharmacokinetic profile a uPAR-targeting conjugate would have without extensive in vitro and in vivo testing. In the absence of sufficient description of distinguishing identifying characteristics, the skilled artisan cannot envision the detailed structures of the encompassed genus of uPAR-targeting conjugates as claimed.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making of the claimed product, or any combination thereof. In this case, there is no sufficient teachings regarding the structural characteristics of the genus, nor the correlation of structure to function. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed structures of the encompassed genus of molecules, and therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that is part of the invention and reference to a method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only the fluorophore ICG-conjugated uPAR-targeting peptide AE105 and the fluorophore IRDye800CW-conjugated uPAR-targeting peptide AE344, but not the full scope of the claimed uPAR-targeting conjugates, are adequately described in the disclosure.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Juhl et al. (PLoS ONE, 2016, Vol. 11(2): e0147428).
Juhl teaches a conjugate formed from the fluorophore “indocyanine green (ICG)” and the uPAR agonist “AE105”. Juhl teaches that the conjugate (ICG-Glu-Glu-AE105) provides an optical imaging ligand with sufficiently high receptor affinity to allow for a specific receptor targeting in vivo (see Abstract). The conjugate taught by Juhl meets all structural requirements as recited in claim 1. Regarding the properties recited in the instant claims, the conjugate of Juhl inherently possesses these properties because it has the same structure. A compound and all of its properties are inseparable (In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963)), as are their processes and yields (In re Von Schickh, 362 F.2d 821, 150 USPQ 300 (CCPA 1966)).
Therefore, Juhl anticipates the instant claims.
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 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
1) claims 1, 28-29, 42 and 49 of copending Application No. 17/625,937;
2) claims 1, 11, 29, 31 and 32 of copending Application No. 17/792,336; and
3) claims 1-20 of copending Application No. 19/395,728.
Although the claims at issue are not identical, they are not patentably distinct from each other. The claims of the ‘937, ‘336, and ‘728 applications recite a urokinase Plasminogen Activator Receptor (uPAR)-targeting conjugate comprising: a fluorophore; a molecule binding to uPAR; and a linker group which covalently links the fluorophore to the molecule binding to uPAR, or the conjugate ICG-Glu-Glu-AE105. The uPAR-targeting conjugate claimed in the ‘937, ‘336, and ‘728 applications have the same structure as that claimed in the present application, and therefore expressly and inherently anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
NO CLAIM IS ALLOWED.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Xiaozhen Xie, whose telephone number is 571-272-5569. The examiner can normally be reached on M-F, 8:30-5.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa L. Ford, can be reached on 571-272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/XIAOZHEN XIE/Primary Examiner, Art Unit 1674
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