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 .
Election/Restrictions
Applicant’s election without traverse of Group I and [18F]FN-PEG4-GK-TCO-Tz-PEG4-Mal- biomolecule in the reply filed on 5/28/2025 is acknowledged.
Claim 5, 6, 9, 10, 26-28, and 30-31 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group II, 1) a functionalized biomolecule comprising a dienophile and a 18F-containing reagent comprising a diene, and 3) a first compound comprising a guanidine moiety and an alkyne moiety and a second compound comprising a fluoroalkyl azide and a PEG linker, and there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/28/2025.
Note: Claim 11 is no longer withdrawn due to Applicant’s amendments, filed 9/25/2025, which now makes claim 11 dependent upon claim 1. Claim 5 is withdrawn in view of Applicant’s amendments, filed 9/25/2025, which now makes claim 5 drawn to an unelected species.
Status of Claims
Cancelled: 4, 6-10, 13-18, 20, 22-25, 27, 29-50
Withdrawn: 5, 26, 28
Examined Herein: 1, 2, 3, 11, 12, 19, 21
Priority
Acknowledgment is made of applicant's claim for priority based upon an application filed in PRO 62/852,681 on 5/24/2019 and PCT/US2020/034243 on 5/22/2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/21/2022, 11/28/2023, 6/25/2024, and 2/7/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings received on 11/23/2021 are accepted.
Withdrawn Rejections
All rejections of claim 7, 8, and 22 are hereby withdrawn; its cancellation moots the rejection.
The rejection of claims 1, 2, 3, 5, 7, 8, 12, 19, 21, and 22 under 35 U.S.C. 112(b) is hereby withdrawn in view of Applicant’s amendments to claim 1, which removes the limitation “the 18F-labeled residualizing agent,” thereby rendering the rejection moot. [Remarks 9/25/2025, Page 5]
The rejection of claims 1, 2, 3, 5, 7, 8, 12, 19, 21, and 22 under 35 U.S.C. 112(b) is hereby withdrawn in view of Applicant’s amendments to claim 1, which removes limitations like “a first compound comprising…”, and “a second compound… comprising,” thereby rendering the rejection moot. [Remarks 9/25/2025, Page 5]
The rejection of claims 1, 2, 3, 5, 7, 8, 12, 19, 21, and 22 under 35 U.S.C. 112(b) is hereby withdrawn in view of Applicant’s amendments to claim 1, which now makes clear which reactants correspond with which reactions, thereby rendering the rejection moot. [Remarks 9/25/2025, Page 5]
The rejection of claims 1, 2, 3, 7, 8, and 21 under 35 U.S.C. 102(a)(1) over Zhou is hereby withdrawn in view of Applicant’s amendments to claim 1, which limits the prepared 18F-labeled biomolecule to [18F]FN-PEG4-GK-TCO-Tz-PEG4-Mal-biomolecule, [18F]FN-PEG4-GK-TCO-Tz-PEG4-Mal-biomolecule, or N-succinimidy13-(1-(2-(2-(2-(2-[18F|fluoroethoxy)ethoxy)ethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)-5-(guanidinomethyl)benzoate, and Applicant’s persuasive arguments that Zhou does not teach the claimed limitations as amended. [Remarks 9/25/2025, Page 6]
The rejection of claims 1, 2, and 3 under 35 U.S.C. 102(a)(1) and 102(a)(2) over Weissleder is hereby withdrawn in view of Applicant’s amendments to claim 1, which limits the prepared 18F-labeled biomolecule to [18F]FN-PEG4-GK-TCO-Tz-PEG4-Mal-biomolecule, [18F]FN-PEG4-GK-TCO-Tz-PEG4-Mal-biomolecule, or N-succinimidy13-(1-(2-(2-(2-(2 [18F|fluoroethoxy)ethoxy)ethoxy)ethyl)-1H- 1,2,3-triazol-4-yl)-5-(guanidinomethyl)benzoate, and Applicant’s persuasive arguments that Weissleder does not teach the claimed limitations as amended. [Remarks 9/25/2025, Page 6]
The rejection of claims 2, 3, 5, 7, and 8, under 35 U.S.C. 103 over Zhou and Krishnan is hereby withdrawn in view of Applicant’s cancellation of claim 7 and 8, Applicant’s amendments to claims 1, 2, 3, and 5, and Applicant’s persuasive arguments that Zhou and Krishnan do not teach the claimed limitations as amended. [Remarks 9/25/2025, Page 6]
The rejection of claims 1, 2, 3, and 22 under 35 U.S.C. 103 over Weissleder and Ju is hereby withdrawn in view of Applicant’s cancellation of claim 22. [Remarks 9/25/2025, Page 5]
Claim Objections
Applicant is advised that should claim 2 be found allowable, claim 3 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
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 1, 2, 3, 11, 12, 19, and 21 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.
Claim 1 recites the limitation "the functionalized biomolecule comprising a dienophile" in line 2 of the second reaction described (the reaction that provides [18F]FN-PEG4-GK-TCO-Tz-PEG4-Mal-biomolecule). There is insufficient antecedent basis for this limitation in this section of the claim. Moreover, the recited functionalized biomolecule, biomolecule-Mal-PEG4-Tz, does not comprise a dienophile. The first reaction described (the reaction that provides the [18F]FN-PEG4-Tz-TCO-GK-PEG4-biomolecule) recites the limitation “a functionalized biomolecule comprising a dienophile,” but it is unclear whether the recited limitation is intended to refer back to the first reaction. Further clarification and/or correction is required. Dependent claims fall therewith. For examination purposes, the recited limitation is interpreted as ”the functionalized biomolecule comprising a diene.”
Claim 1 recites the limitation “wherein the functionalized biomolecule comprising a dienophile is a biomolecule-TCO-GK-PEG4.” As written, the TCO moiety is positioned between the biomolecule and GK and it is unclear whether the dienophile can undergo the recited IEDDA reaction with tetrazine, when TCO is effectively “sandwiched” within the functionalized biomolecule. The specification does not describe a functionalized biomolecule comprising biomolecule-TCO-GK-PEG4. However, the specification does describe a functionalized biomolecule comprising TCO-GK-PEG4-biomolecule and it is clear the reaction can be carried out with this dienophile configuration. In the absence of support from the specification, it is unclear whether the claimed reaction can actually be carried out if the functionalized biomolecule comprising a dienophile is biomolecule-TCO-GK-PEG4. Further clarification and/or correction is required. Dependent claims fall therewith. For examination purposes, the recited limitation is interpreted as “wherein the functionalized biomolecule comprising a dienophile is TCO-GK-PEG4-biomolecule.”
Claim 19 recites the limitation "the 18F-containing biomolecule." There is insufficient antecedent basis for this limitation in the claim. Claim 1 describes an 18F-labeled biomolecule and an 18F-containing reagent, but not an 18F-containing biomolecule.
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.
Claims 1, 11, 12, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou (18F-labeling of an anti-HER2 sdAb with a renal brush border enzyme-cleavable linker-containing prosthetic agent via a trans-cyclooctene (TCO)-terazine (Tz) inverse electron-demand Diels-Alder reaction (IEDDAR) for reduced renal uptake, 5/1/2018, Journal of Nuclear Medicine, Vol. 59, Issue 1), in view of Krishnan (18F-Labeling of Sensitive Biomolecules for Positron Emission Tomography, 11/7/2017, Chemistry – A European Journal, Volume 23, Issue 62).
With respect to claim 1 and 12, Zhou discloses a method of preparing an 18F-labeled biomolecule, [18F]AIF-NOTA-TCO-Tz-GK-2RS15d, comprising:
Reacting a functionalized biomolecule comprising a dienophile,
wherein the functionalized biomolecule comprising a dienophile is TCO-GK-PEG4-2Rs15d, and
a 18F-containing reagent comprising a diene,
wherein the 18F-containing reagent comprising a diene is [18F]AIF-NOTA-PEG4-Tz,
via an inverse electron-demand Diels-Alder cycloaddition reaction to provide the 18F-labeled biomolecule, [18F]AIF-NOTA-PEG4-Tz-TCO-GK-PEG4-2RS15d,
wherein the biomolecule, 2Rs15d, is a nanobody. [Zhou, Abstract and Page 3]
With respect to claim 11 and 21, Zhou discloses the biomolecule is 2Rs15d. [Zhou, Abstract and Page 3] 2Rs15d is a HER2-specific nanobody.
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[Zhou, Page 3]
Zhou does not disclose the 18F-containing reagent comprising a diene is [18F]FN-PEG4-Tz or the provided the 18F-labeled biomolecule is [18F]FN-PEG4-Tz-TCO-GK-PEG4-2Rs15d.
However, with respect to claim 1 and 12, Krishnan discloses several methods for 18F-labeling biomolecules including using [Al18F]NOTA and 18F-F-Py-TFP. Krishanan discloses biomolecules may be radiolabeled by attaching a chelating group, NOTA, to a biomolecule and binding Al-18F to said chelating group. [Krishnan, Page 15559, Col. 1, Paragraph 2 – Col. 2, Paragraph 1-2 and Page 15561, Figure 7] Krishanan also discloses biomolecules may be radiolabeled by utilizing prosthetic groups, like [18F]F-Py-TFP, by conjugating the prosthetic group to the biomolecule. [Krishanan, Page 155662, Col. 1, Paragraph 2 and Figure 8, 48]
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[Krishanan, Page 15562, Figure 8, 48]
Modifying the method disclosed by Zhou by replacing the [18F]AIF-NOTA moiety in [18F]AIF-NOTA-PEG4-Tz with 18F-F-Py-TFP, results in the method of claim 1 and 12, wherein the 18F-containing reagent comprising a diene is [18F]FN-PEG4-Tz and the provided 18F-labeled biomolecule is [18F]FN-PEG4-Tz-TCO-GK-PEG4-2Rs15d.
It would be obvious to one of ordinary skill in the art to modify the method disclosed by Zhou by replacing the [18F]AIF-NOTA moiety in [18F]AIF-NOTA-PEG4-Tz with 18F-F-Py-TFP, and have a reasonable expectation of success. Zhou discloses a method of preparing an 18F-labeled biomolecule, [18F]AIF-NOTA-TCO-Tz-GK-2RS15d, comprising reacting a functionalized biomolecule comprising a dienophile, TCO-GK-PEG4-2Rs15d, with an 18F-containing reagent comprising a diene, [18F]AIF-NOTA-PEG4-Tz, via an inverse electron-demand Diels-Alder cycloaddition reaction. Zhou demonstrates that 18F labeling the biomolecule is accomplished using [18F]AIF-NOTA. Krishanan discloses biomolecules may be radiolabeled by attaching a chelating group, NOTA, to a biomolecule and binding Al-18F to said chelating group or by utilizing prosthetic groups, like [18F]F-Py-TFP, by conjugating the prosthetic group to the biomolecule. So, Zhou discloses a method of preparing an 18F-labeled biomolecule, wherein radiolabeling is achieved using [18F]AIF-NOTA and Krishanan discloses radiolabeling may be alternatively achieved by utilizing prosthetic groups, like [18F]F-Py-TFP. Thus, the combined teachings of Zhou and Krishanan suggests the method of preparing an 18F-labeled biomolecule disclosed by Zhou may utilize [18F]F-Py-TFP by conjugating the prosthetic group to the biomolecule to achieve radiolabeling. Therefore, it is reasonable to expect the method disclosed by Zhou may be modified by replacing the [18F]AIF-NOTA moiety in [18F]AIF-NOTA-PEG4-Tz with 18F-F-Py-TFP to form [18F]FN-PEG4-Tz and provide the 18F-labeled biomolecule, [18F]FN-PEG4-Tz-TCO-GK-PEG4-2Rs15d. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. In the instant case, Krishanan discloses the [18F]F-Py-TFP prosthetic group can conveniently be prepared in one step from the trimethylammonium precursor. [Krishanan, Page 15562, Col. 1, Paragraph 3] Therefore, one would have been motivated by the expectation that the [18F]F-Py-TFP prosthetic group can be prepared in one step, in the method for preparing an 18F labeled biomolecule disclosed by Zhou.
Claims 1, 2, 3, 11, 12, 19, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Zhou and Krishanan, as applied to claim 1, 11, 12, and 21 above, and further in view of Fox (US 2013/0266512 A1, Published 7/10/2013).
With respect to claim 1, Zhou and Krishanan disclose the teachings above.
Zhou and Krishnan do not disclose the method comprises reacting a functionalized biomolecule comprising a diene, wherein the functionalized biomolecule comprising a diene is biomolecule-Mal-PEG4-Tz, and a 18F-containing reagent comprising a dienophile, wherein 18F-containing reagent comprising a dienophile is [18F]FN-PEG4-GK-TCO, via an inverse electron-demand Diels-Alder cycloaddition reaction to provide [18F]FN-PEG4- GK-TCO-Tz-PEG4-Mal-biomolecule.
However, with respect to claim 2, 3, and 19, Fox discloses a Diels-Alder adduct of a trans-cyclooctene with a tetrazine, wherein the adduct bears a substituent labeled with a radionuclide. [Fox, Claim 1] Fox further discloses the substituent may be on the trans-cyclooctene or tetrazine residue of the Diels-Alder adduct. [Fox, Claim 2 and 3] Moreover, Fox discloses maleimides may be used to conjugate tetrazines to lysine and cysteine residues of proteins. [Fox, 0043] The use of maleimide to form these conjugates has been shown to undergo rapid tetrazine ligation in high yield. [Fox, 0045]
Modifying the method disclosed by Zhou and Krishnan so that the TCO residue of the Diels-Alder adduct (TCO-GK-PEG4-2Rs15d) bears the 18F-labeled substituent ([18F]FN) rather than the Tz residue (PEG4-Tz), results in an 18F-containing reagent comprising a dienophile, [18F]FN-PEG4-GK-TCO, and a functionalized biomolecule comprising a diene, Tz-PEG4-2Rs15d. Further modifying the functionalized biomolecule comprising a diene, Tz-PEG4-2Rs15d, by introducing maleimide to conjugate the protein, 2Rs15d, to tetrazine, results in the method of claim 1, 2, 3, and 19; wherein the functionalized biomolecule comprising a diene is Tz-PEG4-Mal-2Rs15d, wherein the 18F-containing reagent comprising a dienophile is [18F]FN-PEG4-GK-TCO, and the prepared 18F labeled biomolecule is [18F]FN-PEG4- GK-TCO-Tz-PEG4-Mal-2Rs15d.
It would be obvious to one of ordinary skill in the art to modify the method disclosed by Zhou and Krishnan so that the TCO residue of the Diels-Alder adduct (TCO-GK-PEG4) bears the 18F-labeled substituent, [18F]FN, rather than the tetrazine residue (PEG4-Tz), and have a reasonable expectation of success. Zhou and Krishnan disclose a method for preparing an 18F labeled biomolecule, [18F]FN-PEG4-Tz-TCO-GK-PEG4-2Rs15d, comprising reacting [18F]FN-PEG4-Tz with TCO-GK-PEG4-2RS15d, via an inverse electron-demand Diels-Alder cycloaddition reaction. Fox discloses a Diels-Alder adduct of a trans-cyclooctene with a tetrazine, wherein the adduct bears a substituent labeled with a radionuclide and said substituent may be on the trans-cyclooctene or tetrazine residue of the Diels-Alder adduct. So, Zhou and Krishnan disclose a Diels-Alder adduct of a trans-cyclooctene with a tetrazine, [18F]FN-PEG4-Tz-TCO-GK-PEG4-2Rs15d, wherein the Tz residue (PEG4-Tz) bears a substituent labeled with a radionuclide ([18F]FN), which forms [18F]FN-PEG4-Tz, and Fox discloses the TCO residue (TCO-GK-PEG4) may bear the substituent labeled with a radionuclide instead. Thus, the combined teachings of Zhou, Krishnan, and Fox suggest that TCO-GK-PEG4 may bear the [18F]FN substituent to form [18F]FN-PEG4-GK-TCO, while the tetrazine residue forms Tz-PEG4-2Rs15d. Therefore, it is reasonable to expect the method disclosed by Zhou and Krishnan may be modified so that the TCO residue of the Diels-Alder adduct bears the 18F-labeled substituent rather than the tetrazine residue. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. In the instant case, Fox discloses a Diels-Alder conjugate, formed from a reaction of 18F-Labeled trans-cyclooctene with tetrazine, that is stable in PBS buffer and serum media for hours, and produces no degradation products. [Fox, 0030] Therefore, one would have been motivated by the expectation that the aforementioned modification would form an 18F labeled biomolecule that is stable and produces no degradation products.
It would be obvious to one of ordinary skill in the art to modify the method disclosed by Zhou, Krishnan, and Fox by further modifying the functionalized biomolecule comprising a diene, Tz-PEG4-2Rs15d, by introducing maleimide to conjugate the protein, 2Rs15d, to tetrazine, and have a reasonable expectation of success. Zhou, Krishnan, and Fox disclose a method for preparing an 18F labeled biomolecule, [18F]FN-PEG4- GK-TCO-Tz-PEG4-2Rs15d, by reacting a functionalized biomolecule comprising a diene, Tz-PEG4-2Rs15d, with [18F]FN-PEG4-GK-TCO, via an inverse electron-demand Diels-Alder cycloaddition reaction. Fox further discloses that maleimides may be used to conjugate tetrazines to lysine and cysteine residues of proteins. So, Zhou, Krishnan, and Fox disclose a diene, Tz-PEG4-2Rs15d, wherein PEG4 is used to conjugate tetrazine to the protein, 2Rs15d, and Fox discloses maleimide may be introduced to conjugate tetrazine to lysine and cysteine residues of proteins. So, the combined teachings of Zhou, Krishnan, and Fox suggest that maleimide may be introduced to conjugate tetrazine to the lysine or cysteine residues of 2Rs15d, to form Tz-PEG4-Mal-2Rs15d. Therefore, it is reasonable to expect the functionalized biomolecule comprising a diene in the method disclosed by Zhou, Krishnan, and Fox may be further modified by introducing maleimide to conjugate the protein to tetrazine. One would have been motivated to do so because it is prima facie obvious to combine references when some advantage or expected beneficial result would have been produced by their combination. In the instant case, Fox discloses the use of maleimide to form protein-tetrazine conjugates has been shown to undergo rapid tetrazine ligation in high yield. [Fox, 0045] Therefore, one would have been motivated by the expectation that the aforementioned modification would enable the 18F functionalized biomolecule to undergo rapid tetrazine ligation in high yield.
Response to Arguments
Applicant’s arguments, filed 9/25/2025, with respect to the rejections of claims 1, 2, 3, 5, 7, 8, 12, 21, and 22 under U.S.C. 102 and/or 103 over Zhou, Weissleder, Zhou & Krishnan, and/or Weissleder & Ju have been fully considered and are persuasive. Applicant’s arguments essentially state the cited references do not teach the claim limitations as amended. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground of rejection is made in view of the references cited above.
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.
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/K.A.C./Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618