Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings. Figures 1A, 1B, 2A, 3A, 3B all show AA sequences with more than 4 residues, but they do not show the sequence identification number in the figures nor Figure Description.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Drawings
The drawings are objected to because the structures in Figures 3A 3B are too difficult to properly read; the apparent (CH3)2N-Ph-N structure in the bottom left portion of the figures appear to be “floating” near a nitrogen on the rest of the construct (its bond order is not known by looking at the figure); furthermore, the Rhodamine dye is very faint in both figures. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 12 objected to because of the following informalities: line 2 contains an extra article and should be amended to read “comprises the sequence” rather than “comprises of the sequence”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7-9 and 17-20 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.
Claims 7-9 each recite a “solubilising moiety,” but this is not a particular term of art and it is not specially defined in the specification. Clearly, this moiety is meant to improve solubility in a given solvent, but what solvent would that be, and what structural features would determine if a given moiety is ‘solubilising’? The specification provides examples of solubilizing moieties (page 4 second and third paragraphs), but this does not amount to a special definition; it provides the following examples: “(PEG) and related polymers”, “non-PEG moiety”, and “peptides containing multiple units of charged amino acids”. In the interest of compact prosecution, Examiner will interpret “solubilising moiety” to mean “a polar moiety”.
Claim 10 is not rejected with claim 7-9 because it particularly defines “solubilising moiety” and therefore resolves the indefiniteness.
Claim 17 contains the recitation “FAP3, as shown in Figure 3a.” The claimset must not include references to other sections of the application; it should contain all of the desired limitations as part of the claim language, or an image should be included to clearly define the invention/construct. See MPEP 2173.05(s). In the interest of compact prosecution, examiner will interpret “FAP3, as shown in Figure 3a” as being “Lys(MethylRed)-Val-(D)Ser-Pro-Asn-Gln-Gly-Lys(5-FAM)-[PEG2-(D)Lys]3-NH2” because that is what FAP3 is defined as in at least table 1 of the specification.
Claim 18 recites the limitation that “the construct is the construct is resistant to cleavage or degradation at sites of inflammation”. The construct is specifically designed to be selectively cleaved by fibroblast activation protein (FAP), which is an enzyme, so claim 18 is unclear and contradicts claim 1. In the interest of compact prosecution, examiner interprets “the construct is resistant to cleavage or degradation at sites of inflammation” to mean “the construct is resistant to non-FAP cleavage or non-FAP degradation at sites of inflammation.”
Claim 19 recites the limitation that “the construct is resistant to cleavage or degradation by enzymes and/or other inflammatory mediators produced by immune cells”. Again, the construct is specifically designed to be selectively cleaved by fibroblast activation protein (FAP), which is an enzyme, so claim 19 is unclear and contradicts claim 1. In the interest of compact prosecution, examiner interprets “the construct is resistant to cleavage or degradation by enzymes and/or other inflammatory mediators produced by immune cells” to mean “the construct is resistant to non-FAP cleavage or degradation by enzymes and/or other non-FAP inflammatory mediators produced by immune cells.”
Claim 20 recites the limitation “the construct is resistant to cleavage or degradation by dipeptidyl peptidases and/or prolyl oligopeptidases, or by matrix remodelling enzymes.” Again, the construct is specifically designed to be selectively cleaved by fibroblast activation protein (FAP), which is known in the art to be an enzyme that is also classifiable as at least as a serine protease, a prolyl endopeptidase, a dipeptidyl peptidase, and a matrix remodelling enzyme; therefore claim 20 contradicts claim 1. In the interest of compact prosecution, examiner interprets “the construct is resistant to cleavage or degradation by non-FAP dipeptidyl peptidases and/or non-FAP prolyl oligopeptidases, or by non-FAP matrix remodelling enzymes.”
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, 13-15, 18-20, 22-23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bainbridge et al. (Scientific Reports, Vol. 7, No. 1, 2 October, 2017, pgs. 1-12, as cited in the IDS submitted on 06/06/2024), further in view of Šimková et al. (BBA - Proteins and Proteomics, Vol. 1868, No. 140409, 06 April 2020, pgs. 1-17).
Regarding claim 1, Bainbridge teaches a construct that is selectively cleaved by fibroblast activation protein (pg. 2 second paragraph) (This assay utilizes a modified peptide substrate… in a quenched dye format and is selective for FAP.), comprising the peptide sequence A-2-A-1-A0-A+1-A+2, wherein (from figure 1 of Bainbridge):
A-2 is an D- or L- amino acid or derivative thereof (A-2 = P3 below, Val);
A-1 is a D- amino acid, β-alanine ((β)Ala) or derivative thereof (A-1 = P2 below, D-Ala, D-Ser, …));
A0 is proline (Pro) or derivative thereof (A-2 = P1 below);
A+1 is serine (Ser) (A+1 = P1′);
A+2 is a D- or L- amino acid or derivative thereof (A+2 = P2’ below);
See Figure 1 constructs from Bainbridge:
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Bainbridge is silent to A+1 is asparagine (Asn) or derivative thereof.
In the analogous art of oligopeptide constructs that are selectively cleaved by FAP (abstract of Šimková) (we present a detailed analysis of the structural patterns crucial for substrate and inhibitor recognition by the FAP active site and determinants of selectivity), Šimková teaches a construct in which proline is at the P1 position and Asn is at the P1’ position, and that the P1’ position may be substituted with Ser, Asn, Ala, or Tyr to result in effective FAP cleavage (pg. 5 third paragraph of Šimková) (Substrates with Ala, Asn, Ser, and Tyr in P1’ were cleaved more favorably than those with other residues); see also figure 3B from Šimková to see proline at the P1 position:
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As such, Šimková teaches that there were a finite number of solutions (Ser, Asn, Ala, or Tyr residues at the P1’ position relative to Pro) to provide a construct that is favorably cleaved by FAP.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the P1’ serine residue of the construct taught by Bainbridge with Asn as taught by Šimková because one of ordinary skill in the art would have pursued the known potential solutions with a reasonable expectation of success (See Figure 1 of Bainbridge; pg. 5 third paragraph of Šimková). See MPEP 2143(I)(E).
Regarding claim 2, Modified Bainbridge (Bainbridge in view of Šimková) teaches the construct of claim 1 as rejected above, wherein (from figure 1 of Bainbridge):
A-2 is selected from valine (Val), lysine (Lys) or derivative thereof (A-2 = P3, Val);
A-1 is selected from D-alanine ((D)Ala), D-serine ((D)Ser), D-threonine ((D)Thr), 3-alanine ((p)Ala) or derivative thereof (A-1 = P2, D-Ala, D-Ser, …);
A+2 is selected from glutamine (Gln), glutamic acid (Glu), lysine (Lys) or derivative thereof (A+2 = P2’, Gln).
Regarding claim 3, Modified Bainbridge (Bainbridge in view of Šimková) teaches the construct of claim 1 as rejected above. Modified Bainbridge teaches a heptapeptide construct with a peptide sequence of A-2-A-1-A0-A+1-A+2-A+3-A+4, wherein A-2, A-1, A0, A+1 and A+2 are as in claim 1, and A+3 and A+4 are a D or L- amino acid or derivative thereof; see figure 1 from Bainbridge:
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Modified Bainbridge does not teach an octapeptide construct with a peptide sequence of A-3-A-2-A-1-A0-A+1-A+2-A+3-A+4, wherein A-3 is a D or L- amino acid or derivative thereof.
Šimková teaches an octapeptide construct; see figure 1:
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Šimková teaches that adding an uncharged residue to the P4 (or A-3) position allows for optimal FAP recognition (pg. 5 right column third paragraph) (FAP slightly preferred uncharged residues in positions P4). Note that uncharged residues include: Ala, Gly, Ile, Leu, Pro, Val, Phe, Trp, Tye, His, Ser, Thr, Cys, Met, Asn, and Gln.
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the instant application to combine the construct of Modified Bainbridge with the additional uncharged residue as taught by Šimková to provide a peptide sequence of A-3-A-2-A-1-A0-A+1-A+2-A+3-A+4 wherein A-2, A-1, A0, A+1 and A+2 are as in claim 1; A-3, A+3 and A+4 are a D- or L- amino acid or derivative thereof. Doing so would lead to the predictable outcome of improving FAP cleavage of the construct with a reasonable expectation of success (see figure 1 of Bainbridge; see Figure 3B and pg. 5 right column third paragraph of Šimková).
Regarding claim 4, Modified Bainbridge (Bainbridge in view of Šimková) teaches the construct of claim 3 as rejected above, wherein
A-3 is selected from lysine (Lys), arginine (Arg), glutamine (Gln), asparagine (Asn) or derivative thereof (pg. 5 right column third paragraph of Šimková) (FAP slightly preferred uncharged residues in positions P4) (uncharged residues include Asn or Gln);
A+3 is selected from glycine (Gly), cysteine (Cys) or derivative thereof; A+4 is selected from lysine (Lys), arginine (Arg), glutamine (Gln), asparagine (Asn) or derivative thereof (see fig 1 of Bainbridge below) (A+4 is Lys);
A+4 is selected from lysine (Lys), arginine (Arg), glutamine (Gln), asparagine (Asn) or derivative thereof (see fig 1 of Bainbridge below); Fig 1 from Bainbridge, which shows A+4 is Lys:
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Regarding claim 5, Modified Bainbridge teaches the construct according to claim 2, wherein the peptide sequence consists of Val-(D)Ser- Pro-Asn-Gln (see Figure 1 from Bainbridge, “sP” Name, where Ser is substituted with Asn as rejected in claim 1).
Regarding claim 13, Modified Bainbridge (Bainbridge in view of Šimková) teaches the construct of claim 1 as rejected above, wherein the construct further comprises at least one luminescent molecule, fluorescent molecule, quencher molecule, pH sensitive molecule, oxygen sensitive molecule or a combination thereof; see figure 1 of Bainbridge, which shows a luminescent/fluorescent molecule (‘FRET Donor’) and a quencher (‘Dark Quencher’):
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Regarding claim 14, Modified Bainbridge (Bainbridge in view of Šimková) teaches the construct of claim 1 as rejected above, wherein the construct is a fluorescence resonance energy transfer (FRET) probe comprising a fluorescent moiety and a quencher moiety attached to the peptide sequence; see figure 1 of Bainbridge, which shows that the construct is a fluorescence resonance energy transfer (FRET) probe comprising a fluorescent moiety and a quencher moiety attached to the peptide sequence:
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Regarding claim 15, Modified Bainbridge (Bainbridge in view of Šimková) teaches the construct of claim 14 as rejected above, wherein the construct is a fluorescence energy transfer (FRET) probe comprising of a fluorophore moiety attached to A-n and a quencher moiety attached to A+n where n>2, or vice versa, optionally wherein the fluorophore moiety is attached to position A-3 and quencher moiety is attached to position A+4; See modified figure 1 of Bainbridge, which shows that a fluorophore moiety (‘FRET Donor’ below) is attached to the A-2 position (P3 or ‘Val’ below) and a quencher moiety (‘Dark Quencher’ below) is attached to the A+4 position (‘Lys’ below), relative to ‘Pro’ at A0 (‘P1’ below):
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Regarding claim 18, Modified Bainbridge (Bainbridge in view of Šimková) teaches the construct of claim 1 as rejected above, wherein the construct is resistant to cleavage or degradation at sites of inflammation (pg. 9 of Bainbridge) (Second, because of its strict specificity, the activity assay for FAP could substitute for the more cumbersome sandwich ELISA, at least for certain applications).
Regarding claim 19, Modified Bainbridge (Bainbridge in view of Šimková) teaches the construct of claim 18 as rejected above, wherein the construct is resistant to cleavage or degradation by enzymes and/or other inflammatory mediators produced by immune cells (pg. 9 of Bainbridge) (the assay enables the measurement of FAP endopeptidase activity in serum or plasma samples without immunocapture or any other purification steps, even for samples that contain related S9 proteases, most notably PREP. Second, because of its strict specificity, the activity assay for FAP could substitute for the more cumbersome sandwich ELISA, at least for certain applications).
Regarding claim 20, Modified Bainbridge (Bainbridge in view of Šimková) teaches the construct of claim 18 as rejected above, wherein the construct is resistant to cleavage or degradation by dipeptidyl peptidases and/or prolyl oligopeptidases, or by matrix remodelling enzymes (pg. 9 of Bainbridge) (the assay enables the measurement of FAP endopeptidase activity in serum or plasma samples without immunocapture or any other purification steps, even for samples that contain related S9 proteases, most notably PREP. Second, because of its strict specificity, the activity assay for FAP could substitute for the more cumbersome sandwich ELISA, at least for certain applications).
Regarding claim 22, Modified Bainbridge (Bainbridge in view of Šimková) teaches the construct of claim 1 as rejected above. Modified Bainbridge teaches a method of detecting a level of FAP in a sample from a body (pg. 3 first paragraph) ((peptides were used to evaluate the FAP endopeptidase activity in the plasma of wild type (WT), heterozygous and Fap-deficient (KO) mice), the method comprises contacting a construct according to claim 1 with the body sample, ex vivo, in vivo, or in vitro and detecting any signal generated following cleavage of the construct by FAP (Figure 6 legend) ((A) Scatter plot showing FAP activity levels determined by using the aP peptide (x axis) and FAP protein levels determined by ELISA in serum samples); see also figure 6 which shows the detection of a level of FAP in a sample from a body:
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Regarding claim 23, Modified Bainbridge (Bainbridge in view of Šimková) teaches the method according to claim 22, wherein the sample from the body comprises a cell containing sample obtained from a tumour or fibrotic tissue, or the sample from the body comprises bodily fluid, such as blood, serum, urine or plasma (pg. 10 sixth paragraph of Bainbridge) (Mouse plasma samples were prepared… human serum samples were obtained).
Claim 6 rejected under 35 USC 103 as being unpatentable over Bainbridge et al. (Scientific Reports, Vol. 7, No. 1, 2 October, 2017, pgs. 1-12, as cited in the IDS submitted on 06/06/2024), further in view of Šimková et al. (BBA - Proteins and Proteomics, Vol. 1868, No. 140409, 06 April 2020, pgs. 1-17), as applied to claim 1 above, further in view of Li et al. (Bioconjugate Chemistry, Vol. 30, No. 5, 15 May 2019, pgs. 1395-1404, as cited in the IDS submitted on 06/06/2024).
Regarding claim 6, Modified Bainbridge teaches the construct of claim 4 as rejected above, wherein the peptide sequence consists of (Val)-(D)Ser-Pro-Asn-Gln-Gly-Lys (emphasis added to highlight difference between this and the claim language), where the FRET Donor is conjugated to the construct via an amine group (NH) of Valine, as seen in figure 1 of Bainbridge:
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Modified Bainbridge does not teach wherein the peptide sequence consists of Lys-Val-(D)Ser-Pro-Asn-Gln-Gly-Lys.
In the analogous art of constructs (ANPFAP) that are selectively recognized by a FAP (abstract of Li) (ANPFAP… probe for early detection of FAPα expressing tumors), Li teaches a construct in which the FRET donor (QSY21) is conjugated to the construct via an amine group (NH) of a lysine residue; see Scheme 1 of Li:
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Li teaches that using Lys as a means of conjugating a FRET-donor to the peptide construct is optimal for increasing purity of the construct and for labelling the correct residue with the FRET Donor (starting at pg. 1706 right column bottom paragraph) (Conjugation of the two dyes with the peptide substrate was easily realized through the reaction of… the lysine amine with QSY21 NHS ester in ∼26% yield and >95% purity (Scheme 1)).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the instant application to substitute the FRET Donor of Modified Bainbridge with the (QSY21)-Lys residue of Li to provide a peptide sequence consisting of Lys-(D)Ser-Pro-Asn-Gln-Gly-Lys because it would lead to improving the yield, specificity, and purity of the construct with a reasonable expectation of success (see figure 1 of Bainbridge; scheme 1 and pg. 1706-1707 “Design and Synthesis of the FAPα-Specific Probe” of Li).
Claims 7-10 are rejected under 35 USC 103 as being unpatentable over Bainbridge (Scientific Reports, Vol. 7, No. 1, 2 October, 2017, pgs. 1-12, as cited in the IDS submitted on 06/06/2024), further in view of Šimková (BBA - Proteins and Proteomics, Vol. 1868, No. 140409, 06 April 2020, pgs. 1-17), as applied to claim 1 above, further in view of Bainbridge (US20200055896A1). For simplicity, references to Bainbridge et al.’s US PGPub document will appear as “Bainbridge-2”.
Regarding claim 7, Modified Bainbridge (Bainbridge in view of Šimková) teaches the construct of claim 1 as rejected above. Modified Bainbridge teaches a Lys residue at either the C or N terminus of the construct (figure 1 of Bainbridge, Lys is at the C-terminus of the construct below):
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Modified Bainbridge is silent to further comprising a solubilising moiety attached, bound or otherwise linked to one or more amino acids of the peptide sequence.
In the analogous art of constructs for detecting FAP, Bainbridge-2 teaches of appending two polyethylene glycol (PEG) moieties to a lysine residue on a construct ([0049] of Bainbridge-2) (peptides of this disclosure may be modified by PEG polymers… Especially preferred are PEGs with two PEG side-chains (PEG2) linked via the primary amino groups of a lysine). Bainbridge-2 teaches that adding a PEG moiety to the construct improves the half-live of the construct in the blood, and can further improve the solubility of the construct in biologically relevant media ([0049]) (peptides of this disclosure may be modified to enhance solubility and/or half-life upon being administered… polyethylene glycol (PEG) and related polymers have been used to enhance solubility and the half-life of protein therapeutics in the blood).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the instant application to modify the Lys residue of Modified Bainbridge to be covalently bound to PEG as taught by Bainbridge-2 because doing so would increase the solubility and half-live of the construct in biologically relevant media such as blood with a reasonable expectation of success (see figure 1 of Bainbridge; [0049] of Bainbridge-2).
Regarding claim 8, Modified Bainbridge (Bainbridge in view of Šimková further in view of Bainbridge-2) teaches the construct according to claim 7 as rejected above, wherein the solubilising moiety is attached, bound or otherwise linked to N- or C-terminal amino acids. See figure 1 of Bainbridge, where Lys is at the C-terminus of the construct; see also [0049] of Bainbridge-2.
Regarding claim 9, Modified Bainbridge (Bainbridge in view of Šimková further in view of Bainbridge-2) teaches the construct according to claim 7 as rejected above, wherein the amino acid attached, bound or otherwise linked to the solubilising moiety is in the D- or L- configuration; see figure 1 of Bainbridge, which shows Lys in the L- configuration:
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Regarding claim 10, Modified Bainbridge (Bainbridge in view of Šimková further in view of Bainbridge-2) teaches the construct according to claim 7 as rejected above, wherein the solubilising moiety is a polyethylene glycol (PEG) derivative, optionally the solubilising moiety is PEG2 ([0049] of Bainbridge-2) (peptides of this disclosure may be modified by PEG polymers… Especially preferred are PEGs with two PEG side-chains (PEG2) linked via the primary amino groups of a lysine).
Claim 12 rejected under 35 USC 103 as being unpatentable over Bainbridge et al. (Scientific Reports, Vol. 7, No. 1, 2 October, 2017, pgs. 1-12, as cited in the IDS submitted on 06/06/2024) further in view of Šimková et al. (BBA - Proteins and Proteomics, Vol. 1868, No. 140409, 06 April 2020, pgs. 1-17), further in view of Li et al. (Bioconjugate Chemistry, Vol. 30, No. 5, 15 May 2019, pgs. 1395-1404, as cited in the IDS submitted on 06/06/2024), as applied to claim 6 above, further in view of Bainbridge et al. (US20200055896A1). For simplicity, references to Bainbridge et al.’s US PGPub document will appear as “Bainbridge-2”.
Regarding claim 12, Modified Bainbridge (Bainbridge in view of Šimková further in view of Li) teaches the construct according to claim 6, wherein the construct comprises the sequence Lys-Val-(D)Ser-Pro-Asn-Gln-Gly-(L)Lys (see figure 1 of Bainbridge which shows at least the (L)Lys configuration; scheme 1 and pg. 1706-1707 “Design and Synthesis of the FAPα-Specific Probe” of Li for Asn).
Modified Bainbridge is silent to wherein the construct comprises of the sequence Lys-Val-(D)Ser-Pro-Asn-Gln-Gly-[PEG2-(D)Lys]3-NH2.
In the analogous art of constructs for detecting FAP, Bainbridge-2 teaches of appending PEG2 to a lysine residue on a construct ([0049] of Bainbridge-2) (peptides of this disclosure may be modified by PEG polymers… Especially preferred are PEGs with two PEG side-chains (PEG2) linked via the primary amino groups of a lysine). Bainbridge-2 teaches that adding a PEG moiety to the construct improves the half-live of the construct in the blood, and can further improve the solubility of the construct in biologically relevant media ([0049]) (peptides of this disclosure may be modified to enhance solubility and/or half-life upon being administered… polyethylene glycol (PEG) and related polymers have been used to enhance solubility and the half-life of protein therapeutics in the blood).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the instant application to modify the Lys residue of Modified Bainbridge to be covalently bound to PEG2 as taught by Bainbridge-2 to provide a construct comprising the sequence Lys-Val-(D)Ser-Pro-Asn-Gln-Gly-[PEG2-(L)Lys]-NH2 because doing so would increase the solubility and half-live of the construct in biologically relevant media such as blood with a reasonable expectation of success (see figure 1 of Bainbridge; scheme 1 and pg. 1706-1707 of Li; [0049] of Bainbridge-2).
Modified Bainbridge (Bainbridge in view of Šimková further in view of Bainbridge-2) is silent to wherein the construct comprises of the sequence Lys-Val-(D)Ser-Pro-Asn-Gln-Gly-[PEG2-(D)Lys]3-NH2 [emphasis added to show deviation from claim language].
However, it is widely understood that, because amino acids are chiral, amino acids only exist in either the D or L configuration.
Therefore, it would have been obvious to substitute the (L)Lys residue of the construct of Modified Bainbridge (Bainbridge in view of Šimková further in view of Bainbridge-2) with (D)Lys to provide a construct with the sequence Lys-Val-(D)Ser-Pro-Asn-Gln-Gly-[PEG2-(D)Lys]-NH2 because one of ordinary skill in the art would have pursued the known potential solutions with a reasonable expectation of success. See MPEP 2143(I)(E).
Modified Bainbridge (Bainbridge in view of Šimková further in view of Bainbridge-2) is silent to wherein the construct comprises of the sequence Lys-Val-(D)Ser-Pro-Asn-Gln-Gly-[PEG2-(D)Lys]3-NH2.
It would have been obvious for a person having ordinary skill in the art before the effective filing date of the invention to duplicate the [PEG2-(D)Lys] moiety to provide Lys-Val-(D)Ser-Pro-Asn-Gln-Gly-[PEG2-(D)Lys]3-NH2 because doing so would further improve the solubility and half-life of the construct with a reasonable expectation of success. See also MPEP 2144.04. In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960).
Claim 17 is rejected under 35 USC 103 as being unpatentable over Bainbridge (Scientific Reports, Vol. 7, No. 1, 2 October, 2017, pgs. 1-12, as cited in the IDS submitted on 06/06/2024), further in view of Šimková (BBA - Proteins and Proteomics, Vol. 1868, No. 140409, 06 April 2020, pgs. 1-17), as applied to claim 1 above, further in view of Bainbridge et al. (US20200055896A1), further in view of Li et al. (Bioconjugate Chemistry, Vol. 30, No. 5, 15 May 2019, pgs. 1395-1404, as cited in the IDS submitted on 06/06/2024), further in view of Craven et al. (Scientific Reports, Vol. 8, No. 13490, 10 September 2018, pgs. 1-10). For simplicity, references to Bainbridge et al.’s US PGPub document will appear as “Bainbridge-2”.
Regarding claim 17, Modified Bainbridge (Bainbridge in view of Šimková) teaches the construct of claim 1 as rejected above (recall that “FAP3, as shown in Figure 3a” is interpreted to be “Lys(MethylRed)-Val-(D)Ser-Pro-Asn-Gln-Gly-Lys(5-FAM)-[PEG2-(D)Lys]3-NH2”). Modified Bainbridge teaches a construct with a sequence of (FRET Donor)-Val-(D)Ser-Pro-Asn-Gln-Gly-Lys(Dark Quencher); see modified figure 1, row “sP”, from Bainbridge, which shows a Lys residue with a quencher tethered to Gly at P3’ (see also pg. 5 third paragraph of Šimková):
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Modified Bainbridge is silent to Lys(MethylRed)-Val-(D)Ser-Pro-Asn-Gln-Gly-Lys(5-FAM)-[PEG2-(D)Lys]3-NH2.
In the analogous art of constructs for detecting FAP, Bainbridge-2 teaches of appending two polyethylene glycol (PEG2) moieties via lysine residues on a construct ([0049] of Bainbridge-2) (peptides of this disclosure may be modified by PEG polymers… Especially preferred are PEGs with two PEG side-chains (PEG2) linked via the primary amino groups of a lysine). Bainbridge-2 teaches that adding a PEG2 moiety to the construct improves the half-live of the construct in the blood, and can further improve the solubility of the construct in biologically relevant media ([0049]) (peptides of this disclosure may be modified to enhance solubility and/or half-life upon being administered… polyethylene glycol (PEG) and related polymers have been used to enhance solubility and the half-life of protein therapeutics in the blood).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the instant application to modify the Lys residue of Modified Bainbridge to be covalently bound to PEG2 as taught by Bainbridge-2 to provide (FRET Donor)-Val-(D)Ser-Pro-Asn-Gln-Gly-Lys(Dark Quencher)-[PEG2-Lys]-NH2 because doing so would increase the solubility and half-live of the construct in biologically relevant media such as blood with a reasonable expectation of success (see figure 1 of Bainbridge; pg. 5 third paragraph of Šimková; [0049] of Bainbridge-2).
Modified Bainbridge (Bainbridge in view of Šimková further in view of Bainbridge-2) does not teach Lys(MethylRed)-Val-(D)Ser-Pro-Asn-Gln-Gly-Lys(5-FAM)-[PEG2-(D)Lys]3-NH2.
However, it would have been obvious for a person having ordinary skill in the art before the effective filing date of the invention to duplicate the [PEG2-(D)Lys] moiety to provide (FRET Donor)-Val-(D)Ser-Pro-Asn-Gln-Gly-Lys(Dark Quencher)-[PEG2-Lys]3-NH2 because doing so would further improve the solubility and half-life of the construct with a reasonable expectation of success (see figure 1 of Bainbridge; pg. 5 third paragraph of Šimková; [0049] of Bainbridge-2). See also MPEP 2144.04. In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960).
Modified Bainbridge (Bainbridge in view of Šimková further in view of Bainbridge-2) is silent to wherein the construct comprises of the sequence Lys(MethylRed)-Val-(D)Ser-Pro-Asn-Gln-Gly-Lys(5-FAM)-[PEG2-(D)Lys]3-NH2.
However, it is widely understood that, because amino acids are chiral, amino acids only exist in either the D or L configuration.
Therefore, it would have been obvious to substitute the (L)Lys residue of the construct of Modified Bainbridge (Bainbridge in view of Šimková further in view of Bainbridge-2) with (D)Lys to provide a construct with the sequence (FRET Donor)-Val-(D)Ser-Pro-Asn-Gln-Gly-Lys(Dark Quencher)-[PEG2-(D)Lys]-NH2 because one of ordinary skill in the art would have pursued the known potential solutions with a reasonable expectation of success. See MPEP 2143(I)(E).
Modified Bainbridge (Bainbridge in view of Šimková further in view of Bainbridge-2 further in view of Li) does not teach Lys(MethylRed)-Val-(D)Ser-Pro-Asn-Gln-Gly-Lys(5-FAM)-[PEG2-(D)Lys]3-NH2.
In the analogous art of constructs that are selectively recognized by a FAP (abstract of Li) (ANPFAP… probe for early detection of FAPα expressing tumors), Li teaches a construct in which the FRET donor (QSY21) is conjugated to the construct via an amine group (NH) of a lysine residue; see Scheme 1 of Li:
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Li teaches that using Lys as a means of conjugating a FRET-active molecule to the peptide construct is optimal for increasing purity of the construct and for labelling the correct residue with the FRET-active molecule (starting at pg. 1706 right column bottom paragraph of Li) (Conjugation of the two dyes with the peptide substrate was easily realized through the reaction of… the lysine amine with QSY21 NHS ester in ∼26% yield and >95% purity (Scheme 1)).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the instant application to substitute the FRET Donor of Modified Bainbridge with the (QSY21)-Lys residue of Li to provide a construct with a sequence consisting of Lys(QSY21)-Val-(D)Ser-Pro-Asn-Gln-Gly-Lys(Dark Quencher)-[PEG2-(D)Lys]-NH2 because it would lead to improving the yield, specificity, and purity of the construct with a reasonable expectation of success (see figure 1 of Bainbridge; scheme 1 and pg. 1706-1707 “Design and Synthesis of the FAPα-Specific Probe” of Li).
Modified Bainbridge (Bainbridge in view of Šimková further in view of Bainbridge-2) does not teach wherein the construct comprises the sequence of Lys(MethylRed)-Val-(D)Ser-Pro-Asn-Gln-Gly-Lys(5-FAM)-[PEG2-(D)Lys]3-NH2.
In the analogous art of constructs for the detection of serine proteases (abstract of Craven) (the synthesis of a novel chemical sensor… de-quenched by the exemplar serine protease human neutrophil elastase), Craven teaches a FRET donor-acceptor pairing of Methyl Red and 5-carboxyfluorescein (pg. 2 third paragraph of Craven) (functionalised with methyl red, while the Lysine side chain was functionalised with 5(6)-carboxyfluorescein); see also modified figure 1 of Craven:
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Craven teaches that this FRET pairing of Methyl red and 5-carboxyfluoreiscin allows for auto-quenching of the construct to amplify the fluorescent signal of the fluorophore upon cleavage of the construct to improve the visualization of protease activity (pg. 2 second paragraph of Craven) (This offered a single auto-quenching fluorophore based approach for the analysis of proteolytic activity, where amplification of signal upon substrate cleavage was possible… FRET peptide scaffold to give a super-silent quenched sensor with triple horizontal quenching, enabling the visualisation of intracellular and extracellular protease activity).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the instant application to substitute the QSY21 and Dark Quencher FRET pairing of Modified Bainbridge with the MethylRed and 5-carboxyfluoreiscin FRET pairing of Li to provide a construct with a sequence consisting of Lys(MethylRed)-Val-(D)Ser-Pro-Asn-Gln-Gly-Lys(5-FAM)-[PEG2-(D)Lys]3-NH2 because both pairings are known in the art to detect serine proteases and it would lead to amplifying the fluorescent signal of the fluorophore upon cleavage of the construct to improve the visualization of protease activity with a reasonable expectation of success (see figure 1 of Bainbridge; pg. 5 third paragraph of Šimková; scheme 1 and pg. 1706-1707 of Li; scheme 1 and pg. 1706-1707 “Design and Synthesis of the FAPα-Specific Probe” of Li; Figure 1 and pg. 2 third paragraph of Craven).
Conclusion
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/H.D.C./Examiner, Art Unit 1758
/MARIS R KESSEL/Supervisory Patent Examiner, Art Unit 1758
