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 .
Election/Restrictions
Claims 14-16, 18-19, and 21-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/10/2026.
Information Disclosure Statement
The information disclosure statement (IDS) was submitted on 12/11/2023 before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1, 3-13, 14-16, 18-19, and 20-21, filed 4/10/2026 are pending. Claims 14-16, 18-19, and 20-21 are withdrawn. Claims 1 and 3-13 are under examination.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). Specifically, sequences on page 7, line 1; page 34, Table 2 lack sequence identifiers.
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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Specifically, the code is located at page 6, lines 14, 16, 17, 18, and 19.
Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of the term “QSY-series”, which is a trade name or a mark used in commerce, has been noted in this application at page 6, para. 3. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
The use of the term “QXL quenchers”, which is a trade name or a mark used in commerce, has been noted in this application at page 6, para. 3. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
The use of the term “Iowa Black FQ”, which is a trade name or a mark used in commerce, has been noted in this application at page 6, para. 3. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
The use of the term “IRDye”, which is a trade name or a mark used in commerce, has been noted in this application at page 6, para. 3. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
The use of the term Maestro, which is a trade name or a mark used in commerce, has been noted in this application at page 16, para. 4. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The specification is also objected to for lacking required sequence identifiers as described above.
Claim Interpretation
“Detectable moiety” has been interpreted to include peptide chains. The specification at page 5, para. 2 recites: “The detectable moiety, such as a fluorescent moiety may be conjugated to the peptide by any suitable method. Typically, the detectable moiety will be conjugated to the peptide by way of a covalent bond.”
Tryptophan residues are fluorescent moieties and peptide chains are conjugated to each other by covalent peptide bonds.
This logic was employed in the restriction requirement and is formally put on the record here for use in this Office Action.
Regarding claim 7, “when present” is interpreted as equivalent to “optionally”, because “when present” implies there are instances where said element is not present.
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.
Claim 11 is 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.
Regarding claim 11, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 11 is rejected.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 3, 4, 6, 7, and 9-10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more.
Regarding claim 1, claim 1 recites a probe for use in detecting granzyme B, the probe comprising a granzyme B cleavable peptide conjugated or bound to a detectable moiety, wherein the granzyme B cleavable peptide sequence consists of the sequence: IEPDAL (SEQ ID NO:12). This sequence is disclosed by Goodrich et al. WO2018035441, published 2/22/2018, SEQ ID NO: 6:
MEIRRRSVRHLISLLLFLFYSETACHPLGKRPCKMQAFRIWDVNQKTFYMRNNQLVAGYLQESNTKLQEKIDVVPIEPDALFLGLHGRKLCLACVKSGDEIRFQLEAVNITDLSKNKEENKRFTFIRSNSGPTTSFESAACPGWFLCTAQEADRPVSLTNKPKESFMVTKFYLQEDQ (emphasis added).
This sequence is also deposited in UniProt as Accession No. O18999, deposited 12/15/1998.
Step 2A, prong one
The claimed polypeptide is not markedly different than the disclosed polypeptide. The disclosed polypeptide discloses the required peptide sequence. The remainder of the polypeptide qualifies as a detectable moiety, because peptides are detectable.
Step 2A, prong two
This judicial exception is not integrated into a practical application because the claim recites a probe that comprises the disclosed polypeptide sequence and the detectable moiety and no additional elements. The descriptor as a probe and the described intended use do not rise to the level of a practical application.
MPEP 2106.04(II)(A)(2) states: “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017).”
No additional elements are present, and therefore no practical application is present.
Step 2B
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because in this case, the additional element, the detectable moiety, is also a product of nature.
Claim 1 is rejected.
Regarding claim 3, claim 1 is rejected as described above. Claim 3 further recites the probe according to claim 1, wherein the detectable moiety is an isotopic- or radio-label, paramagnetic contrast agent, paramagnetic or superparamagnetic particle, or an optically detectable moiety.
Step 2A, prong one
The claimed polypeptide is not markedly different than the disclosed polypeptide. The disclosed polypeptide discloses the required peptide sequence. The remainder of the polypeptide qualifies as a detectable moiety, because peptides are detectable. Further, polypeptides are optically detectable: “The most frequently employed spectral range for proteins is between 250 and 320 nm, a region referred to as the near ultraviolet. All three aromatic amino acid side chains (i.e., tryptophan, tyrosine, and phenylalanine) have prominent absorption bands in the near ultraviolet (Fig. 1). The only other amino acid with an appreciable contribution in this spectral range (typically, a few percent of total absorbance in most proteins) is cysteine. Assuming the absence of metal ions, cofactors, oxidation byproducts, and other absorbing moieties, these four amino acids are the only important chromophores in this region and they, as well as molecules containing them, are expected to behave according to the Beer-Lambert law.” (Mach et al., page 6, para. 1).
Step 2A, prong two
This judicial exception is not integrated into a practical application because the claim recites a probe that comprises the disclosed polypeptide sequence and detectable moiety and no additional elements. The descriptor as a probe and the described intended use do not rise to the level of a practical application.
MPEP 2106.04(II)(A)(2) states: “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017).”
No additional elements are present, and therefore no practical application is present.
Step 2B
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because in this case, the additional element, the detectable moiety, is also a product of nature.
Claim 3 is rejected.
Regarding claim 4, claim 3 is rejected as described above. Claim 4 further recites the probe according to claim 1, wherein the optically detectable moiety is a fluorescent moiety.
Step 2A, prong one
The claimed polypeptide is not markedly different than the disclosed polypeptide. The disclosed polypeptide discloses the required peptide sequence. The remainder of the polypeptide qualifies as a detectable moiety, because peptides are detectable.
The sequence of Goodrich contains a tryptophan on both the N-terminal and C-terminal side of the required motif IEPDAL: MEIRRRSVRHLISLLLFLFYSETACHPLGKRPCKMQAFRIWDVNQKTFYMRNNQLVAGYLQESNTKLQEKIDVVPIEPDALFLGLHGRKLCLACVKSGDEIRFQLEAVNITDLSKNKEENKRFTFIRSNSGPTTSFESAACPGWFLCTAQEADRPVSLTNKPKESFMVTKFYLQEDQ (emphasis added, Goodrich et al, SEQ ID NO: 6)
Sasaki discloses that tryptophan is a fluorescent moiety:
“Digestion of proteins with a mixture of chymotrypsin and pronase followed by dilution in 6 M urea eliminates the quenching effects usually observed when tryptophan fluorescence is measured in native or denatured proteins. Following proteolysis, the tryptophan content can be estimated from the fluorescence emission, using free tryptophan as an internal standard. The values obtained for a number of proteins are in agreement with the literature values. The method can be applied to as little as 40 μg of protein sample.” (Sasaki et al., Abstract).
Step 2A, prong two
This judicial exception is not integrated into a practical application because the claim recites a probe that comprises the disclosed polypeptide sequence and detectable moiety and no additional elements. The descriptor as a probe and the described intended use do not rise to the level of a practical application.
MPEP 2106.04(II)(A)(2) states: “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017).”
No additional elements are present, and therefore no practical application is present.
Step 2B
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because in this case, the additional element, the detectable moiety, is also a product of nature.
Claim 4 is rejected.
Regarding claim 6, claim 3 is rejected as described above. Claim 3 further recites the case wherein the detectable moiety is conjugated to the peptide by way of a covalent bond.
Step 2A, prong one
The claimed polypeptide is not markedly different than the disclosed polypeptide. The disclosed polypeptide discloses the required peptide sequence. The remainder of the polypeptide qualifies as a detectable moiety, because peptides are detectable. Further, polypeptides are optically detectable: “The most frequently employed spectral range for proteins is between 250 and 320 nm, a region referred to as the near ultraviolet. All three aromatic amino acid side chains (i.e., tryptophan, tyrosine, and phenylalanine) have prominent absorption bands in the near ultraviolet (Fig. 1). The only other amino acid with an appreciable contribution in this spectral range (typically, a few percent of total absorbance in most proteins) is cysteine. Assuming the absence of metal ions, cofactors, oxidation byproducts, and other absorbing moieties, these four amino acids are the only important chromophores in this region and they, as well as molecules containing them, are expected to behave according to the Beer-Lambert law.” (Mach et al., page 6, para. 1).
Peptide bonds are covalent bonds.
Step 2A, prong two
This judicial exception is not integrated into a practical application because the claim recites a probe that comprises the disclosed polypeptide sequence and detectable moiety and no additional elements. The descriptor as a probe and the described intended use do not rise to the level of a practical application.
MPEP 2106.04(II)(A)(2) states: “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017).”
No additional elements are present, and therefore no practical application is present.
Step 2B
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because in this case, the additional element, the detectable moiety, is also a product of nature.
Claim 6 is rejected.
Regarding claim 7, claim 1 is rejected as described above. Claim 3 further recites the case wherein the detectable moiety is conjugated to the N or C terminal amino acid of the peptide and when present, a quencher moiety is conjugated to the respective C or N terminal to which a fluorescent moiety is conjugated.
Step 2A, prong one
The claimed polypeptide is not markedly different than the disclosed polypeptide. The disclosed polypeptide discloses the required peptide sequence. The remainder of the polypeptide qualifies as a detectable moiety, because peptides are detectable. Further, polypeptides are optically detectable: “The most frequently employed spectral range for proteins is between 250 and 320 nm, a region referred to as the near ultraviolet. All three aromatic amino acid side chains (i.e., tryptophan, tyrosine, and phenylalanine) have prominent absorption bands in the near ultraviolet (Fig. 1). The only other amino acid with an appreciable contribution in this spectral range (typically, a few percent of total absorbance in most proteins) is cysteine. Assuming the absence of metal ions, cofactors, oxidation byproducts, and other absorbing moieties, these four amino acids are the only important chromophores in this region and they, as well as molecules containing them, are expected to behave according to the Beer-Lambert law.” (Mach et al., page 6, para. 1).
The detectable moiety is conjugated to the N or C terminal of the peptide. The quencher need not be addressed because it has been interpreted as an optional feature.
Step 2A, prong two
This judicial exception is not integrated into a practical application because the claim recites a probe that comprises the disclosed polypeptide sequence and detectable moiety and no additional elements. The descriptor as a probe and the described intended use do not rise to the level of a practical application.
MPEP 2106.04(II)(A)(2) states: “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017).”
No additional elements are present, and therefore no practical application is present.
Step 2B
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because in this case, the additional element, the detectable moiety, is also a product of nature.
Claim 7 is rejected.
Regarding claim 9, claim 3 is rejected as described above. Claim 9 further recites the case wherein the detectable moiety is conjugated to the peptide by way of a linker molecule.
Step 2A, prong one
The claimed polypeptide is not markedly different than the disclosed polypeptide. The disclosed polypeptide discloses the required peptide sequence. The remainder of the polypeptide qualifies as a detectable moiety, because peptides are detectable.
The sequence of Goodrich contains a tryptophan on both the N-terminal and C-terminal side of the required motif IEPDAL: MEIRRRSVRHLISLLLFLFYSETACHPLGKRPCKMQAFRIWDVNQKTFYMRNNQLVAGYLQESNTKLQEKIDVVPIEPDALFLGLHGRKLCLACVKSGDEIRFQLEAVNITDLSKNKEENKRFTFIRSNSGPTTSFESAACPGWFLCTAQEADRPVSLTNKPKESFMVTKFYLQEDQ (emphasis added, Goodrich et al, SEQ ID NO: 6)
Sasaki discloses that tryptophan is a fluorescent moiety:
“Digestion of proteins with a mixture of chymotrypsin and pronase followed by dilution in 6 M urea eliminates the quenching effects usually observed when tryptophan fluorescence is measured in native or denatured proteins. Following proteolysis, the tryptophan content can be estimated from the fluorescence emission, using free tryptophan as an internal standard. The values obtained for a number of proteins are in agreement with the literature values. The method can be applied to as little as 40 μg of protein sample.” (Sasaki et al., Abstract).
The tryptophan moieties are connected to the peptide by other peptide residues forming a linker molecule.
Step 2A, prong two
This judicial exception is not integrated into a practical application because the claim recites a probe that comprises the disclosed polypeptide sequence and detectable moiety and no additional elements. The descriptor as a probe and the described intended use do not rise to the level of a practical application.
MPEP 2106.04(II)(A)(2) states: “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017).”
No additional elements are present, and therefore no practical application is present.
Step 2B
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because in this case, the additional element, the detectable moiety, is also a product of nature.
Claim 9 is rejected.
Regarding claim 10, claim 9 is rejected as described above. Claim 9 further wherein the linker molecule is an alkyl, alkenyl, or polyether chain, with optionally C2 - C24 repeating units, or one or more natural or non-naturally occurring amino or imino acids.
Step 2A, prong one
The claimed polypeptide is not markedly different than the disclosed polypeptide. The disclosed polypeptide discloses the required peptide sequence. The remainder of the polypeptide qualifies as a detectable moiety, because peptides are detectable.
The sequence of Goodrich contains a tryptophan on both the N-terminal and C-terminal side of the required motif IEPDAL: MEIRRRSVRHLISLLLFLFYSETACHPLGKRPCKMQAFRIWDVNQKTFYMRNNQLVAGYLQESNTKLQEKIDVVPIEPDALFLGLHGRKLCLACVKSGDEIRFQLEAVNITDLSKNKEENKRFTFIRSNSGPTTSFESAACPGWFLCTAQEADRPVSLTNKPKESFMVTKFYLQEDQ (emphasis added, Goodrich et al, SEQ ID NO: 6)
Sasaki discloses that tryptophan is a fluorescent moiety:
“Digestion of proteins with a mixture of chymotrypsin and pronase followed by dilution in 6 M urea eliminates the quenching effects usually observed when tryptophan fluorescence is measured in native or denatured proteins. Following proteolysis, the tryptophan content can be estimated from the fluorescence emission, using free tryptophan as an internal standard. The values obtained for a number of proteins are in agreement with the literature values. The method can be applied to as little as 40 μg of protein sample.” (Sasaki et al., Abstract).
The tryptophan moieties are connected to the peptide by other peptide residues forming a linker molecule. The linker in this case is one more amino acids.
Step 2A, prong two
This judicial exception is not integrated into a practical application because the claim recites a probe that comprises the disclosed polypeptide sequence and detectable moiety and no additional elements. The descriptor as a probe and the described intended use do not rise to the level of a practical application.
MPEP 2106.04(II)(A)(2) states: “Because a judicial exception is not eligible subject matter, Bilski, 561 U.S. at 601, 95 USPQ2d at 1005-06 (quoting Chakrabarty, 447 U.S. at 309, 206 USPQ at 197 (1980)), if there are no additional claim elements besides the judicial exception, or if the additional claim elements merely recite another judicial exception, that is insufficient to integrate the judicial exception into a practical application. See, e.g., RecogniCorp, LLC v. Nintendo Co., 855 F.3d 1322, 1327, 122 USPQ2d 1377 (Fed. Cir. 2017).”
No additional elements are present, and therefore no practical application is present.
Step 2B
The claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because in this case, the additional element, the detectable moiety, is also a product of nature.
Claim 10 is rejected.
Regarding claim 11-13, these claims recite additional properties of the structure recited by claim 1. These properties amount to an element that is significantly more than what is found in nature as disclosed by Goodrich or any other sequence entry. Therefore, these claims are not subject to rejection under U.S.C. 101.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3, 4, 6, 7, and 9-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Goodrich et al. WO2018035441, published 2/22/2018, as evidenced by Mach et al. (Mach, Henryk, et al. "Ultraviolet absorption spectroscopy." Protein stability and folding: Theory and practice (1995): 91-114.) and Sasaki et al. (Sasaki, et al. Analytical Biochemistry 65.1-2: 396-404 (1975)).
Regarding claim 1, claim 1 recites a probe for use in detecting granzyme B, the probe comprising a granzyme B cleavable peptide conjugated or bound to a detectable moiety, wherein the granzyme B cleavable peptide sequence consists of the sequence: IEPDAL (SEQ ID NO:12).
Goodrich discloses SEQ ID NO: 6:
MEIRRRSVRHLISLLLFLFYSETACHPLGKRPCKMQAFRIWDVNQKTFYMRNNQLVAGYLQESNTKLQEKIDVVPIEPDALFLGLHGRKLCLACVKSGDEIRFQLEAVNITDLSKNKEENKRFTFIRSNSGPTTSFESAACPGWFLCTAQEADRPVSLTNKPKESFMVTKFYLQEDQ (emphasis added, Goodrich et al, SEQ ID NO: 6)
The remainder of the polypeptide qualifies as a detectable moiety because polypeptides are detectable by UV detection as evidenced by Mach:
“The most frequently employed spectral range for proteins is between 250 and 320 nm, a region referred to as the near ultraviolet. All three aromatic amino acid side chains (i.e., tryptophan, tyrosine, and phenylalanine) have prominent absorption bands in the near ultraviolet (Fig. 1). The only other amino acid with an appreciable contribution in this spectral range (typically, a few percent of total absorbance in most proteins) is cysteine. Assuming the absence of metal ions, cofactors, oxidation byproducts, and other absorbing moieties, these four amino acids are the only important chromophores in this region and they, as well as molecules containing them, are expected to behave according to the Beer-Lambert law.” (Mach et al., page 6, para. 1).
Consequently, claim 1 is anticipated by Goodrich et al. as evidenced by Mach et al. and rejected.
Regarding claim 3, claim 1 is anticipated as described above as evidenced by Mach. Claim 3 further recites the case wherein the detectable moiety is an isotopic- or radio-label, paramagnetic contrast agent, paramagnetic or superparamagnetic particle, or an optically detectable moiety.
As described above, Mach discloses that polypeptides (the detectable moiety) are optically detectable by UV.
Consequently, claim 3 is anticipated by Goodrich et al. as evidenced by Mach et al. and rejected.
Regarding claim 4, claim 3 is anticipated as described above as evidenced by Mach. Claim 4 further recites the case wherein the optically detectable moiety is a fluorescent moiety.
The sequence of Goodrich contains a tryptophan on both the N-terminal and C-terminal side of the required motif IEPDAL: MEIRRRSVRHLISLLLFLFYSETACHPLGKRPCKMQAFRIWDVNQKTFYMRNNQLVAGYLQESNTKLQEKIDVVPIEPDALFLGLHGRKLCLACVKSGDEIRFQLEAVNITDLSKNKEENKRFTFIRSNSGPTTSFESAACPGWFLCTAQEADRPVSLTNKPKESFMVTKFYLQEDQ (emphasis added, Goodrich et al, SEQ ID NO: 6)
Sasaki discloses that tryptophan is a fluorescent moiety:
“Digestion of proteins with a mixture of chymotrypsin and pronase followed by dilution in 6 M urea eliminates the quenching effects usually observed when tryptophan fluorescence is measured in native or denatured proteins. Following proteolysis, the tryptophan content can be estimated from the fluorescence emission, using free tryptophan as an internal standard. The values obtained for a number of proteins are in agreement with the literature values. The method can be applied to as little as 40 μg of protein sample.” (Sasaki et al., Abstract).
Consequently, claim 4 is anticipated by Goodrich et al. as evidenced by Mach et al and Sasaki et al. and rejected.
Regarding claim 6, claim 3 is anticipated as described above as evidenced by Mach. Claim 6 further recites the case wherein the detectable moiety is conjugated to the peptide by way of a covalent bond.
Peptide bonds are covalent bonds and therefore the detectable moiety in this case is conjugated via a covalent bond.
Consequently, claim 6 is anticipated by Goodrich et al. as evidenced by Mach et al. and rejected.
Regarding claim 7, claim 1 is anticipated as described above as evidenced by Mach. Claim 7 further recites the case wherein the detectable moiety is conjugated to the N or C terminal amino acid of the peptide and when present, a quencher moiety is conjugated to the respective C or N terminal to which a fluorescent moiety is conjugated.
In the case of Goodrich, the detectable moiety is conjugated to the N or C terminal of the peptide. The quencher need not be addressed because it has been interpreted as an optional feature.
Consequently, claim 6 is anticipated by Goodrich et al. as evidenced by Mach et al. and rejected.
Regarding claim 9, claim 3 is anticipated as described above by Mach. Claim 9 further recites the case wherein the detectable moiety is conjugated to the peptide by way of a linker molecule.
Tryptophan residues are detectable moieties as described above by Sasaki:
“Digestion of proteins with a mixture of chymotrypsin and pronase followed by dilution in 6 M urea eliminates the quenching effects usually observed when tryptophan fluorescence is measured in native or denatured proteins. Following proteolysis, the tryptophan content can be estimated from the fluorescence emission, using free tryptophan as an internal standard. The values obtained for a number of proteins are in agreement with the literature values. The method can be applied to as little as 40 μg of protein sample.” (Sasaki et al., Abstract).
The tryptophan residues are connected to be peptide by a linker of other amino acids, which forms a linker molecule.
Consequently, claim 9 is anticipated by Goodrich et al. as evidenced by Mach et al and Sasaki et al. and rejected.
Regarding claim 10, claim 9 is anticipated as described above as evidenced by Sasaki. Claim 10 further recites the case wherein the linker molecule is an alkyl, alkenyl, or polyether chain, with optionally C2 - C24 repeating units, or one or more natural or non-naturally occurring amino or imino acids.
Here, the linker is one or more amino acids.
Consequently, claim 10 is anticipated by Goodrich et al. as evidenced by Mach et al and Sasaki et al. and rejected.
Regarding claim 11, claim 1 is anticipated as described above as evidenced by Mach. Claim 11 further recites the case wherein the probe is capable of detecting granzyme B in a sample, in an amount of less than 10nM, such as less than 1nM, 500pM, 250pM, 100pM, or less than 50pM.
The structure of the probe is anticipated as described above.
MPEP 2112.01(II) states: “"Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”.
The recited properties are necessarily present in the given structure.
Consequently, claim 11 is anticipated by Goodrich et al. as evidenced by Mach et al. and rejected.
Regarding claim 12, claim 1 is anticipated as described above as evidenced by Mach. Claim 12 further recites the case wherein the probe has a Km for Granzyme B of less than 30pM, 25pM, 20pM, 15pM, or 10pM.
The structure of the probe is anticipated as described above.
MPEP 2112.01(II) states: “"Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”.
The recited properties are necessarily present in the given structure.
Consequently, claim 12 is anticipated by Goodrich et al. as evidenced by Mach et al. and rejected.
Regarding claim 13, claim 1 is anticipated as described above as evidenced by Mach. Claim 13 further recites the case wherein the probe has a Kcat/KM value of greater than 1x104, 1x105, 1x106, or 1x107.
The structure of the probe is anticipated as described above.
MPEP 2112.01(II) states: “"Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id.”.
The recited properties are necessarily present in the given structure.
Consequently, claim 13 is anticipated by Goodrich et al. as evidenced by Mach et al. and rejected.
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 5 is rejected under 35 U.S.C. 103 as being unpatentable over Goodrich et al. WO2018035441, published 2/22/2018, as evidenced by Mach et al. (Mach, Henryk, et al. "Ultraviolet absorption spectroscopy." Protein stability and folding: Theory and practice (1995): 91-114.) and Sasaki et al. (Sasaki, et al. Analytical Biochemistry 65.1-2: 396-404 (1975)) in view of Arachea et al. (Arachea, Analytical biochemistry 522: 30-36 (2017)).
Goodrich discloses SEQ ID NO: 6:
MEIRRRSVRHLISLLLFLFYSETACHPLGKRPCKMQAFRIWDVNQKTFYMRNNQLVAGYLQESNTKLQEKIDVVPIEPDALFLGLHGRKLCLACVKSGDEIRFQLEAVNITDLSKNKEENKRFTFIRSNSGPTTSFESAACPGWFLCTAQEADRPVSLTNKPKESFMVTKFYLQEDQ (emphasis added, Goodrich et al, SEQ ID NO: 6)
The remainder of the polypeptide qualifies as a detectable moiety because polypeptides are detectable by UV detection as evidenced by Mach:
“The most frequently employed spectral range for proteins is between 250 and 320 nm, a region referred to as the near ultraviolet. All three aromatic amino acid side chains (i.e., tryptophan, tyrosine, and phenylalanine) have prominent absorption bands in the near ultraviolet (Fig. 1). The only other amino acid with an appreciable contribution in this spectral range (typically, a few percent of total absorbance in most proteins) is cysteine. Assuming the absence of metal ions, cofactors, oxidation byproducts, and other absorbing moieties, these four amino acids are the only important chromophores in this region and they, as well as molecules containing them, are expected to behave according to the Beer-Lambert law.” (Mach et al., page 6, para. 1).
Furthermore, the sequence of Goodrich contains a tryptophan on both the N-terminal and C-terminal side of the required motif IEPDAL: MEIRRRSVRHLISLLLFLFYSETACHPLGKRPCKMQAFRIWDVNQKTFYMRNNQLVAGYLQESNTKLQEKIDVVPIEPDALFLGLHGRKLCLACVKSGDEIRFQLEAVNITDLSKNKEENKRFTFIRSNSGPTTSFESAACPGWFLCTAQEADRPVSLTNKPKESFMVTKFYLQEDQ (emphasis added, Goodrich et al, SEQ ID NO: 6)
The tryptophan amino acids in the sequence of Goodrich constitute a fluorescent moiety as evidenced by Sasaki:
“Digestion of proteins with a mixture of chymotrypsin and pronase followed by dilution in 6 M urea eliminates the quenching effects usually observed when tryptophan fluorescence is measured in native or denatured proteins. Following proteolysis, the tryptophan content can be estimated from the fluorescence emission, using free tryptophan as an internal standard. The values obtained for a number of proteins are in agreement with the literature values. The method can be applied to as little as 40 μg of protein sample.” (Sasaki et al., Abstract).
Goodrich does not disclose a quencher moiety.
However, Arachea discloses that quencher moieties combined with fluorescence moieties are used to measure enzyme activity:
“Following excitation, emission of the fluor is quenched by a moiety located on the other side of the scissile bond. While the quenching can occur by a collisional mechanism, the vast majority of Intramolecular Quenching of Fluorescence (IQF) substrates utilizes fluorescence resonant energy transfer (FRET) to an acceptor that does not emit [6] (sometimes referred to as a “dark” quencher). Cleavage of the substrate by the protease physically separates the FRET pair, dequenches the fluorescence emission, and measurement of fluorescence emission versus time yields the initial velocity Vi at that substrate concentration. The initial velocity Vi is monitored at a single substrate concentration in the presence of a compound from a chemical library, with reduction of Vi as the readout for enzyme inhibition by a putative lead compound. Alternatively, a set of Vi values as a function of substrate concentration [S] is the primary input data for fitting kinetic models, typically yielding values of the Michaelis constant KM, maximum velocity Vmax and Hill coefficient n.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the quencher described by Arachea with the probe of Goodrich to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to add the quencher to be able to detect enzymatic activity as described by Arachea.
A person of ordinary skill in the art would have a reasonable expectation of success because adding a quencher to the probe of Goodrich, Mach, and Sasaki will result in post-cleavage dequenching of half of the tryptophan residues, creating a measurable signal as described by Arachea.
Consequently claim 5 is obvious over Goodrich et al. as evidenced by Mach et al. and Sasaki et al. in view of Arachea et al. and rejected.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Goodrich et al. WO2018035441, published 2/22/2018, as evidenced by Mach et al. (Mach, Henryk, et al. "Ultraviolet absorption spectroscopy." Protein stability and folding: Theory and practice (1995): 91-114.) as applied to claim 3 above, further in view of Kim et al. (Kim, et al. ChemBioChem 17.4: 275-282 (2016)) as evidenced by Sasaki et al. (Sasaki, et al. Analytical Biochemistry 65.1-2: 396-404 (1975)).
Regarding claim 8, claim 3 is anticipated as described above as evidenced by Mach. Claim 8 further recites the case wherein the detectable moiety is conjugated, bound and/or embedded within a nanoparticle, wherein the nanoparticle is conjugated to the peptide.
Goodrich discloses SEQ ID NO: 6:
MEIRRRSVRHLISLLLFLFYSETACHPLGKRPCKMQAFRIWDVNQKTFYMRNNQLVAGYLQESNTKLQEKIDVVPIEPDALFLGLHGRKLCLACVKSGDEIRFQLEAVNITDLSKNKEENKRFTFIRSNSGPTTSFESAACPGWFLCTAQEADRPVSLTNKPKESFMVTKFYLQEDQ (emphasis added, Goodrich et al, SEQ ID NO: 6)
The remainder of the polypeptide qualifies as a detectable moiety because polypeptides are detectable by many means, for example, UV detection as evidenced by Mach:
“The most frequently employed spectral range for proteins is between 250 and 320 nm, a region referred to as the near ultraviolet. All three aromatic amino acid side chains (i.e., tryptophan, tyrosine, and phenylalanine) have prominent absorption bands in the near ultraviolet (Fig. 1). The only other amino acid with an appreciable contribution in this spectral range (typically, a few percent of total absorbance in most proteins) is cysteine. Assuming the absence of metal ions, cofactors, oxidation byproducts, and other absorbing moieties, these four amino acids are the only important chromophores in this region and they, as well as molecules containing them, are expected to behave according to the Beer-Lambert law.” (Mach et al., page 6, para. 1).
As described above, Mach discloses that polypeptides (the detectable moiety) are optically detectable by UV.
Furthermore, the sequence of Goodrich contains a tryptophan on both the N-terminal and C-terminal side of the required motif IEPDAL: MEIRRRSVRHLISLLLFLFYSETACHPLGKRPCKMQAFRIWDVNQKTFYMRNNQLVAGYLQESNTKLQEKIDVVPIEPDALFLGLHGRKLCLACVKSGDEIRFQLEAVNITDLSKNKEENKRFTFIRSNSGPTTSFESAACPGWFLCTAQEADRPVSLTNKPKESFMVTKFYLQEDQ (emphasis added, Goodrich et al, SEQ ID NO: 6)
The tryptophan amino acids in the sequence of Goodrich constitute a fluorescent moiety as evidenced by Sasaki:
“Digestion of proteins with a mixture of chymotrypsin and pronase followed by dilution in 6 M urea eliminates the quenching effects usually observed when tryptophan fluorescence is measured in native or denatured proteins. Following proteolysis, the tryptophan content can be estimated from the fluorescence emission, using free tryptophan as an internal standard. The values obtained for a number of proteins are in agreement with the literature values. The method can be applied to as little as 40 μg of protein sample.” (Sasaki et al., Abstract).
Goodrich does not disclose any nanoparticles.
However, Kim et al. discloses the use of fluorescent enzyme assays on the surface of nanoparticles:
“Over the past decades, the use of nanoparticles (NPs) has opened a new way for assaying a panel of biochemical reactions in the field of biological sciences. Owing to their unprecedented properties, NPs have been extensively explored as biosensors for the detection of biomolecules and have proved able to meet many practical requirements including sensitivity, specificity and accuracy. Whereas many immunoassays in combination with NPs have been predominantly developed for detecting biomarkers, such as oligonucleotides, proteins and small-molecule compounds, enzyme assays based on NPs have also rapidly evolved. Through a series of enzyme–substrate reactions, NP-based biosensors reveal distinct changes in the functions of the NPs. As illustrated in Scheme 1, NPs serve both as excellent carriers of bioreceptors and as signal transducers, leading to amplified signals with different formats including electric, optical and magnetic properties. The resulting signals are the products of high surface-to-volume ratios at the nanoscale; they would not be observable by using traditional approaches.” (Kim et al., page 275, col. 1, para. 2).
Kim also explicitly shows the usage of fluorometric readouts:
PNG
media_image1.png
618
636
media_image1.png
Greyscale
(Kim et al., page 275, Scheme 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the peptide of Goodrich on a nanoparticle as disclosed by Kim to arrive at the claimed invention.
A person of ordinary skill in the art would be motivated to use a nanoparticle because Kim discloses that nanoparticles serve both as excellent carriers of bioreceptors and as signal transducers, leading to amplified signals with different formats including electric, optical and magnetic properties.
A person of ordinary skill in the art would have a reasonable expectation of success because Kim shows both bioreceptors and fluorescence readouts being usable with nanoparticles in Scheme 1 above.
Consequently, claim 8 is obvious over Goodrich et al. as evidenced by Mach et al. as applied to claim 3, further in view of Kim et al. as evidenced by Sasaki et al. and rejected.
Conclusion
No claim is allowed.
Claims 1 and 3-13 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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