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 .
Status of Application
Claims 1-14 and 16-21 are under examination.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Rejections - 35 USC § 112(a)
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, 3-6, and 18 is 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 claim(s) contains 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant specification teaches a radioisotope labeled sstr2-agonists with linkers, where the linkers are pip or amcha (pg 14, lines 5-10, formulae Ia and Ib) and provides several examples of compounds (pg 17, lines 11-25; pg 18, lines 27-33; pg 19, lines 1-13) and tabulates the results of compounds (pg 19, Table 1; pg 20, Table 2; pg 23, Table 3). However, the instant specification does not offer sufficient description of the common structural elements or identifying characteristics that constitute a radioisotope labeled sstr2-agonist with linkers comprising R3 and R4, where R3 and R4 are anything other than bonds, particularly when R3 and R4 are spacers, or aliphatic and peptidic spacers, or peptide spacers (Xaa)1-4, where Xaa can be proteinogenic or non-proteinogenic amino acid residues. There is no description of structural elements of a radioisotope labeled sstr2-agonist with such linkers that are sufficient to distinguish the claimed R3 and R4 in the linkers from other types of products. Furthermore, the instant specification does not indicate that the inventors have possession of the details of the structural elements that would comprise these distinguishing characteristics.
A person of ordinary skill in the art would appreciate that there are many different structural elements that would constitute the R3 and R4 spacers to facilitate the functions recited in the instant claims. However, the instant specification is silent as to which structural elements the inventor has determined to be sufficient to characterize radioisotope labeled sstr2-agonist with such linkers. Therefore, the instant specification does not provide a disclosure of corresponding structure in sufficient detail to demonstrate to one of ordinary skill in the art that the inventor possessed the invention including how the inventor intended what features constitute the radioisotope labeled sstr2-agonist to allow the function recited in the instant claims.
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, 3-6, and 18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential structural cooperative relationships of elements, such omission amounting to a gap between the necessary structural connections. See MPEP § 2172.01. The omitted structural cooperative relationships are as follows: the connectivity from the spacers to the remainder of the molecule is unclear. It is unclear whether the connectivity is through a covalent bond or ionic bond, whether the connectivity is along a peptidic backbone or at varied locations on the amino resid type residue, or whether the connectivity to the spacer is close to each other or far from each other.
Claim 19 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential structural cooperative relationships of elements, such omission amounting to a gap between the necessary structural connections. See MPEP § 2172.01. The omitted structural cooperative relationships are: details of “analogues thereof” in line 12. It is unclear to what extent the chelators are modified to create an analogue and it is unclear what the connectivity between the analogue and the rest of the radiopharmaceutical compound is.
Claims 1-4, 6-7, 11-13, and 18-21 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 group" in line 20. There is insufficient antecedent basis for this limitation in the claim. The applicant is recommended to amend “the group” to “a group”.
Claim 2 recites the limitation "the group" in line 3. There is insufficient antecedent basis for this limitation in the claim. The applicant is recommended to amend “the group” to “a group”.
Claim 3 recites the limitation "the group" in line 12. There is insufficient antecedent basis for this limitation in the claim. The applicant is recommended to amend “the group” to “a group”.
Claim 4 recites the limitation "the group" in lines 11-13. There is insufficient antecedent basis for this limitation in the claim. The applicant is recommended to amend “the group” to “a group”.
Claim 6 recites the limitation "the group" in line 3. There is insufficient antecedent basis for this limitation in the claim. The applicant is recommended to amend “the group” to “a group”.
Claim 7 recites the limitation "the group" in line 3. There is insufficient antecedent basis for this limitation in the claim. The applicant is recommended to amend “the group” to “a group”.
Claim 11 recites the limitation "the group" in line 6. There is insufficient antecedent basis for this limitation in the claim. The applicant is recommended to amend “the group” to “a group”.
Claim 12 recites the limitation "the group" in line 3. There is insufficient antecedent basis for this limitation in the claim. The applicant is recommended to amend “the group” to “a group”.
Claim 13 recites the limitation "the group" in line 6. There is insufficient antecedent basis for this limitation in the claim. The applicant is recommended to amend “the group” to “a group”.
Claim 18 recites the limitation "the group" in lines 3 and 5. There is insufficient antecedent basis for this limitation in the claim. The applicant is recommended to amend “the group” to “a group”.
Claim 19 recites the limitation "the group" in line 3. There is insufficient antecedent basis for this limitation in the claim. The applicant is recommended to amend “the group” to “a group”.
Claim 20 recites the limitation "the group" in line 2. There is insufficient antecedent basis for this limitation in the claim. The applicant is recommended to amend “the group” to “a group”.
Claim 21 recites the limitation "the group" in line 2. There is insufficient antecedent basis for this limitation in the claim. The applicant is recommended to amend “the group” to “a group”.
Claim Interpretation
Claims 1 and 3-6 recite the term “spacers”. The examiner notes that the specification does not define spacers. Therefore, for the purposes of examination, the examiner interprets “spacers” to mean anything which separates the groups that R3 and R4 are between by more the length of a bond. Therefore, the examiner interprets any prior art containing any moiety, covalent bond or otherwise, that separates the groups that R3 and R4 are between by more than the length of a bond, reads on this limitation.
Claim 6 recites aliphatic spacers. The examiner notes that the specification does not define aliphatic spacer. However, the examiner notes that an aliphatic group must be present but is not necessarily exclusively present. Therefore, for the purposes of examination, the examiner interprets any prior art containing a spacer comprising an aliphatic portion to read on aliphatic spacers limitation.
Claim 6 recites “peptidic spacers”. The examiner notes that the specification does not define “peptidic spacers”. Additionally, the examiner interprets that peptidic to mean the spacer includes amide bonds. Therefore, for the purposes of examination, the examiner interprets any prior art containing a spacer comprising an amide bond reads on this limitation.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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 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.
Claim(s) 1-5, 7-13, 17, and 19-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lee, D.; et al., WO 2021/154921 A1 (as cited in the IDS filed on 12/31/2024) and Mansi, R.; et al., Development of a potent DOTA-conjugated bombesin antagonist for targeting GRPr-positive tumours, Eur. J. Nucl. Med. Mol. Imaging, 2011, 38, 97-107.
Lee, D.; et al. (hereafter referred to as Lee) is drawn to optimization methods to improve the theranostic performance of peptide receptor-targeted radionuclides for cancers (title; abstract). Lee teaches neuroendocrine neoplasms are a heterogeneous group of neoplasm and has been increasing over decades (pg 1, lines 15-16) and they are subcategorized into well-differentiated neuroendocrine tumors and poorly-differentiated neuroendocrine carcinomas by histological, biological, and pathological differences (pg 1, lines 16-19). Lee teaches the majority of neuroendocrine neoplasms express somatostatin receptors with SSTR2 as a well-known target for specific therapy called peptide receptor radionuclide therapy (pg 1, lines 21-23) and the developments are often based on beta-particle emitters such as 177Lu (pg 1, lines 21-25) and lutetium-177 radiolabeled DOTATATE is a FDA-approved radiotherapeutic drug (pg 1, lines 25-27). Lee teaches alpha-particle emitters, such as lead-212 is an attractive alpha-particle emitter and is well-matched with biological half-lives of peptides in vivo (pg 2, lines 1-5). Lee teaches changes in peptide structure can shift binding affinity, pharmacokinetics, and biodistribution and some modifications can improve therapeutic outcomes (pg 2, lines 10-13). Lee teaches varying the linker insertions between the tumor targeting moiety and the chelator can improve in vivo performance (pg 2, lines 20-22). Lee teaches adding a linker between the Tyr3-octreotide and DOTA chelator for optimization (pg 2 , lines 26-28). Lee teaches a general formula I, T-L-X, wherein T is a SST2R targeting ligand, L is a linker, and X is a chelator (pg 3, lines 9-15) and wherein T can be Tyr3-octreotide (pg 3, lines 18), X can be Pb-212 or Lu-177 (pg 3, lines 24-25), where L can be inserted between the peptide backbone and the chelator and the linker can improve retention of the composition in tumors, improve clearance of residual composition and minimize radiation exposure in other organs (pg 3, lines 26-34). Lee teaches L can be a polyether linker and aliphatic carbon chain (pg 3, lines 33-34). Lee teaches the synthesis (pg 8, lines 20-35; pg 9, lines 1-10), imaging (pg 11, lines 6-14), stability (pg 11, lines 16-24).
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As to claim 1, Lee teaches a pharmaceutical compound of formula (I) of instant claim Ch(M)-L-T as prior art T-L-X (pg 3, lines 10-11) where prior art “T” is a SST2R targeting ligand and is equivalent to instant claim “T” (pg 3, line 12), where prior art “L” is a linker and is equivalent in position to instant claim “L” (pg 3, line 13), where prior art “X” is a chelator and is equivalent to “Ch” (pg 3, lines 14 and 19-21), and where prior art X can be bound with a radionuclide and is equivalent to instant claim “M”, reproduced and annotated below (pg 3, lines 19-21).
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Lee does not teach the linker comprises a moiety having structure of either formulae IIa or IIb.
Mansi, R.; et al. (hereafter referred to as Mansi) is drawn to radiolabeled DOTA-conjugated targeting peptides with improved uptake in tumor-bearing mouse models (title; abstract). Mansi teaches radiolabeled peptides have attracted considerable interest because of applicability in target-specific radiopharmaceuticals (pg 97, col 2, para 5, lines 1-3) and somatostatin receptor targeting is established for imaging somatostatin receptor-positive tumors (pg 1, col 2, para 5, lines 3-5) and efficient accumulation of radioligand in cells is crucial for optimal tumor visualization (pg 98, col 1, para 1, lines 1-3). Mansi teaches bombesin is highly expressed on major human tumors and are useful in clinical and preclinical applications (pg 98, col 1, para 1, lines 3-16). Mansi teaches design of bombesin agonists is working toward metabolically stable and selective antagonists and used for imaging and targeting (pg 98, col 1, para 2, lines 1-8). Mansi teaches that linkers in the radioconjugate can improve tumor uptake (pg 98, col 1, para 2, lines 6-21) and DOTA-conjugated bombesin with a 4-amino-1-carboxymethyl piperidine linker, structure reproduced below (pg 98, col 1, para 3, lines 1-14; pg 101, Figure 1). Mansi teaches the synthesis (pg 99, col 1, para 2-3), biodistribution (pg 100, col 1, para 4), and imaging (pg 199, col 2, para 2-3). Mansi teaches the compound is a good candidate for diagnostic purposes and potentially good for human studies (pg 106, para 2, lines 6-10).
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Regarding L is a linker comprising formulae IIa or IIb, Mansi teaches Formula IIa, where X1-X4 are carbon atoms, where Y1 is a carbon atom and Y2 is a nitrogen atom, where R1 is a bond and R2 is a linear hydrocarbylene, methylene, and where R3 and R4 are bonds (pg 101, Figure 1, reproduced and annotated below).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the linker in the Ch-L-T compound of Lee with the linker in the Ch-L-T compound as taught by Mansi because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of the compound of formula Ch-L-T where the chelator and targeting peptide are separated by a linker.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting one linker between a chelator and targeting peptide with another linker between a chelator and targeting peptide because the prior art of Lee disclosed varying the linker insertions between the tumor targeting moiety and the chelator known to improve in vivo performance (Lee, pg 2, lines 20-22) and that linkers can improve retention of the composition in tumors, improve clearance of residual composition and minimize radiation exposure in other organs (Lee, pg 3, lines 26-34). Additional prior art of Mansi suggested a cyclic linker to have similar properties of improving tumor uptake (Mansi, pg 98, col 1, para 2, lines 6-21) and that the cyclic linker was a good candidate for diagnostic purposes with potential for human studies (Mansi, pg 106, lines 6-10) and that there would be reasonable success because of the overlap in structure between the chelator and peptides in Lee and Mansi involves known chemistry.
The skilled artisan would have been motivated to substitute the PEG-type linker of Lee with the cyclic type linker of Mansi because the cyclic linker is a modified amino acid which can inhibit degradation between the chelator and the targeting peptide enhancing circulation time and Mansi suggested the cyclic linker was ready for use in humans (pg 106, lines 6-10). Therefore, it would have been prima facie obvious to combine the teachings of Lee with Mansi.
As to claim 2, Mansi teaches R1 is a bond and R2 hydrocarbylene, methylene, and where R3 and R4 are bonds (pg 101, Figure 1).
As to claim 3, Mansi teaches formula IIaa, where X1-X4 are carbon, R3 is a bond and R4 is a bond (pg 101, Figure 1).
As to claim 4, Mansi teaches formula IIc where Y is nitrogen and R3 and R4 are bonds (pg 101, Figure 1).
As to claim 5, Mansi teaches formula IIca, where R3 and R4 are bonds (pg 101, Figure 1).
As to claim 7, Mansi teaches the linker has a structure according to formula IIm (pg 101, Figure 1).
As to claim 8, Lee teaches the sstr2-agonist, T, is Tyr3-octreotide (TOC) (Sheet 1, Figure 1C).
As to claim 9, Lee teaches the sstr2-agonist, T, has a structure according to formula (III) where Z is -CH2OH, reproduced below (Sheet 1, Figure 1C).
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As to claim 10, Lee teaches the radioisotope chelator, Ch, comprises a cyclic polyaminopolycarboxylic moiety (Sheet 1, Figure 1A) and a cyclic polyaminopolycarboxylic moiety with a amide derivative (Sheet 1, Figure 1C).
As to claim 11, Lee teaches a radioisotope chelator, Ch, has a structure according to formula (IV) where n is 1, and where A1, A2 are aliphatic carboxylic acids, and A3 is an aliphatic amide (Sheet 1, Figure 1C). Additionally, Lee teaches “M” in the chelator is a radioisotope bound to the chelator (pg 3, lines 19-21).
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As to claim 12, Lee teaches the radioisotope M can be 212Pb or 177Lu (pg 3, lines 24-25)
As to claim 13, Lee teaches the structure according to Ib, reproduced and annotated below (Sheet 1, Figure 1C).
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Lee does not teach the linker L is according to formula IIm.
Regarding the linker L, Mansi teaches the linker L is according to formula IIm, reproduced below (pg 101, Figure 1).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the linker in the Ch-L-T compound of Lee with the linker in the Ch-L-T compound as taught by Mansi because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of the compound of formula Ch-L-T where the chelator and targeting peptide are separated by a linker.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting one linker between a chelator and targeting peptide with another linker between a chelator and targeting peptide because the prior art of Lee disclosed varying the linker insertions between the tumor targeting moiety and the chelator known to improve in vivo performance (Lee, pg 2, lines 20-22) and that linkers can improve retention of the composition in tumors, improve clearance of residual composition and minimize radiation exposure in other organs (Lee, pg 3, lines 26-34). Additional prior art of Mansi suggested a cyclic linker to have similar properties of improving tumor uptake (Mansi, pg 98, col 1, para 2, lines 6-21) and that the cyclic linker was a good candidate for diagnostic purposes with potential for human studies (Mansi, pg 106, lines 6-10) and that there would be reasonable success because of the overlap in structure between the chelator and peptides in Lee and Mansi involves known chemistry.
The skilled artisan would have been motivated to substitute the PEG-type linker of Lee with the cyclic type linker of Mansi because the cyclic linker is a modified amino acid which can inhibit degradation between the chelator and the targeting peptide enhancing circulation time and Mansi suggested the cyclic linker was ready for use in humans (pg 106, lines 6-10). Therefore, it would have been prima facie obvious to combine the teachings of Lee with Mansi.
As to claim 17, Mansi teaches formula IIca, where R3 and R4 are bonds (pg 101, Figure 1).
As to claim 19, Lee teaches the chelator is DOTA (Sheet 1, Figure 1A).
As to claim 20, Lee teaches DOTA (Sheet 1, Figure 1A).
As to claim 21, Lee teaches A1, A2, and A3 are all the same and are -CH2CO2H (Sheet 1, Figure 1A).
Claim(s) 6, 16, and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lee and Mansi as applied to claims 1-5, 7-13, 17, and 19-21 above, and further in view of Haberkorn, U.; et al., WO 2020/065045 A1. The teachings of Lee and Mansi as applied in the previous rejection are incorporated in this rejection.
As to claim 6, Lee teaches a pharmaceutical compound of formula (I) of instant claim Ch(M)-L-T as prior art T-L-X (pg 3, lines 10-11) where prior art “T” is a SST2R targeting ligand and is equivalent to instant claim “T” (pg 3, line 12), where prior art “L” is a linker and is equivalent in position to instant claim “L” (pg 3, line 13), where prior art “X” is a chelator and is equivalent to “Ch” (pg 3, lines 14 and 19-21), and where prior art X can be bound with a radionuclide and is equivalent to instant claim “M”, reproduced and annotated below (pg 3, lines 19-21).
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Lee does not teach where the linker is a structure according to formulae IIa or IIb.
Lee does not teach where R3 and R4 are spacers selected from the groups consisting of aliphatic spacers and peptide spacers.
Regarding L is a linker comprising formulae IIa or IIb, Mansi teaches Formula IIa, where X1-X4 are carbon atoms, where Y1 is a carbon atom and Y2 is a nitrogen atom, where R1 is a bond and R2 is a linear hydrocarbylene, methylene, and where R3 and R4 are bonds (pg 101, Figure 1, reproduced and annotated below).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the linker in the Ch-L-T compound of Lee with the linker in the Ch-L-T compound as taught by Mansi because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of the compound of formula Ch-L-T where the chelator and targeting peptide are separated by a linker.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting one linker between a chelator and targeting peptide with another linker between a chelator and targeting peptide because the prior art of Lee disclosed varying the linker insertions between the tumor targeting moiety and the chelator known to improve in vivo performance (Lee, pg 2, lines 20-22) and that linkers can improve retention of the composition in tumors, improve clearance of residual composition and minimize radiation exposure in other organs (Lee, pg 3, lines 26-34). Additional prior art of Mansi suggested a cyclic linker to have similar properties of improving tumor uptake (Mansi, pg 98, col 1, para 2, lines 6-21) and that the cyclic linker was a good candidate for diagnostic purposes with potential for human studies (Mansi, pg 106, lines 6-10) and that there would be reasonable success because of the overlap in structure between the chelator and peptides in Lee and Mansi involves known chemistry.
The skilled artisan would have been motivated to substitute the PEG-type linker of Lee with the cyclic type linker of Mansi because the cyclic linker is a modified amino acid which can inhibit degradation between the chelator and the targeting peptide enhancing circulation time and Mansi suggested the cyclic linker was ready for use in humans (pg 106, lines 6-10). Therefore, it would have been prima facie obvious to combine the teachings of Lee with Mansi.
The combined teachings of Lee and Mansi do not teach R3 and R4 are aliphatic or peptidic spacers.
Haberkorn, U.; et al. (hereafter referred to as Haberkorn) is drawn to compounds targeting PSMA-expressing cancers with variations in the linker (title; abstract). Haberkorn teaches prostate cancer is the leading cancer in the US and European populations (pg 1, lines 12-13) and imaging methods with high resolution predominate for imaging of prostate cancer (pg 1, lines 16-20) and different labeling methods are available (pg 1, lines 21-31). Haberkorn teaches overexpression of proteins on the surface of tumor cells offers the opportunity to diagnose and characterize the disease through radioactive molecules that selectively bind specific tumor cell surface proteins (pg 1, lines 32-37). Haberkorn teaches that targeting PSMA can be done by a radioimmunoconjugate with the protein targeting group (pg 2, lines 15-16) and that radionuclides are useful with chelators such as DOTA (pg 2, 25-35) and neuroendocrine tumors can be treated with beta-emitting radioisotopes on radiopharmaceuticals such as 177Lu-DOTATOC (pg 2, lines 16-19). Haberkorn teaches that developing improved ligands can provide advantageous options for detection and treatment and management of cancers (pg 3, lines 32-34) and Haberkorn suggests variable regions of chelator and non-proteinogenic linkers on the ligand for improving the properties of the radiopharmaceutical, reproduced and annotated below (pg 4, formula (I)).
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Regarding R3 and R4 are independently aliphatic or peptidic spacers, Haberkorn also teaches a linker with formulae IIa or IIb (pg 4, formula 1) where instant claim X1-X4 are carbon atoms and Y1-Y6 are carbon atoms and R1 is a hydrocarbylene and R2 is a bond, where R3 is a spacer, and where R4 is a spacer, reproduced and annotated below (Sheet 14, structure CA030). And, Haberkorn teaches where R3 is an aliphatic spacer connecting the formula IIa to the chelator and R3 is a peptidic spacer connecting the formula IIa to the targeting moiety (Sheet 14, structure CA030).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the linker of the combined teachings of Lee and Mansi to include spacers as taught by Haberkorn because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a linker with aliphatic or peptidic spacers.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the linker with spacer groups because the prior art of Lee disclosed varying the linker insertions between the tumor targeting moiety and the chelator known to improve in vivo performance (Lee, pg 2, lines 20-22) and that linkers can improve retention of the composition in tumors, improve clearance of residual composition and minimize radiation exposure in other organs (Lee, pg 3, lines 26-34). And the prior art of Mansi suggested a cyclic linker to have similar properties of improving tumor uptake (Mansi, pg 98, col 1, para 2, lines 6-21) and that the cyclic linker was a good candidate for diagnostic purposes with potential for human studies (Mansi, pg 106, lines 6-10). And additional prior art of Haberkorn suggested developing improved ligands can provide advantageous options for detection and treatment and management of cancers (Haberkorn, pg 3, lines 32-34) and Haberkorn suggests variable regions of chelator and non-proteinogenic linkers on the ligand for improving the properties of the radiopharmaceutical (Haberkorn, pg 4, formula (I)) and that spacers between the cyclic linker portion and the targeting moiety and a spacer between the cyclic linker portion and the chelator to have similar targeting abilities and imaging abilities (Haberkorn, Sheet 16, Figure 3, entries 68Ga-CA030 and 68Ga-PSMA-617).
The skilled artisan would have been motivated to add spacers around the Formula IIa segment of the linker because it is known that adjustments to the linker can improve resistance to peptidases, improve circulation time, and improve targeting abilities. Therefore, it would have been prima facie obvious to combine the teachings of Lee and Mansi with Haberkorn.
As to claim 16, Haberkorn teaches a compound where the linker is such that X is C and Y is C and both R3 and R4 are both a bond when Haberkorn, general formula 1, s, u, and w are 0 and t is 1 (pg 4, lines 1-4) and Y1 is a cycloalkyl (pg 4, lines 7-10) and furthermore is a cyclohexyl (pg 9, lines 36-42).
As to claim 18, Lee teaches a spacer between the chelator and targeting moiety that is non-proteinogenic NH2(CH2)2[O(CH2)2]2C(O)OH, which corresponds to R3 (Sheet 1, Figure 1C).
Lee does not teach R3 connected to a cyclic group and another non-proteinogenic group, R4.
Regarding the central cyclic group and R4, Haberkorn teaches the central cyclic group in general formula (1), reproduced and annotated below, when Y1 is cyclohexyl (pg 4, formula (1); pg 9, lines 36-40) and Haberkorn teaches R4 is a non-proteinogenic peptide phenylalanine when the prior art “X” is benzyl (pg 7, lines 15-19). Haberkorn teaches nonstereospecific phenylalanine which includes D-phenylalanine. compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. Particularly, stereoisomers are prima facie obvious. See MPEP 2144.09(II).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the linker of Lee to include additional linker moieties as taught by Haberkorn because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of a linker with three segments as taught by Haberkorn with two-non-proteinogenic terminal moieties and a cyclic non-proteinogenic central moiety as taught by Lee and Haberkorn.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the linker connected to the chelator of Lee with additional linker moieties connecting it to the targeting moiety because the prior art of Lee disclosed varying the linker insertions between the tumor targeting moiety and the chelator known to improve in vivo performance (Lee, pg 2, lines 20-22) and that linkers can improve retention of the composition in tumors, improve clearance of residual composition and minimize radiation exposure in other organs (Lee, pg 3, lines 26-34). Additional prior art of Haberkorn suggested developing improved ligands can provide advantageous options for detection and treatment and management of cancers (Haberkorn, pg 3, lines 32-34) and Haberkorn suggests variable regions of chelator and non-proteinogenic linkers on the ligand for improving the properties of the radiopharmaceutical (Haberkorn, pg 4, formula (I)) and that spacers between the cyclic linker portion and the targeting moiety and a spacer between the cyclic linker portion and the chelator to have similar targeting abilities and imaging abilities (Haberkorn, Sheet 16, Figure 3, entries 68Ga-CA030 and 68Ga-PSMA-617).
The skilled artisan would have been motivated to modify the linker of Lee connected to the chelator with additional linker moieties connecting Lee’s linker to the targeting moiety because PEG linkers have good hydrophilic properties and flexibility and the cyclic and non-proteinogenic moieties of Haberkorn reduce degradation of the linkage between the chelator and the targeting moiety. Therefore, it would have been prima facie obvious to combine the teachings of Lee with Haberkorn.
Claim(s) 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lee and Mansi and Haberkorn as applied to claims 1-13 and 16-21 above, and further in view of Verlikyan, I.; et al., Robust labeling and comparative preclinical characterization of DOTA-TOC and DOTA-TATE, Nuclear Medicine and Biology, 2012, 39, 628-639. The teachings of Lee, Mansi, and Haberkorn as applied in the previous rejection are incorporated in this rejection.
As to claim 14, Lee teaches the compound of formula Ib (Sheet 1, Figure 1A) where the chelator is DOTA (Sheet 1, Figure 1A), and the radioisotope is 177Lu (pg 3, lines 24-25).
Lee does not teach the linker is amcha.
Lee does not teach the sstr2-agonist is TATE.
Regarding the linker is amcha, Haberkorn teaches amcha when in the prior art general formula (1), reproduced and annotated below, s, u, and w are 0, and t is 1 (pg 4, lines 3-4), and when Y3 is oxygen, and when Y1 is cyclohexyl (pg 9, lines 36-40).
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It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the linker of Lee with the amcha linker as taught by Haberkorn because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of the substitution of the amcha linker of Haberkorn in place of the PEG linker of Lee.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the amcha linker of Haberkorn in place of the PEG linker of Lee because the prior art of Lee disclosed varying the linker insertions between the tumor targeting moiety and the chelator known to improve in vivo performance (Lee, pg 2, lines 20-22) and that linkers can improve retention of the composition in tumors, improve clearance of residual composition and minimize radiation exposure in other organs (Lee, pg 3, lines 26-34). Additional prior art of Haberkorn suggested developing improved ligands can provide advantageous options for detection and treatment and management of cancers (Haberkorn, pg 3, lines 32-34) and Haberkorn suggests variable regions of chelator and non-proteinogenic linkers on the ligand for improving the properties of the radiopharmaceutical (Haberkorn, pg 4, formula (I)) and that spacers between the cyclic linker portion and the targeting moiety and a spacer between the cyclic linker portion and the chelator to have similar targeting abilities and imaging abilities (Haberkorn, Sheet 16, Figure 3, entries 68Ga-CA030 and 68Ga-PSMA-617).
The skilled artisan would have been motivated to substitute the amcha linker of Haberkorn in place of the PEG linker of Lee because replacing the more flexible and more hydrophilic PEG linker with the less flexible and more hydrophobic amcha linker could favorably reduce the chance of degradation by proteases. Therefore, it would have been prima facie obvious to combine the teachings of Lee with Haberkorn.
Velikyan, I.; et al. (hereafter referred to as Velikyan) is drawn to the comparison of somatostatin analouges DOTA-TOC and DOTA-TATE (title; abstract). Velikyan teaches the importance of early and personalized diagnosis for efficient therapy and molecular imaging is useful in diagnosis (pg 628, col 12, para 1, lines 1-6) and receptor radionuclide therapy is more efficient than chemotherapy (pg 629, col 1, para 1, lines 1-4) and somatostatin receptors are a means of monitoring neuroendocrine tumors with SSTR2 and SSTR5 expressed most frequently on tumors (pg 629, col 1, para 1, lines 8-16). Velikyan teaches various radiopharmaceuticals such as 68Ga-DOTA-TOC and 177Lu-DOTA-TATE are commonly administered to patients (pg 629, col 2, para 2, lines 1-13) and that DOTA_TOC and DOTA-TATE are both frequently used in imaging and radiotherapy with DOTA-TATE having up to a 10-fold higher affinity for SSTR2 compared to DOTA-TOC (pg 629, col 2, para 3, lines 1-9). Velikyan teaches the synthesis of the complexes (pg 630, col 1, par 2; pg 630, col 2, para 1-2) and biodistribution (pg 631, col 2, para 5).
Regarding the sstr2-agonist is TATE, Velikyan teaches TATE (pg 630, Figure 1).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the sstr2-agonist, TOC, of Lee with the sstr2-agonist as taught by Velikyan because the substituted components and their functions were known in the art and a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have yielded the predictable outcome of substituting TATE in place of TOC.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting TATE in place of TOC because the prior art of Lee disclosed TOC known to be an sstr2 targeting peptide (Lee, abstract). Additional prior art of Velikyan suggested TATE and TOC to have similar sstr2 targeting behavior (Velikyan, pg 630, Figure 1) because of the overlap of structure between them involves known chemistry and biology.
The skilled artisan would have been motivated to substitute TATE in place of TOC because Velikyan teaches that TATE can have up to a 10-fold higher affinity for sstr2 compared to TOC in vitro (pg 629, col 2, para 3, lines 1-9). Therefore, it would have been prima facie obvious to combine the teachings of Lee with Velikyan.
Conclusion
No claims allowed.
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/EVAN M LEWOCZKO/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
