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 .
Information Disclosure Statement
The information disclosure statement filed October 27, 2023 is acknowledged and has been considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, 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.
Specification
The disclosure is objected to because of the following informalities:
In [0037], it is recited that cells were cultured in a 6-well plate with a cell density of 1x106 cells/well. However, in view of the other examples provided in the specification, it appears that this value should instead be 1x106 cells/well.
In the last sentence of [0043], the phrase “a novel peptide drug in diagnosis and treatment of cancers which overexpressing cholecystokinin B receptor” appears to contain a grammatical error. It appears what is meant is “…of cancers which overexpress cholecystokinin B receptor.”
Appropriate correction is required.
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 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Behe (US 2021/0145990 A1) in view of Li (US 2022/0089574 A1) as evidenced by Grob (Grob, N. M.; et al., Cancers, 2021).
Behe teaches analogs of mini-gastrin peptides for use in CCK2 expressing cancers (Title and Abstract). More specifically, Behe teaches PP-F11N, which is a complex comprising DOTA, six glutamic acids, and a peptide with the amino acid sequence Ala-Tyr-Gly-Trp-Nle-Asp-Phe with a modification making the C-terminus carboxylate an amide, ending the chain with an NH2 (Figure 1). Behe teaches preparing solutions of a Lu-177 labeled PP-F11N in PBS further supplemented with DTPA (pg. 3, [0060]-[0063]).
Behe does not teach a peptide complex further comprising Lys(-4-TBA)-6-AHA or Lys(-4-TBA)-AMBA as an albumin affinity tag.
Li teaches a CXCR4 targeting complex (Title and Abstract). More specifically, the complexes of Li have the structure D-L2(-B)-L1-A wherein A is a CXCR4 binding cyclic peptide, B is an albumin binding moiety, D is a radioactive chelator structure, and L1 and L2 are linking groups connecting the aforementioned moieties (pg. 3, [0018]; and Figures 1-6). Li teaches that the radioactive chelator structure may be DOTA (Figures 1-6 and pg. 8, [0037]). Li teaches that the L2(-B)-L1 structure can be Lys(-4-TBA)-6-AHA or Lys(-4-TBA)-AMBA (Figures 1 and 2 respectively) wherein the 6-AHA or AMBA groups connect to an NH2 group of the CXCR4 targeting peptide. Li teaches that the chelator may be labeled with a radiometal selected from one of In-111, Ga-68, Ga-67, Y-90, or Lu-177 (pg. 11, [0039]). Li teaches that the introduction of the albumin binding group increases accumulation of the targeting complex in CXCR4 expressing tumors and prolongs the accumulation in the tumors (pg. 3, [0029]-[0030]; and Figure 10).
Grob teaches Lu-177-PP-F11N and analogs thereof (pg. 1, Abstract; and pg. 3, Figure 1). Grob teaches the use of Lu-177-PP-F11N in SPECT/CT imaging of mice with tumor xenografts (pg. 7, Figure 5; and pg. 4, Section 2.5). Grob teaches that the radiolabeled conjugate was administered to mice for the imaging in a PBS solution (pg. 4, Section 2.5).
A person of ordinary skill in the art would have recognized that both Behe and Li teach peptide receptor targeting radiopharmaceutical compounds wherein a receptor targeting peptide is conjugated to a chelating group that binds to a radiometal. It would also be recognized that Li teaches that the introduction of an albumin binding moiety increases tumor accumulation of a radioconjugate. It would also be recognized that the PP-F11N of both Behe and Grob are the same molecule.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the CCK-2 targeting radiopharmaceutical peptide complex of Behe with the insertion of the albumin binding moiety as taught by Li because Li teaches that the incorporation of this group increases tumor accumulation of a DOTA-linked receptor targeting peptide in receptor expressing tumors (MPEP § 2143(I)(C) and § 2143(I)(G)). This would predictably result in a cholecystokinin B receptor targeted complex comprising the peptide Ala-Tyr-Gly-Trp-Nle-Asp-Phe; a metal chelator; 6 glutamic acids; and an albumin affinity tag.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because Li teaches adding the albumin binding moiety in between a peptide and a DOTA chelator using L1 and L2 groups that link to the COOH of the DOTA and an NH2 of the peptide. The insertion of an albumin binding group between the DOTA and peptide region of PP-F11N would involve the same chemistry using the COOH of DOTA and the NH2 of the amino terminus of the peptide.
The skilled artisan would have been motivated to make this modification because Li teaches that this modification increases tumor accumulation of a receptor targeting radioconjugate. The skilled artisan would be motivated to increase the tumor accumulation of PP-F11N to reduce off-target toxicities and to potentially reduce the dose administered.
Regarding claim 1, Behe teaches PP-F11N, which comprises DOTA, six glutamic acids, and the peptide sequence Ala-Tyr-Gly-Trp-Nle-Asp-Phe (Figure 1). Behe teaches that such a conjugate targets cholecystokinin-2 receptor (CCK-2 R) (pg. 1, [0002]; and [0008]). In view of the instant specification describing cholecystokinin B receptor expressing cells as CCK2R(+), the examiner interprets cholecystokinin-2 receptor and cholecystokinin-B receptor to be the same protein. Additionally, Li teaches the incorporation of an albumin binding group between a peptide and DOTA through the structure L2(-B)-L1 (pg. 3, [0018]) and specifically teaches examples wherein this structure is Lys(-4-TBA)-6-AHA or Lys(-4-TBA)-AMBA (Figures 1 and 2 respectively). Analogously incorporating the L2(B)-L1 group of Li into the PP-F11N of Behe would result in a structure wherein the albumin affinity tag is disposed between the glutamic acid peptide chain and the DOTA metal chelating group. These structures would be identical to D1 and D3 of Figure 1 of the instant application. Therefore, the combined teachings of Behe, Li, and Grob render claim 1 obvious.
Regarding claim 2, the PP-F11N complex of Behe comprises DOTA as the metal chelator (Figure 1; and claim 14). Additionally, Li also teaches the use of DOTA in such complexes (Figures 1 and 2). Therefore, the combined teachings of Behe, Li, and Grob render claim 2 obvious.
Regarding claims 3-5, Behe teaches that PP-F11N may be labeled with Lu-177 or In-111 radionuclides (pg. 1, [0010]; and claim 15). Behe specifically teaches the preparation of a Lu-177 labeled complex (pg. 2-3, [0036]-[0062]). Therefore, the combined teachings of Behe, Li, and Grob render claims 3-5 obvious.
Regarding claims 6 and 7, Behe teaches preparing a formulation of Lu-177-PP-F11N for i.v. injection into a mouse wherein the complex is provided in PBS and DTPA is added (pg. 3, [0060]-[0063]). As evidenced by Grob (pg. 4, Section 2.5), PBS is a suitable carrier to use to administer Lu-177-PP-F11N to mice for SPECT/CT imaging. Therefore, the examiner interprets the preparation of the Lu-177 labeled complex in PBS (as taught by Behe) to be a method of preparing a pharmaceutical composition using a cholecystokinin B receptor targeted complex. As described above, the combination of Li and Behe render the complex of claim 1 obvious, so the combined method would be a method using the complex of claim 1.
Claims 6 and 7 are interpreted to be drawn to a method of making a pharmaceutical composition and not a method of use of a pharmaceutical composition. The recitation of “for treating or diagnosing a disease” in the preamble is interpreted to state an intended use of the pharmaceutical composition to be prepared by the claimed method. The examiner also interprets “wherein the disease is a cancer overexpressing or highly expressing cholecystokinin B receptor” in claim 6 and the entirety of claim 7 to further limit the intended use of the pharmaceutical composition prepared by the method of claim 6. The examiner interprets the only required structural process step required by claims 6 and 7 to be “using the cholecystokinin B receptor-targeted complex of claim 1.” Per MPEP 2111.02(II), a recitation of intended use must be evaluated to determine whether or not the recited intended use results in a manipulative difference between the claimed invention and the prior art. In this instance, the examiner notes that as pharmaceutical compositions comprising cholecystokinin B targeted complexes are used for the treatment or diagnosis of cholecystokinin B receptor expressing cancers, any method of making a pharmaceutical composition using a cholecystokinin B targeted complex reading on claim 1 will read on these method claims.
Furthermore, Behe teaches that the PP-F11N complex may be used for the treatment or diagnosis of cholecystokinin B receptor associated diseases (pg. 1, [0008] and [0011]). Additionally, Behe teaches that the complex may be used for the treatment of medullary thyroid cancer (claim 12), which express cholecystokinin B receptor (pg. 1, [0002]-[0004]).
Therefore, the combined teachings of Behe, Li, and Grob render claims 6 and 7 obvious.
Regarding claim 8, Behe teaches preparing a formulation of Lu-177-PP-F11N for i.v. injection into a mouse wherein the complex is provided in PBS and DTPA is added (pg. 3, [0060]-[0063]). As evidenced by Grob, Lu-177-PP-F11N can be used for SPECT/CT imaging (pg. 7, Figure 5). Thus, as Lu-177 labeled cholecystokinin B receptor targeting complexes can be used for SPECT/CT imaging, the examiner interprets this formulation taught by Behe to be a contrast agent. As further evidenced by Grob (pg. 4, Section 2.5), PBS is a suitable carrier to use to administer Lu-177-PP-F11N to mice for SPECT/CT imaging. Thus, the examiner interprets PBS to be a pharmaceutically acceptable carrier or solvent, which the examiner interprets to be within the scope of “a contrast excipient.” As the combination of Behe and Li results in molecules within the scope of claim 1, the preparation of such molecules in PBS (as taught by Behe) result in contrast agent formulations that read on claim 8. Therefore, the combined teachings of Behe, Li, and Grob render claim 8 obvious.
Pertinent Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
As pertinent art, the examiner cites Siwowska (Siwowska, K.; et al., Mol. Pharmaceutics, 2017). Siwowska teaches radioconjugates comprising a folic acid group to target folate receptor expressing cancers (pg. 523, Abstract). These conjugates comprise a folic acid moiety and a DOTA chelator and may comprise an albumin binding group (pg. 523, Abstract Figure; and pg. 524, Figure 1). Specifically, Siwowska teaches one compound without an albumin binding group, and three compounds containing an albumin binding group with different linking groups (Figure 1). Siwowska teaches that the introduction of the albumin binding group increases the stability of the radioconjugate in PBS (pg. 527, Figure 2). Siwowska also teaches that the introduction of the albumin binding group increases the tumor uptake of the radioconjugate (pg. 529, Table 2) and significantly increases the tumor-to-kidney uptake ratios (pg. 529, Figure 6). Siwowska teaches that similar results obtained by introducing albumin binding groups into radioconjugates has resulted in interest from researchers in radiopharmaceutical sciences to apply the same concept in the development of other radiopharmaceuticals to improve in vivo properties (pg. 530, left column, third paragraph). The examiner notes that this reference teaches several benefits to introducing an albumin binding group into a radioconjugate and suggests that such a modification can potentially be applied broadly across radiopharmaceutical compounds.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Eric P Mosher whose telephone number is (571)272-3258. The examiner can normally be reached Monday-Friday 9am-5pm.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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