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 .
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The noncompliant sequence disclosures are located in the first paragraph of page 9 of the instant specification, lines 8-10.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Information Disclosure Statement
The information disclosure statements filed on December 27, 2023 and April 9, 2026 are acknowledged and have been considered by the examiner.
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.
Specification
The disclosure is objected to because of the following informalities:
On page 22, line 15, the lyophilization method freeze set-point is recited as -45°V, but should instead read as -45°C.
Appropriate correction is required.
Claim Objections
Claims 3, 5, and 7 are objected to because of the following informalities:
Claim 3 recites “the radiostabilizer.” Claim 3 depends on claim 1, which recites “a radio stabilizer.” In view of the disclosure as a whole, the examiner understands these terms to mean the same thing. For clarity, the examiner suggests using consistent terminology between claims and amending claim 3 to recite “the radio stabilizer.” Alternatively, claim 1 may be amended to “a radiostabilizer” instead.
Claim 5 recites options for the structure of the chelating moiety required in claim 1. The list describes both cyclic and open chain chelating groups (see Claim Interpretation). The claim recites “chelating moiety is selected from … (THP) and derivatives, chelates open chain such as HBED …” The transition between the cyclic and open chain lists lacks proper punctuation and grammar. The transition should instead read as “… (THP) and derivatives; or chelates with open chains such as HBED …”
Claim 7 recites “…wherein said a GRP receptor (GRPr) targeting molecule…” The “a” is superfluous and should be removed from between said and GRP.
Appropriate correction is required.
Claim Interpretation
Claim 1 recites “a lyophilized kit formulation” in the preamble of the claim. In view of the disclosure as a whole, the examiner interprets this claim and the dependent claims with similar preambles to be drawn to a composition of matter (formulation) rather than an assembly (kit). Furthermore, it is interpreted that the formulation of claim 1 must be in a lyophilized form. It is thus interpreted that similar formulation claims dependent on claim 1 (claims 2-8) are also required to be lyophilized. The examiner interprets “kit” in “lyophilized kit formulation” to describe the intended use of the formulation and is not limiting the structural requirements of the claimed composition of matter (MPEP § 2111.02(II)). Any lyophilized formulation that reads on the rest of the limitations of claim 1 and is capable of being incorporated into a kit will read on the “lyophilized kit formulation” requirement.
Claims 1 and 8 recite that the formulation is “for the preparation of radiometal labeled chelate-functionalized targeting conjugates.” This is interpreted to be intended use language and not limiting the structure of the claimed composition (MPEP § 2111.02(II)). Any art that teaches the structural limitations of claim 1 or 8 and is capable of this function will read on the respective claim.
Claim 1 requires the formulation comprise “at least one radio stabilizer, selected from the group comprising ascorbic acid, ascorbic acid salts, gentisic acid, gentisic acid salts, or mixtures thereof.” The examiner interprets “radio stabilizer” to be a functional limitation (MPEP § 2173.05(g)). The claim requires the formulation contain either ascorbic acid, ascorbic acid salts, gentisic acid, gentisic acid salts, or mixtures thereof. A chemical composition and its properties are inseparable (MPEP § 2112.01). Therefore, art that teaches a formulation comprising any of the specifically recited molecules will read on the claim regardless of whether the art teaches the molecules as radio stabilizers.
Claim 1 requires the formulation contain at least one GRP receptor targeting peptide. The examiner interprets “targeting” in this context to mean that the peptide is capable of binding to the GRP receptor. Therefore, art that teaches any peptide that binds to the GRP receptor will read on this limitation.
Claim 5 recites a number of potential structures of the chelating moiety in the conjugate required in claim 1. The second half of this list is described as “chelates open chain.” The examiner interprets the chelating moiety options recited to be a list of cyclic or closed chain chelating moieties (TACN through THP) and open chain chelating moieties (HBED through citrate). The examiner further interprets the two recitations of “and derivatives thereof” at the ends of these lists to include the scope of all previous cyclic or open chain chelating moieties in the lists, not just the immediately prior recited structure.
Claim 9 includes a step in which a labeling buffer is added to the formulation. The examiner interprets “labeling buffer” to be a functional limitation. Art that teaches the use of a buffer capable of performing the structural requirements of the claimed method will therefore read on this limitation.
Similarly, in the kit of claim 12, the labeling buffer will be interpreted to be any buffer capable of use in a radiolabeling reaction. Therefore, any art that teaches a kit comprising a vial or syringe comprising at least one buffer or a mixture of buffers that are capable of use in radiolabeling will read on this limitation.
Claim 10 is interpreted to be a product-by-process claim (MPEP § 2113). The patentability of a product does not depend on its method of production. Therefore, any art that teaches a product with the structural requirements required in claim 10 will read on this claim, regardless of the method by which it was made.
Claim Rejections - 35 USC § 112(b)
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 1-12 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 an open list of alternatives to define the limitation of non-reducing sugar. The scope of this list is unclear, as it contains a of alternatives in the presence of “comprising” language. It is unclear what other alternatives are intended to be encompassed by the claim (MPEP § 2173.05(h)). Therefore, claim 1 is considered indefinite. Additionally, claims 2-12 are also rejected due to their dependence on claim 1.
Claim 1 recites an open list of alternatives to define the limitation of radio stabilizer. The scope of this list is unclear, as it contains a of alternatives in the presence of “comprising” language. It is unclear what other alternatives are intended to be encompassed by the claim (MPEP § 2173.05(h)). Therefore, claim 1 is considered indefinite. Additionally, claims 2-3 and 5-12 are also rejected due to their dependence on claim 1. Claim 4 requires the radio stabilizer to be ascorbic acid and therefore does not include the open list of radio stabilizer alternatives.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance,
claim 2 recites the broad recitation 10-600 µmol, and the claim also recites 20-500 µmol and 50-300 µmol, which are narrower statements of the range/limitation;
claim 3 recites the broad recitation 1-500 µmol, and the claim also recites 5-250 µmol and 10-100 µmol, which are narrower statements of the range/limitation; and
claim 4 recites the broad recitation 1-20 mg, and the claim also recites 1-10 mg, which is the narrower statement of the range/limitation.
The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. For the purpose of examination, the examiner will interpret the scope of these claims to be that of the widest recited range in each instance.
Claim 2 recites that the “concentration of the non-reducing sugar in said formulation is 10-600 µmol…” However, the unit µmol describes a measurement of the amount of a material present, not a concentration. A concentration is a measurement of an amount of a component relative to the sum of a particular measure of amount of all components in a mixture, typically volume of a solution. Thus, it is unclear whether the intended scope of the claim is to relate to the concentration of non-reducing sugar in the formulation or the amount, rendering the claim indefinite. As the examiner understands claim 2 to be drawn to a lyophilized composition (not in-solution) (see Claim Interpretation), the examiner will interpret claim 2 to require the amount of non-reducing sugar be between 10 and 600 µmol.
Claim 3 recites that the “concentration of said radiostabilizer in the formulation is 1-500 µmol…” However, the unit µmol describes a measurement of the amount of a material present, not a concentration. Therefore, for the reasons described above the claim is considered indefinite in scope. As the examiner understands claim 3 to be drawn to a lyophilized composition (not in-solution) (see Claim Interpretation), the examiner will interpret claim 3 to require the amount of radiostabilizer be between 1 and 500 µmol.
Claim 5 recites several possible chelating moieties that may be present in different embodiments of the claimed invention. Among this list includes cyclic chelating moieties (TACN through THP) “and derivatives” and open chain moieties (HBED through citrate) “and derivatives thereof” (see Claim Interpretation) and “H2dedpa and its derivatives.” However, it is unclear what the scope of “derivatives” is in this context. It is unclear what molecular modifications are included in the scope of this phrase. Therefore, the scope of the claim is rendered indefinite. For the purpose of examination, the examiner will interpret any art that teaches the inclusion of any of the specifically recited chelating moieties in a chelate-functionalized targeting conjugate that reads on claim 1 to read on this limitation.
Claim 5 recites an open list of alternatives to define the limitation of the chelating moiety. The scope of this list is unclear, as it contains a of alternatives in the presence of “comprising” language. It is unclear what other alternatives are intended to be encompassed by the claim (MPEP § 2173.05(h)). Therefore, claim 5 is considered indefinite.
Regarding claim 5, the phrase "such as" (as recited in line 4 of the claim) renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 6 recites an open list of alternatives to define the limitation of the structure of the linker required by claim 1. The scope of this list is unclear, as it contains a of alternatives in the presence of “comprising” language. It is unclear what other alternatives are intended to be encompassed by the claim (MPEP § 2173.05(h)). Therefore, claim 6 is considered indefinite.
Claim 7 recites an open list of alternatives to define the limitation of the GRP receptor targeting molecules. The scope of this list is unclear, as it contains a of alternatives in the presence of “comprising” language. It is unclear what other alternatives are intended to be encompassed by the claim (MPEP § 2173.05(h)). Therefore, claim 7 is considered indefinite.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-7 and 9-12 are rejected under 35 U.S.C. 103 as being unpatentable over Mariani (WO 2021053040 A1 – provided by applicant in IDS filed April 9, 2026) in view of Delporte (WO 2019243489 A1 – provided by applicant in IDS filed December 27, 2023)
Mariani teaches radiolabeled gastrin-releasing peptide receptor (GRPr) targeting compounds, methods of preparing, and kits thereof (Abstract). Mariani teaches that the GRPr targeting compounds contain a chelator capable of chelating a radioactive isotope, a spacer linking group, and a GRPr peptide antagonist that can include one of several provided sequences (pg. 10, line 25 through pg. 11, line 23). The chelator and spacer group may also vary in structure (pg. 13, line 4 through pg. 14, line 6) and radiolabeling may be performed with several radioactive isotopes suitable in contrast agents (pg. 19, line 25 through pg. 20, line 2). Mariani further discloses a method of preparing the radiolabeled targeting conjugate wherein a vial comprising the GRPr targeting conjugate in a dried form is provided, a solution of the radioactive isotope is added, and mixing is performed to obtain the radiolabeled conjugate (pg. 7, lines 8-17). Mariani also teaches providing a kit for performing the described method comprising a first vial containing a dried formulation containing the GPRr targeting conjugate, a second vial comprising at least a buffering agent, and optionally an accessory cartridge for eluting radioactive isotopes (pg. 24, lines 9-20). Mariani teaches that the dried form of the formulation containing the GRPr targeting conjugate comprises a GPRr targeting conjugate, a radiolysis protector (such as gentisic acid), optionally a bulking agent (such as the sugar mannitol), and optionally a surfactant (pg. 23, lines 24-30). Mariani teaches that the dried formulation can be obtained by freeze-drying methods known in the art, such as lyophilization (pg. 19, lines 16-17). Mariani also teaches that instead of the accessory cartridge for eluting radioactive isotopes, the kit may include the radioactive isotope in a ready-for-use product (pg. 25, lines 10-11).
Mariani does not teach a lyophilized formulation of a GRPr targeting conjugate containing ascorbic acid, or salts thereof; or trehalose or sucrose non-reducing sugars.
Delporte teaches a radiopharmaceutical composition comprising a somatostatin receptor binding peptide conjugated to a chelator (pg. 2, line 14 through pg. 3, lines 8) in a formulation with an antioxidant and a bulking agent (pg. 3, lines 9-13). Delporte teaches that the composition may be provided in a lyophilized form (pg. 7, lines 5-8). Delporte teaches that the antioxidant may be ascorbic acid or a salt thereof or gentisic acid or a salt thereof (pg. 5, lines 1-5). Delporte also teaches that the bulking agent may be a disaccharide such as sucrose or trehalose (pg. 5, lines 6-10). Delporte also teaches the composition in a radiolabeled form for use as a radiopharmaceutical (pg. 16, lines 3-4) in which the chelate-functionalized targeting peptide conjugate is labeled with various radionuclides suitable for imaging or therapeutic uses (pg. 16, lines 22-30). Delporte also teaches a method of radiolabeling the chelator-peptide conjugate (pg. 21, line 29 through pg. 22, line 5) and a kit for the preparation of the radiolabeled conjugate (pg. 22, lines 13-19). Delporte discloses several specific examples of the above described formulation in which a somatostatin receptor peptide conjugated to a NODAGA chelator group by a linking group is prepared in a lyophilized formulation with ascorbic acid and trehalose (pg. 27, Table 1). Delporte teaches that these formulations exhibit good stability (pg. 28-30, Tables 2-4).
A person of ordinary skill in the art would have recognized that both Mariani and Delporte teach radiolabeled peptide-based targeted pharmaceutical compounds and related lyophilized formulations, kits, and methods of radiolabeling. It would be recognized that the ascorbic acid and trehalose containing formulation of Delporte provided good stability for storage of the lyophilized formulation of a peptide-chelator conjugate. It would be understood that the excipients of Delporte (ascorbic acid and trehalose) could be used with the GRPr-targeting conjugate of Mariani in place of the gentisic acid and mannitol, as these are alternative excipients known in the art.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the GRPr-targeting conjugate composition of Mariani with the ascorbic acid and trehalose excipient formulation of Delporte through a simple substitution (MPEP § 2143(I)(B)). This would predictably result in a stable formulation of a GRPr-targeting conjugate that can be lyophilized, provided in a kit, and radiolabeled to prepare a radiopharmaceutical composition.
Regarding claim 1, Mariani teaches a lyophilized composition comprising a chelate-functionalized targeting conjugate comprising a chelating moiety, a GRP receptor targeting peptide (antagonist), and a linker (spacer) and gentisic acid (pg. 10, line 23 through pg. 11, line 23; and pg. 23, lines 23-30). Mariani teaches that this lyophilized composition may be provided in a vial in a kit (pg. 24, lines 9-20). Delporte teaches a lyophilized composition comprising a chelate-functionalized targeting conjugate comprising a chelating moiety, a targeting peptide, and a linker with an antioxidant and a bulking agent (pg. 3, lines 9-13). Delporte teaches that the antioxidant may be ascorbic acid, ascorbic acid salts, gentisic acid, or gentisic acid salts (pg. 5, lines 1-5) and the bulking agent may be trehalose or sucrose (pg. 5, lines 6-10). Though Delporte does not describe the ascorbic acid or gentisic acid with the term “radio stabilizer” or trehalose and sucrose with the term “non-reducing sugar,” the inclusion of these compounds in the formulation still reads on these limitations of claim 1, as radio stabilizer and non-reducing sugar are understood to describe the component by its properties rather than structure (see Claim Interpretation) and a chemical composition and its properties are inseparable (MPEP § 2112.01). Delporte teaches that this composition is suitable for lyophilization (pg. 6, lines 26-27) and may be provided in a kit (pg. 22, lines 13-19). Therefore, the combined teachings of Mariani and Delporte render claim 1 obvious.
Regarding claim 2, Delporte teaches specific examples within the scope of the taught formulation in which the trehalose excipient is present in amounts of 30-100 mg (pg. 27, Table 1). The molecular weight of trehalose is 342.3 g/mol. Using that conversion factor, it can be determined that 30-100 mg trehalose is equivalent to 87-292 µmol trehalose. This taught range falls within the claimed range of 10-600 µmol (see claim interpretation associated with 112(b) rejection). Therefore, the combined teachings of Mariani and Delporte render claim 2 obvious.
Regarding claims 3 and 4, Delporte teaches specific examples within the scope of the taught formulation in which ascorbic acid (which is a radiostabilizer) is present in present in amounts of 5-8 mg (pg. 27, Table 1). The molecular weight of ascorbic acid is 176.12 g/mol. Using that conversion factor, it can be determined that 5-8 mg ascorbic acid is equivalent to 28-45 µmol ascorbic acid. Both the taught mg and µmol ranges fall within the claimed ranges of 1-500 µmol and 1-20 mg (see claim interpretation in associated 112(b) rejections). Therefore, the combined teachings of Mariani and Delporte render claims 3 and 4 obvious.
Regarding claim 5, Mariani teaches that the GRPr targeting peptide may be conjugated to chelators including EDTA and TETA (pg. 13, line 4 through pg. 14, line 3). Additionally, Delporte teaches that a radiopharmaceutical comprising a chelating group for radiolabeling linked to a peptide-based targeting group can include NODAGA as the chelating group (pg. 2, lines 19-21). Therefore, the combined teachings of Mariani and Delporte render claim 5 obvious.
Regarding claim 6, Mariani teaches that the GRPr targeting peptide may be conjugated to a chelating moiety through linkers of a variety of structures (pg. 14, line 4 through pg. 17. Line 3). These structures include chemical groups that contain bonds, natural amino acids, unnatural amino acids, linear diamines, linear carboxylic acids, and polyethylene glycol. Therefore, the combined teachings of Mariani and Delporte render claim 6 obvious.
Regarding claim 7, Mariani teaches that the GRPr targeting molecule comprises a peptide sequence described by the formula Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Z wherein, among other possibilities, Xaa1 may be D-Phe or absent, Xaa2 may be Gln, Xaa3 may be Trp, Xaa4 may be Ala, Xaa5 may be Val, Xaa6 may be Gly, and Xaa7 may be His (pg. 11, lines 3-15). This description includes peptides with the sequences Gln-Trp-Ala-Val-Gly-His and D-Phe-Gln-Trp-Ala-Val-Gly-His; both of which are among the claimed sequences. Therefore, the combined teachings of Mariani and Delporte render claim 7 obvious.
Regarding claim 9, Mariani teaches a method for preparing a radiometal labeled chelate-functionalized GRP receptor targeting conjugate using a lyophilized formulation comprising adding a solution of a radioactive isotope into a vial comprising the lyophilized formulation of the chelate-functionalized GRP receptor targeting conjugate and mixing the obtained solution with a buffering agent and incubating the mixture for a sufficient period of time to obtain the radiolabeled product (pg. 7, lines 8-17). The addition of the buffering agent reads on the optional step of adding at least one labeling buffer as the buffer was added for the radiolabeling reaction (see Claim interpretation). The incubation step leading to a labeled product reads on the “complexing” limitation, as labeling of a chelator containing compound occurs through forming a complex between the radioactive isotope and the chelator. While Mariani describes the method by reciting “radioactive isotope” instead of radiometal, Mariani teaches that the radiolabel is preferably 68Ga, 67Ga, or 64Cu, which are all radiometals (pg. 7, lines 21-25). Therefore, the combined teachings of Mariani and Delporte render claim 9 obvious.
Regarding claim 10, Mariani teaches a radiolabeled GRPr targeting conjugate product of the above method of radiolabeling (pg. 4, lines 3-6). Therefore, the combined teachings of Mariani and Delporte render claim 10 obvious.
Regarding claim 11, Mariani teaches that the radiolabeled GRPr-targeting conjugate is preferably for the use as a contrast agent for PET/CT, SPECT, or PET/MRI imaging (pg. 7, lines 18-20). This reads on the concept of a radiopharmaceutical composition. Additionally, Mariani describes the disclosed kit in the examples as a radiopharmaceutical kit (pg. 39, lines 2-4). Since the kit is for the production of the conjugate, the product would be considered a radiopharmaceutical. Therefore, the combined teachings of Mariani and Delporte render claim 11 obvious.
Regarding claim 12, Mariani teaches a kit comprising a first vial containing a GRPr targeting conjugate (chelator-linker-GRPr binding peptide) and excipients in a dried form, a second vial comprising at least a buffering agent, and optionally an accessory cartridge as a source for eluting a radioactive isotope (pg. 24, lines 9-20). Mariani teaches that the dried formulation can be obtained by freeze-drying methods known in the art, such as lyophilization (pg. 19, lines 16-17). Mariani teaches that the buffering agent is to be used in the radiolabeling reaction to maintain pH (pg. 25, lines 6-8), therefore reading on the phrase “labeling buffer.” Mariani also teaches that instead of the accessory cartridge for eluting radioactive isotopes, the kit may include the radioactive isotope in a ready-for-use product (pg. 25, lines 10-11), which reads on the limitation of a vial or syringe comprising a solution of the radiometal. Therefore, the combined teachings of Mariani and Delporte render claim 12 obvious.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Mariani and Delporte as applied to claims 1-7 and 9-12 above, and further in view of Reinier (US 2016/0199524 A1- provided by applicant in IDS filed April 9, 2026).
As described above, Mariani teaches radiolabeled gastrin-releasing peptide receptor (GRPr) targeting compounds, methods of preparing, and kits thereof (Abstract). Mariani teaches that the GRPr targeting compounds contain a chelator capable of chelating a radioactive isotope, a spacer linking group, and a GRPr peptide antagonist (pg. 10, line 25 through pg. 11, line 23). The radiolabeling may be performed with several radioactive isotopes suitable in contrast agents (pg. 19, line 25 through pg. 20, line 2). Mariani also teaches providing a kit for performing the described method comprising a first vial containing a dried formulation containing the GPRr targeting conjugate, a second vial comprising at least a buffering agent, and optionally an accessory cartridge for eluting radioactive isotopes (pg. 24, lines 9-20). Mariani teaches that the dried formulation can be obtained by freeze-drying methods known in the art, such as lyophilization (pg. 19, lines 16-17). Furthermore, Delporte teaches a radiopharmaceutical composition comprising a somatostatin receptor binding peptide conjugated to a chelator (pg. 2, line 14 through pg. 3, lines 8) in a formulation with an antioxidant and a bulking agent (pg. 3, lines 9-13). Delporte teaches that the composition may be provided in a lyophilized form (pg. 7, lines 5-8). Delporte teaches that the antioxidant may be ascorbic acid or a salt thereof or gentisic acid or a salt thereof (pg. 5, lines 1-5). Delporte also teaches that the bulking agent may be a disaccharide such as sucrose or trehalose (pg. 5, lines 6-10). Delporte also teaches the composition in a radiolabeled form for use as a radiopharmaceutical (pg. 16, lines 3-4) in which the chelate-functionalized targeting peptide conjugate is labeled with various radionuclides suitable for imaging or therapeutic uses (pg. 16, lines 22-30). Delporte teaches that these formulations with ascorbic acid and trehalose exhibit good stability (pg. 28-30, Tables 2-4).
The combined teachings of Mariani and Delporte do not teach a formulation of a chelate-functionalized GRP receptor targeting conjugate with a radio stabilizer and a non-reducing sugar that is labeled with a trivalent or bivalent radiometal cation in the lyophilized form.
Reinier teaches dual-labeled molecules possessing fluorescent probes and radionuclides conjugated to a polypeptide and peptide-based targeting group for targeted imaging purposes (Abstract). This includes a chelate-functionalized peptide conjugate, IMP-493, which contains the peptide sequence Gln-Trp-Ala-Val-Gly-His (Fig. 13C). Reinier teaches labeling a similar chelate-functionalized peptide, IMP467, with the radiolabel 18F through fluorine-labeling of an aluminum metal atom complexed in the chelator group (pg. 32, Example 12). In this example, Reinier teaches pre-incubating the aluminum with the peptide-chelator conjugate prior to lyophilization (pg. 32, [0363]). This increased radiolabeling yield after reconstituting the lyophilized product, indicating the aluminum metal remained stably chelated during the lyophilization and reconstitution processes.
A person of ordinary skill in the art would have recognized that Mariani, Delporte, and Reinier all teach radiolabeled peptide-based targeted pharmaceutical compounds and related lyophilized formulations and methods of radiolabeling. It would be recognized that Reinier teaches that chelated metals remain stably complexed in a conjugate during the lyophilization and reconstitution processes. A person of ordinary skill in the art would recognize that if this process can be done with aluminum, it could be done with a radiometal such as 68Ga. It would also be recognized that radiolabeling a chelator containing compound before or after lyophilization amounts to a change in the order of steps in the synthesis and a practitioner would be readily able to perform the modified method.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the GRPr-targeting conjugate formulation of Mariani and Delporte with metal complexation step prior to lyophilization as taught by Reinier, as this is an alternative preparation method known in the art (MPEP § 2143(I)(A)). This would predictably result in a lyophilized formulation of a GRPr-targeting conjugate that is radiolabeled with a radiometal.
Regarding claim 8, as described above, Mariani and Delporte combine to teach a formulation that reads on claim 1. Mariani teaches a lyophilized composition comprising a chelate--functionalized targeting conjugate comprising a chelating moiety, a GRP receptor targeting peptide, and a linker (pg. 10, line 23 through pg. 11, line 23). Mariani teaches that the radiolabel is preferably 68Ga, 67Ga, or 64Cu, which are all radiometals (pg. 7, lines 21-25). Of these, 68Ga and 67Ga are 3+ trivalent cations and 64Cu is a 2+ bivalent cation. Delporte teaches a lyophilized formulation comprising a chelate-functionalized targeting conjugate with ascorbic acid and trehalose excipients (and pg. 27, Table 1). Delporte teaches that this formulation exhibits good stability (pg. 28-30, Tables 2-4). Reinier teaches that a metal can be complexed with a chelator prior to lyophilization (pg. 32, Example 12). Modifying the method of Mariani in which the GRPr-targeting conjugate composition is lyophilized prior to radiolabeling to form the radiometal complex with 68Ga, 67Ga, or 64Cu prior to lyophilization, would result in a lyophilized formulation of the conjugate labeled with a trivalent or bivalent radiometal cation. Therefore, the combined teachings of Mariani, Delporte, and Reinier render claim 8 obvious.
Conclusion
All claims are rejected.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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