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 1-20 are under examination.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
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.
The specification lacks SEQ ID NO. designation in the following locations: enumerated structures (pg 4, Formula 1; pg 5, formula 6; pg 5, Reaction Formula 1; pg 7, Formula 1; pg 8, Formula 6; pg 10, Reaction Formula 1; pg 14, Reaction of example 1; pg 15, reaction of example 2; pg 16, reaction of example 3; pg 18, reaction of example 4) and in the body of the text (pg 14, line 3).
Specification
The disclosure is objected to because of the following informalities: formula 6 and formula 5 (pg 5, lines 1-2 and lines 7-10; pg 8, lines 15-16; pg 10, line 1) have the same structure but are labeled differently and formulas 2-4 are not referenced.
Appropriate correction is required.
Claim Objections
Claims 4 and 7 are objected to because of the following informalities: formula 5 and formula 6 appear to be the same structure but are labeled differently.
Appropriate correction is required.
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.
Claim 7 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: “R” group of formula 5 is undefined. And as such the structure and cooperative relationships of the structures are indefinite.
Claim Interpretation
Claim 7 recites an R group on formula 5 in reaction formula 1. The examiner notes that neither the specification nor the claims define “R” for formula 5. For the purposes of examination, the examiner interprets any prior art containing any R-group as a leaving group which can be replaced by fluorine as reading on this claim limitation.
Claim 8 recites the functional language, “as an active ingredient”. The examiner notes that the specification is silent as to details of what is required of an active ingredient. For the purposes of examination, the examiner interprets any compound of formula I in the prior art reads on the limitation of “an active ingredient”.
Claim 9 recites, “the composition binds to phosphatidylserine”. The examiner notes that the composition in claim 8 uses comprising language and claim 9 does not specify what in the composition is binding to phosphatidylserine. Therefore, for the purposes of examination, the examiner interprets any prior art containing a composition which binds to phosphatidylserine as reading on this limitation.
Claim 10 recites functional language, “used for positron emission tomography…”. The examiner notes that any composition which meets the requirements of the compound of formula I could be used for PET when F is 18F or 19F. Therefore, for the purposes of examination, any prior art which reads on a composition of a compound of formula 1, reads on this limitation.
Claim 11 recites functional language, “used to image…”. The examiner notes that any composition which meets the requirements of the compound of formula I could be used for PET when F is 18F or 19F. Therefore, for the purposes of examination, any prior art which reads on a composition of a compound of formula 1, reads on this limitation.
Claim 13 recites functional language, “for diagnosing neurodegenerative diseases”. The examiner notes that any composition which meets the requirements of the compound of formula I could be used to diagnose neurodegenerative diseases. Therefore, for the purposes of examination, any prior art which reads on a composition of a compound of formula 1, reads on this limitation.
Claim 15 recites functional language, “for imaging apoptosis …”. The examiner notes that any composition which meets the requirements of the compound of formula 1 could be used for PET when F is 18F or 19F. Therefore, for the purposes of examination, any prior art which reads on a composition of a compound of formula 1, reads on this limitation.
Claim 16 recites functional language, “for diagnosing a disease…”. The examiner notes that any composition which meets the requirements of the compound of formula 1 could be used to diagnose a disease selected from the group. Therefore, for the purposes of examination, any prior art which reads on a composition of a compound of formula 1, reads on this limitation.
Claim 17 recites functional language, “for imaging inflammatory tissue…”. The examiner notes that any composition which meets the requirements of the compound of formula 1 could be used for PET when F is 18F or 19F. Therefore, for the purposes of examination, any prior art which reads on a composition of a compound of formula 1, reads on this limitation.
Claim 18 recites functional language, “for diagnosing inflammatory diseases.” The examiner notes that any composition which meets the requirements of the compound of formula 1 could be used to diagnose inflammatory diseases. Therefore, for the purposes of examination, any prior art which reads on a composition of a compound of formula 1, reads on this limitation.
Claim 19 recites functional language, “for diagnosing autoimmune diseases.” The examiner notes that any composition which meets the requirements of the compound of formula 1 could be used to diagnose autoimmune diseases. Therefore, for the purposes of examination, any prior art which reads on a composition of a compound of formula 1, 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) 1-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lee, B-H.; et al. US 2017/0340698 A1 (as cited in the IDS filed on 02/15/2024) and Guembe, L.; et al. Immunocytochemical Mapping of the Amidating Enzyme PAM in the Developing and Adult Mouse Lung, J. Histochemistry and Cytochemistry, 1999, 47, 5, 623-636 and Kim, I-S.; et al., KR10-2012-0066550 and Ravert, H. T.; et al. An improved synthesis of the radiolabeled prostate-specific membrane antigen inhibitor, [18F]DCFPyL, J. Label Compd. Radiopharm, 2016, 1-13.
Lee, B-H.; et al. (hereafter referred to as Lee) is drawn to cyclic peptides (CQRPPRC) for binding to apoptotic cells with detection and imaging of the apoptotic cells (title; abstract). Lee teaches both linear and cyclic peptide with the sequence CQRPPRC (ApoPep-1) (Figure 1 and Figure 2). Lee teaches gastric cancer is the second leading cause of cancer death worldwide and that chemotherapies use additional agents (pg 1, para [0004], lines 1-4) and that PET imaging is known to help early determination of tumor response to treatment (pg 1, para [0006], lines 1-8) and that 18F FDG has limited use due to poor uptake by some tumors (pg 1, para [0007], lines 1-7). Lee teaches targeting apoptotic cells with Apopep-1 can target apoptosis that occurs in apoptotic cell-related diseases, such as tumor diseases, neurodegenerative diseases, myocardial infarction, and arteriosclerosis (pg 1, para [0009], lines 5-9). Lee teaches that while the peptides have increased detection rate, there are limiting factors associated with structure, stability, etc (pg 1, para [0010], lines 4-10). Lee teaches cyclic ApoPep-1 to improve sensitivity over linear ApoPep-1 (pg 2, para [0023], lines 1-12). Lee teaches administration of the peptide as an anti-tumor agent (pg 2, para [0025]), as a neurodegenerative disease (pg 2, para [0026]), a myocardial infarction (pg 2, para [0027], an arteriosclerosis (pg 2, para [0028]), and a stroke therapeutic (pg 2, para [0029]). Lee teaches that the cyclic ApoPep-1 may be derived from natural sources, synthesized by known peptide synthetic methods, and amino acids can be exchanged, modified, deleted, or substituted without substantially changing the molecular activity (pg 3, para [0044], lines 1-16). Lee teaches that cyclic ApoPep-1 performs better than linear ApoPep-1 (pg 3, para [0046], lines 4-11; pg 3, para [0047], lines 1-8). Lee teaches that to facilitate detection and quantification of the peptide, the peptide can be labeled with chromogenic enzymes, radioactive isotopes, luminescent or fluorescent materials, etc (pg 4, para [0054], lines 1-18) and that the cyclic ApoPep-1 can be used as a probe for PET imaging (pg 4, col 2, para [0055], lines 6-9). Lee teaches the peptide is an active ingredient with any labeling means (pg 4, para [0058], lines 1-8). Lee teaches methods of synthesis (pg 9, para [0123], lines 1-9), methods of treating (pg 10, para [0128]), and methods of analysis (pg 10, para [0134]).
As to claim 1, Lee teaches a compound represented by the cyclic peptide with the amino acid sequence of Formula I (CQRPPRC) (pg 2, para [0023], lines 5-6).
Lee does not teach the C-terminal amide group.
Lee does not teach the fluorinate nicotinamide N-substituent on the N-terminus cysteine.
Guembe, L.; et al. (hereafter referred to as Guembe) is drawn to an amidating enzyme required for activation of many peptide hormones (title; abstract). Guembe teaches bioactive peptides are generated biosynthetically from larger precursors via a variety of posttranslational modifications (pg 623, col 1, para 1, lines 1-3) and that amidation of the peptide carboxy terminal amino acid is the best studied with respect to biological significance (pg 623, col 1, para 1, lines 3-6) and that more than half of the known peptide hormones of mammals are amidated (pg 623, col 1, para 1, lines 7-9) and that amidation frequently confers biological activity to the peptide as much as 100- to 1000-fold more active (pg 623, col 1, para 1, lines 10-14). Guembe teaches that amidation is often performed by PAM enzymes (pg 623, col 2 para 1, lines 1-7). Guembe teaches testing mice (pg 624, col 1, para 2, lines 1-7) and immunoreactivity for PAM in mice was localized in certain tissue and no immunoreaction was observed (pg 624, col 2, para 5, lines 1-9).
Regarding C-terminal amide on a C-terminus cysteine, Guembe teaches C-terminal amide groups (pg 623, col 1, para 1, lines 10-14).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the C-terminal carboxylic acid of Lee to include C-terminal amide as taught by Guembe because there was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference of Lee with the reference of Guembe and one of skill in the art could have combined these elements by known methods, and the combination would have yielded the predictable outcome of a cyclic peptide with a C-terminal amide.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the C-terminal group because the prior art of Lee disclosed cyclic peptides known to have a limitation of stability against carboxypeptidase degradation and effect (pg 1, para [0010], lines 1-11). Additional prior art of Guembe suggested C-terminal amides improve effect by 100- to 1000-fold and Guembe teaches this moiety is on more than half of the known peptide hormones of mammals (pg 623, col 1, para 1, lines 5-9).
The skilled artisan would have been motivated to modify the C-terminal group because Guembe suggested that C-terminal amide groups significantly improved resistance to carboxypeptidase degradation and increased effect by as much as 1000-fold.
Regarding fluorinated nicotinamide N-substituent on the N-terminus cysteine, the combined teachings of Lee and Guembe do not teach fluorinated nicotinamide N-substituents.
Kim, I-S.; et al. (hereafter referred to as Kim) is drawn to ApoPep-1 labeled with fluorine-18 for PET of apoptotic cells (title; abstract). Kim teaches 18F labeled ApoPep-1 can be used to diagnose a variety of disease conditions associated with apoptosis and to image cells related to diseases (pg 2, para 2-3). Kim teaches ApoPep-1 can have 18F substituent as a N-substituent group on a N-terminus cysteine defined as X-Y-Z-F, in the case where X is a carbonyl, Y is a methyl and an aromatic ring compound consisting of 5 carbons and a nitrogen, and Z is a methyl and 18F or 19F (pg 2, claim 1). Kim teaches a method of producing the labeled ApoPep-1 (pg 8, para [0027], Equation 2) and imaging with the 18F labeled ApoPep-1 (pg 21, para [0140]-[0145]).
Regarding fluorinated nicotinamide N-substituent on the N-terminus cysteine, Kim teaches ApoPep-1 with a fluorinated aromatic group as an N-substituent on the N-terminus cysteine (pg 6, para [0013]), where X is a carbonyl (claim 1, line 2), Y is an aromatic ring consisting of 5 carbons and a nitrogen (claim 1, lines 3-4), Z is a C1, and F is 18F or 19F (claim 1, lines 5-6).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of Lee and Guembe to include the N-terminus cysteine N-substituent as taught by Kim 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 an fluorinated N-substituent on the N-terminus cysteine.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the unspecified radiolabel of Lee with the fluorinated N-substituent on the N-terminus cysteine because the prior art of Lee disclosed cyclic and linear ApoPep-1 peptides known to be able to be labeled with fluorine for PET or with fluorescent molecules and other labels (pg 4, para [0054], lines 1-18) and known to be able to have the amino acids modified without significantly altering the apoptotic nature of the peptide (pg 3, para [0044], lines 1-16). Additional prior art of Kim suggested a specific radiolabel at the N-terminus cysteine to have similar apoptotic targeting capabilities and to be useful for PET because of the overlap of the amino acid sequence (pg 2, para 2, lines 1-3; pg 2, para 3, lines 1-3).
The skilled artisan would have been motivated to modify the labeled ApoPep-1 of Lee with the radiolabel of Kim because PET with 18F is one of the most useful probes for real time imaging of tissues.
The combined teachings of Lee, Guembe, and Kim do not expressly teach the specific fluorinated nicotinamide N-substituent.
Ravert, H. T.; et al. (hereafter referred to as Ravert) is drawn to improving radiolabeling of PSMA targeting moieties (title; abstract). Ravert teaches that prostate cancer is the most common cancer in men (pg 1, col 1, para 1, lines 1-4) and that 18F radiotracers are useful for PET imaging of the cancers (pg 1, col 1, para 2, lines 7-13) and that many preparations of 18F labeled compounds are accomplished in multistep synthetic routes (pg 1, col 2, para 2, lines 1-6) resulting in low to moderate radiochemical yield (pg 1, col 2, para 2, lines 6-11). Ravert teaches that a precursor can enable direct fluorination of the compound with improved radiochemical yield (pg 1, para 2, lines 11-17) and enabled full compliance with USP (pg 2, col 1, para 1, lines 1-2). Ravert teaches synthesis methods (pg 2, col 2, para 2, lines 1-15; pg 2, col 2, para 4, lines 1-8; pg 3, col 1, para 1, lines 1-10 and para 2, lines 1-12). Ravert teaches characterization by visual inspection (pg 3, col 2, para 3, lines 1-5), radiochemical identity (pg 3, col 2, para 4, lines 1-12), radiochemical purity, pg 3, col 2, para 5, lines 1-11), etc. Ravert teaches the method can be adapted for human studies (pg 5, col 1, para 1, lines 1-8) and that radiofluorination of the trimethylammonium precursor produces a clean reaction profile in high yield (pg 5, para 4, liens 1-3). Ravert teaches that this method of radiofluorination can also be automated (pg 5, col 2, para 3, lines 1-16). Ravert teaches the direct radiofluorination of a compound from the trimethylammonium precursor (pg 8, Figure 4) and characterization (pg 9, Figure 5).
Regarding the fluorinated nicotinamide N-substituent, Ravert teaches the specific fluorinated nicotinamide (pg 8, Figure 4).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the fluorinated aromatic N-substituent of the N-terminus of Kim with the fluorinated nicotinamide as taught by Ravert 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 a fluorinated nicotinamide N-substituted N-terminus cysteine.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting one fluorinated aromatic group for the fluorinated nicotinimide because the prior art of Kim disclosed fluorinated aromatic group as an N-substituent on the N-terminus cysteine (pg 6, para [0013]), where X is a carbonyl (claim 1, line 2), Y is an aromatic ring consisting of 5 carbons and a nitrogen (claim 1, lines 3-4), Z is a C1, and F is 18F or 19F (claim 1, lines 5-6) known to work as a PET trace (abstract, line 1). Additional prior art of Ravert suggested fluorinated nicotinimide to have similar properties of serving as a PET tracer because of the overlap of the heteroaromatic ring and the 18F between them involves known irradiation.
The skilled artisan would have been motivated to substitute the fluorinated heteroaromatic ring of Kim with the fluorinated nicotinamide of Ravert because fluorinated nicotinamide of Ravert has a precursor that can be used to enable synthesis of the peptide precursor with labeling in one step in clean reactions with high yields (pg 5, para 4, lines 1-3).
As to claim 2, Ravert teaches the F is 18F or 19F (claim 1, lines 5-6).
As to claim 3, Ravert teaches the F is 18F (claim 1, lines 5-6).
As to claim 4, Lee teaches a compound represented by the cyclic peptide with the amino acid sequence of Formula I (CQRPPRC) (pg 2, para [0023], lines 5-6).
Lee does not teach the C-terminal amide groups.
Lee does not teach the N-substituent on the N-terminus of a cysteine.
Lee does not teach the trialkylammonium nicotinamide N-substituent on the N-terminus cysteine, where the trialkylammonium nicotinamide is N+R1R2R3; wherein R1, R2, and R3 are independently C1-C10 alkyl.
Regarding C-terminal amide on a cysteine, Guembe teaches C-terminal amide groups (pg 623, col 1, para 1, lines 10-14).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the C-terminal carboxylic acid of Lee to include C-terminal amide as taught by Guembe because there was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference of Lee with the reference of Guembe and one of skill in the art could have combined these elements by known methods, and the combination would have yielded the predictable outcome of a cyclic peptide according to Lee with a C-terminal amide.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the C-terminal group because the prior art of Lee disclosed cyclic peptides known to have a limitation of stability against carboxypeptidase degradation and effect (pg 1, para [0010], lines 1-11). Additional prior art of Guembe suggested C-terminal amides improve effect by 100- to 1000-fold and Guembe teaches this moiety is on more than half of the known peptide hormones of mammals (pg 623, col 1, para 1, lines 5-9).
The skilled artisan would have been motivated to modify the C-terminal group because Guembe suggested that C-terminal amide groups significantly improved resistance to carboxypeptidase degradation and increased effect by as much as 1000-fold.
Regarding the N-substituent of the N-terminus cysteine, the combined teachings of Lee and Guembe do not teach a N-substituent on the N-terminus cysteine.
Kim teaches ApoPep-1 with a fluorinated aromatic group as an N-substituent on the N-terminus cysteine (pg 6, para [0013]), where X is a carbonyl (claim 1, line 2), Y is an aromatic ring consisting of 5 carbons and a nitrogen (claim 1, lines 3-4), Z is a C1, and F is 18F or 19F (claim 1, lines 5-6).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of Lee and Guembe to include the N-terminus cysteine N-substituent as taught by Kim 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 an fluorinated N-substituent on the N-terminus cysteine.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the unspecified radiolabel of Lee with the fluorinated N-substituent on the N-terminus cysteine because the prior art of Lee disclosed cyclic and linear ApoPep-1 peptides known to be able to be labeled with fluorine for PET or with fluorescent molecules and other labels (pg 4, para [0054], lines 1-18) and known to be able to have the amino acids modified without significantly altering the apoptotic nature of the peptide (pg 3, para [0044], lines 1-16). Additional prior art of Kim suggested a specific radiolabel at the N-terminus cysteine to have similar apoptotic targeting and to be useful for PET (pg 2, para 2, lines 1-3; pg 2, para 3, lines 1-3) because of the overlap of the amino acid sequence.
The skilled artisan would have been motivated to modify the N-terminal group because Kim demonstrates a N-substituent group on the N-terminal cysteine that is effective for PET imaging of apoptosis for a variety of applications.
Regarding the trialkylammonium nicotinamide N-substituent on the N-terminus cysteine, where the trialkylammonium nicotinamide is N+R1R2R3; wherein R1, R2, and R3 are independently C1-C10 alkyl, the combined teachings of Lee, Guembe, and Kim do teach this feature.
Ravert teaches trialkylammonium nicotinamide where N+R1R2R3; wherein R1, R2, and R3 are each C1 alkyl (pg 8, Figure 4). In such cases when, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art. See MPEP 2131.03. In the instant case, since the claim as a whole is made obvious, this range is made obvious since one of the values for the alkyl lengths is in the prior art.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the N-substituent of the N-terminus of Kim with the trialkylammonium nicotinamide as taught by Ravert 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 a fluorinated nicotinamide N-substituted N-terminus cysteine.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting one N-substituted N-terminus cysteine group for the N-substituted trialkylammonium nicotinimide N-terminus cysteine group because the prior art of Kim disclosed fluorinated aromatic group as an N-substituent on the N-terminus cysteine (pg 6, para [0013]), where X is a carbonyl (claim 1, line 2), Y is an aromatic ring consisting of 5 carbons and a nitrogen (claim 1, lines 3-4), Z is a C1, and F is 18F or 19F (claim 1, lines 5-6) known to work as a PET tracer (abstract, line 1). Additional prior art of Ravert suggested fluorinated nicotinimide to have similar properties of serving as a PET tracer because of the overlap of the heteroaromatic ring and the 18F between them involves known irradiation and the prior art of Ravert disclosed a trialkylammonium for the fluorinated nicotinamide known to serve as a precursor to the fluorinated nicotinamide (pg 8, Figure 4).
The skilled artisan would have been motivated to substitute the fluorinated heteroaromatic ring of Kim with the trialkylammonium nicotinamide of Ravert because trialkylammonium nicotinamide of Ravert can be stored for long periods without concern of the half-life of radiolabel decay and when the radiolabeled compound is desired, radiolabelling the trialkylammonium nicotinamide can occur in clean reactions with high yields (pg 5, para 4, lines 1-3).
As to claim 5, Ravert teaches R1, R2, and R3 are C1 alkyl (pg 8, Figure 4). In such cases when, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art. See MPEP 2131.03. In the instant case, since the claim as a whole is made obvious, this range is made obvious since one of the values for the alkyl lengths is in the prior art.
As to claim 6, Ravert teaches R1, R2, and R3 are methyl (pg 8, Figure 4).
As to claim 7, Lee teaches a compound represented by the cyclic peptide with the amino acid sequence of Formula I (CQRPPRC) (pg 2, para [0023], lines 5-6).
Lee does not teach the C-terminal amide groups.
Lee does not teach the N-substituent on the N-terminus of a cysteine.
Lee does not teach the trialkylammonium nicotinamide N-substituent on the N-terminus cysteine, where the trialkylammonium nicotinamide is N+R1R2R3; wherein R1, R2, and R3 are independently C1-C10 alkyl.
Lee does not teach a method for producing the fluorinated compound from the precursor.
Regarding C-terminal amide on a cysteine, Guembe teaches C-terminal amide groups (pg 623, col 1, para 1, lines 10-14).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the C-terminal carboxylic acid of Lee to include C-terminal amide as taught by Guembe because there was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference of Lee with the reference of Guembe and one of skill in the art could have combined these elements by known methods, and the combination would have yielded the predictable outcome of a cyclic peptide according to Lee with a C-terminal amide.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the C-terminal group because the prior art of Lee disclosed cyclic peptides known to have a limitation of stability against carboxypeptidase degradation and effect (pg 1, para [0010], lines 1-11). Additional prior art of Guembe suggested C-terminal amides improve effect by 100- to 1000-fold and Guembe teaches this moiety is on more than half of the known peptide hormones of mammals (pg 623, col 1, para 1, lines 5-9).
The skilled artisan would have been motivated to modify the C-terminal group because Guembe suggested that C-terminal amide groups significantly improved resistance to carboxypeptidase degradation and increased effect by as much as 1000-fold.
Regarding the N-substituent of the N-terminus cysteine, the combined teachings of Lee and Guembe do not teach a N-substituent on the N-terminus cysteine.
Kim teaches ApoPep-1 with a fluorinated aromatic group as an N-substituent on the N-terminus cysteine (pg 6, para [0013]), where X is a carbonyl (claim 1, line 2), Y is an aromatic ring consisting of 5 carbons and a nitrogen (claim 1, lines 3-4), Z is a C1, and F is 18F or 19F (claim 1, lines 5-6).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of Lee and Guembe to include the N-terminus cysteine N-substituent as taught by Kim 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 an fluorinated N-substituent on the N-terminus cysteine.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the unspecified radiolabel of Lee with the fluorinated N-substituent on the N-terminus cysteine because the prior art of Lee disclosed cyclic and linear ApoPep-1 peptides known to be able to be labeled with fluorine for PET or with fluorescent molecules and other labels (pg 4, para [0054], lines 1-18) and known to be able to have the amino acids modified without significantly altering the apoptotic nature of the peptide (pg 3, para [0044], lines 1-16). Additional prior art of Kim suggested a specific radiolabel at the N-terminus cysteine to have similar apoptotic targeting and to be useful for PET (pg 2, para 2, lines 1-3; pg 2, para 3, lines 1-3) because of the overlap of the amino acid sequence.
The skilled artisan would have been motivated to modify the N-terminal group because Kim demonstrates a N-substituent group on the N-terminal cysteine that is effective for PET imaging of apoptosis for a variety of applications.
Regarding the trialkylammonium nicotinamide N-substituent on the N-terminus cysteine, where the trialkylammonium nicotinamide is N+R1R2R3; wherein R1, R2, and R3 are independently C1-C10 alkyl, the combined teachings of Lee, Guembe, and Kim do teach this feature.
Ravert teaches trialkylammonium nicotinamide where N+R1R2R3; wherein R1, R2, and R3 are each C1 alkyl (pg 8, Figure 4). In such cases when, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art. See MPEP 2131.03. In the instant case, since the claim as a whole is made obvious, this range is made obvious since one of the values for the alkyl lengths is in the prior art.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the N-substituent of the N-terminus of Kim with the trialkylammonium nicotinamide as taught by Ravert 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 a fluorinated nicotinamide N-substituted N-terminus cysteine.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting one N-substituted N-terminus cysteine group for the N-substituted trialkylammonium nicotinimide N-terminus cysteine group because the prior art of Kim disclosed fluorinated aromatic group as an N-substituent on the N-terminus cysteine (pg 6, para [0013]), where X is a carbonyl (claim 1, line 2), Y is an aromatic ring consisting of 5 carbons and a nitrogen (claim 1, lines 3-4), Z is a C1, and F is 18F or 19F (claim 1, lines 5-6) known to work as a PET tracer (abstract, line 1). Additional prior art of Ravert suggested fluorinated nicotinimide to have similar properties of serving as a PET tracer because of the overlap of the heteroaromatic ring and the 18F between them involves known irradiation and the prior art of Ravert disclosed a trialkylammonium for the fluorinated nicotinamide known to serve as a precursor to the fluorinated nicotinamide (pg 8, Figure 4).
The skilled artisan would have been motivated to substitute the fluorinated heteroaromatic ring of Kim with the trialkylammonium nicotinamide of Ravert because trialkylammonium nicotinamide of Ravert can be stored for long periods without concern of the half-life of radiolabel decay and when the radiolabeled compound is desired, radiolabelling the trialkylammonium nicotinamide can occur in clean reactions with high yields (pg 5, para 4, lines 1-3).
Regarding a method for producing the fluorinated compound from the precursor, Ravert teaches a method for producing a compound comprising a step of substituting a group with fluorine, where F is 18F or 19F as shown in the figure below (pg 8, Figure 4).
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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 compound of Lee, Guembe, Kim, and Ravert to include the method of producing the fluorinated product from the precursor as taught by Ravert 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 method of producing a fluorinated compound from its precursor.
A person of ordinary skill in the art would have had a reasonable expectation of success in a method of making the compound because the prior art of Lee, Guembe, Kim, and Ravert disclosed both a radiofluorinated compound and its precursor where the precursor is known to be able to react with 18F- to produce the radiofluorinated compound (Ravert, pg 8, Figure 4). Additionally, the prior art of Ravert suggested that this trialkylammonium nicotinamide precursor has similar ability to produce the radiofluorinated compound with 18F or 19F (pg 8, Figure 4).
The skilled artisan would have been motivated to modify the compound of Lee, Guembe, Kim, and Ravert to have the method of radiofluorinating as taught by Ravert because this method of radiofluorinating enables the precursor to be stored without concern for the half-life of the radiolabel and when the radiolabeled compound is desired, radiolabelling the trialkylammonium nicotinamide can occur in clean reactions with high yields (pg 5, para 4, lines 1-3).
As to claim 8, Lee teaches a composition for imaging apoptosis (pg 1, para [0002], lines 1-6) with the compound as the active ingredient (pg 4, para [0058], lines 1-8).
As to claim 9, Kim teaches a composition which can bind to phosphatidylserine on the surface of apoptotic cells (pg 4, para [0004], line 1; pg 4, para [0006], lines 3-6).
As to claim 10, Kim teaches a composition used for positron emission tomography of apoptotic cells (abstract, lines 1-3).
As to claim 11, Kim teaches imaging apoptosis of cancer cells after administration of an anticancer agent (pg 22, para [0149], liens 1-5).
As to claim 12, Lee teaches the cancer is colorectal cancer (pg 4, para [0061], line 5).
As to claim 13, Lee teaches diagnosing neurodegenerative diseases (pg 4, para [0059], lines 1-2; pg 5, para [0062, lines 1-4).
As to claim 14, Lee teaches the neurodegenerative disease is Alzheimer’s disease (pg 5, para [0062], lines 1-4).
As to claim 15, Lee teaches imaging apoptosis in high-risk atherosclerotic plaque tissue (pg 5, para [0065], lines 4-9).
As to claim 16, Lee teaches diagnosing a disease selected from the groups consisting of stroke and myocardial infarction (pg 6, para [0084], lines 4-6).
As to claim 17, Lee teaches imaging inflammatory tissue (pg 4, para [0059], lines 1-3; pg 4, para [0060], lines 1-9; pg 5, para [0065], lines 8-10).
As to claim 18, Lee teaches a composition for diagnosing inflammatory diseases (pg 4, para [0059], lines 1-3; pg 4, para [0060], lines 1-9; pg 5, para [0065], lines 8-10).
As to claim 19, Lee teaches diagnosing autoimmune diseases (pg 5, para [0065], lines 20-24).
As to claim 20 Lee teaches a compound represented by the cyclic peptide with the amino acid sequence of Formula I (CQRPPRC) (pg 2, para [0023], lines 5-6).
Lee does not teach the C-terminal amide group.
Lee does not teach the fluorinate nicotinamide N-substituent on the N-terminus cysteine.
Guembe, L.; et al. (hereafter referred to as Guembe) is drawn to an amidating enzyme required for activation of many peptide hormones (title; abstract). Guembe teaches bioactive peptides are generated biosynthetically from larger precursors via a variety of posttranslational modifications (pg 623, col 1, para 1, lines 1-3) and that amidation of the peptide carboxy terminal amino acid is the best studied with respect to biological significance (pg 623, col 1, para 1, lines 3-6) and that more than half of the known peptide hormones of mammals are amidated (pg 623, col 1, para 1, lines 7-9) and that amidation frequently confers biological activity to the peptide as much as 100- to 1000-fold more active (pg 623, col 1, para 1, lines 10-14). Guembe teaches that amidation is often performed by PAM enzymes (pg 623, col 2 para 1, lines 1-7). Guembe teaches testing mice (pg 624, col 1, para 2, lines 1-7) and immunoreactivity for PAM in mice was localized in certain tissue and no immunoreaction was observed (pg 624, col 2, para 5, lines 1-9).
Regarding C-terminal amide on a C-terminus cysteine, Guembe teaches C-terminal amide groups (pg 623, col 1, para 1, lines 10-14).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the C-terminal carboxylic acid of Lee to include C-terminal amide as taught by Guembe because there was some teaching, suggestion, or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference of Lee with the reference of Guembe and one of skill in the art could have combined these elements by known methods, and the combination would have yielded the predictable outcome of a cyclic peptide with a C-terminal amide.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the C-terminal group because the prior art of Lee disclosed cyclic peptides known to have a limitation of stability against carboxypeptidase degradation and effect (pg 1, para [0010], lines 1-11). Additional prior art of Guembe suggested C-terminal amides improve effect by 100- to 1000-fold and Guembe teaches this moiety is on more than half of the known peptide hormones of mammals (pg 623, col 1, para 1, lines 5-9).
The skilled artisan would have been motivated to modify the C-terminal group because Guembe suggested that C-terminal amide groups significantly improved resistance to carboxypeptidase degradation and increased effect by as much as 1000-fold.
Regarding fluorinated nicotinamide N-substituent on the N-terminus cysteine, the combined teachings of Lee and Guembe do not teach fluorinated nicotinamide N-substituents.
Kim, I-S.; et al. (hereafter referred to as Kim) is drawn to ApoPep-1 labeled with fluorine-18 for PET of apoptotic cells (title; abstract). Kim teaches 18F labeled ApoPep-1 can be used to diagnose a variety of disease conditions associated with apoptosis and to image cells related to diseases (pg 2, para 2-3). Kim teaches ApoPep-1 can have 18F substituent as a N-substituent group on a N-terminus cysteine defined as X-Y-Z-F, in the case where X is a carbonyl, Y is a methyl and an aromatic ring compound consisting of 5 carbons and a nitrogen, and Z is a methyl and 18F or 19F (pg 2, claim 1). Kim teaches a method of producing the labeled ApoPep-1 (pg 8, para [0027], Equation 2) and imaging with the 18F labeled ApoPep-1 (pg 21, para [0140]-[0145]).
Regarding fluorinated nicotinamide N-substituent on the N-terminus cysteine, Kim teaches ApoPep-1 with a fluorinated aromatic group as an N-substituent on the N-terminus cysteine (pg 6, para [0013]), where X is a carbonyl (claim 1, line 2), Y is an aromatic ring consisting of 5 carbons and a nitrogen (claim 1, lines 3-4), Z is a C1, and F is 18F or 19F (claim 1, lines 5-6).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of Lee and Guembe to include the N-terminus cysteine N-substituent as taught by Kim 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 an fluorinated N-substituent on the N-terminus cysteine.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the unspecified radiolabel of Lee with the fluorinated N-substituent on the N-terminus cysteine because the prior art of Lee disclosed cyclic and linear ApoPep-1 peptides known to be able to be labeled with fluorine for PET or with fluorescent molecules and other labels (pg 4, para [0054], lines 1-18) and known to be able to have the amino acids modified without significantly altering the apoptotic nature of the peptide (pg 3, para [0044], lines 1-16). Additional prior art of Kim suggested a specific radiolabel at the N-terminus cysteine to have similar apoptotic targeting capabilities and to be useful for PET because of the overlap of the amino acid sequence (pg 2, para 2, lines 1-3; pg 2, para 3, lines 1-3).
The skilled artisan would have been motivated to modify the labeled ApoPep-1 of Lee with the radiolabel of Kim because PET with 18F is one of the most useful probes for real time imaging of tissues.
The combined teachings of Lee, Guembe, and Kim do not expressly teach the specific fluorinated nicotinamide N-substituent.
Ravert, H. T.; et al. (hereafter referred to as Ravert) is drawn to improving radiolabeling of PSMA targeting moieties (title; abstract). Ravert teaches that prostate cancer is the most common cancer in men (pg 1, col 1, para 1, lines 1-4) and that 18F radiotracers are useful for PET imaging of the cancers (pg 1, col 1, para 2, lines 7-13) and that many preparations of 18F labeled compounds are accomplished in multistep synthetic routes (pg 1, col 2, para 2, lines 1-6) resulting in low to moderate radiochemical yield (pg 1, col 2, para 2, lines 6-11). Ravert teaches that a precursor can enable direct fluorination of the compound with improved radiochemical yield (pg 1, para 2, lines 11-17) and enabled full compliance with USP (pg 2, col 1, para 1, lines 1-2). Ravert teaches synthesis methods (pg 2, col 2, para 2, lines 1-15; pg 2, col 2, para 4, lines 1-8; pg 3, col 1, para 1, lines 1-10 and para 2, lines 1-12). Ravert teaches characterization by visual inspection (pg 3, col 2, para 3, lines 1-5), radiochemical identity (pg 3, col 2, para 4, lines 1-12), radiochemical purity, pg 3, col 2, para 5, lines 1-11), etc. Ravert teaches the method can be adapted for human studies (pg 5, col 1, para 1, lines 1-8) and that radiofluorination of the trimethylammonium precursor produces a clean reaction profile in high yield (pg 5, para 4, liens 1-3). Ravert teaches that this method of radiofluorination can also be automated (pg 5, col 2, para 3, lines 1-16). Ravert teaches the direct radiofluorination of a compound from the trimethylammonium precursor (pg 8, Figure 4) and characterization (pg 9, Figure 5).
Regarding the fluorinated nicotinamide N-substituent, Ravert teaches the specific fluorinated nicotinamide (pg 8, Figure 4).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to substitute the fluorinated aromatic N-substituent of the N-terminus of Kim with the fluorinated nicotinamide as taught by Ravert 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 a fluorinated nicotinamide N-substituted N-terminus cysteine.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting one fluorinated aromatic group for the fluorinated nicotinimide because the prior art of Kim disclosed fluorinated aromatic group as an N-substituent on the N-terminus cysteine (pg 6, para [0013]), where X is a carbonyl (claim 1, line 2), Y is an aromatic ring consisting of 5 carbons and a nitrogen (claim 1, lines 3-4), Z is a C1, and F is 18F or 19F (claim 1, lines 5-6) known to work as a PET trace (abstract, line 1). Additional prior art of Ravert suggested fluorinated nicotinimide to have similar properties of serving as a PET tracer because of the overlap of the heteroaromatic ring and the 18F between them involves known irradiation.
The skilled artisan would have been motivated to substitute the fluorinated heteroaromatic ring of Kim with the fluorinated nicotinamide of Ravert because fluorinated nicotinamide of Ravert has a precursor that can be used to enable synthesis of the peptide precursor with labeling in one step in clean reactions with high yields (pg 5, para 4, lines 1-3).
Pertinent Art
Pertinent Art
The prior art of Siahaan, T. H.; et al. WO 2020/257745 A1 is deemed pertinent to the application.
Siahaan, T. J.; et al. (hereafter referred to as Siahaan) is drawn to composition and methods for treating brain diseases by affecting the BBB (title; abstract). Siahaan teaches cyclic and linear peptides (pg 1, para [0004]) using them to diagnose or treat or image brain disease (pg 2, para [0005], lines 7-9) and compositions thereof (pg 2, para [0006], lines 1-2). Siahaan teaches delivery therapeutic and diagnostic agents across the BBB is challenging (pg 12, para [0040), lines 1-4). Siahaan teaches several peptides that cross that BBB (pg 14, structures HAVN1, HAVN2, cyclic-ADTHAV, ADTN1, ADTN2; pg 16, structure, linear ADTHAV; pg 17, structure HAV6; pg 18, structureADTC5, HAV4, and cHAVc3). Siahaan teaches cyclic peptides can have amide (pg 18, ADTC5, HAV4, cHAVc3) or carboxylic C-terminal groups (pg 15, structures ADTN1 and ADTN2). Siahaan teaches formulation (pg 27, par [0062], lines 1-6), compositions (pg 28, para [0066], lines 1-6). Siahaan teaches synthesis of ADTC5 (pg 33, para [0080], lines 1-6). Siahaan teaches that ADTC5 works well at crossing the BBB (pg 36, para [0088], lines 3-6; pg 59, Table 3; Figure 2).
The examiner considers the C-terminal amide cyclic peptides to render this art pertinent to this application.
The prior art of Neumaier, B.; et al. US 10,112,974 B2 is deemed pertinent to the application.
Neumaier, B.; et al. (hereafter referred to as Neumaier) is drawn to methods for producing 18F labeled esters on cancer targeting PET tracers (title; abstract). Neumaier teaches novel efficient, time-saving, and related radiofluorination procedures for the production of 18F-labeled active esters via nucleophilic substitution of ammonium precursors with 18F- (col 1, lines 6-18). Neumaier teaches PET is important for visualizing physiological processes at molecular levels and essential in clinical diagnostics (col 1, lines 22-27) and that 18F is the mainly used PET radionuclide (col 1, lines 35-40). Neumaier teaches a method of labeling that goes directly from a precursor to a radiolabeled moiety (col 3, Scheme 1; col 4, Scheme 4). Neumaier teaches that 18F labeling through this method is possible on PSMA moieties (col 7, lines 40-60) and peptides (col 8, lines 1-67). Neumaier teaches synthesis of the compounds (col 65, Example 1, lines 35-60; col 76, lines 1-30).
The examiner considers the detailing of radiofluorination methods on various targeting moieties including peptides to render this art pertinent to this application.
Conclusion
No claims allowed.
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/EVAN M LEWOCZKO/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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