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 .
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.
Status of Claims
Claims 1-4, 13 and 15-24 are pending and under examination. Claims 5-12 and 14 are cancelled.
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-4 and 22-24) in the reply filed on 01/09/2026 is acknowledged. The traversal is on the ground(s) that the prior art does not teach combining the amino acids to produce the peptide of Trp-Glu-Gly-Asn as claimed. The argument is found persuasive and hereby withdraw the restriction requirement.
In view of the withdrawal of the restriction requirement, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Nucleotide and/or Amino Acid Sequence Disclosures
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). For example, page 6, lines 18-20, of specification (filed 11/30/22) discloses Trp-Glu-Gly-Asn but is not accompanied by a sequence identifier such as SEQ ID NO: 1. Please provide a sequence identifier for each sequence in the instant disclosure that is required by CFR §§1.821 -1.825 and MPEP §2422.
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.
Claim Objections
Claims 1, 4 and 23-24 are objected to because of the following informalities:
Claim 1 recites Trp-Glu-Gly-Asn must be accompanied with a SEQ number, as amino acid sequences with 4 or more (must conform to CFR §§1.821 -1.825 and MPEP §2422). In this particular case, Trp-Glu-Gly-Asn must be accompanied by SEQ ID NO: 1.
Claim 1 also recites X1- Trp-Glu-Gly-Asn-X2 (formula 1) should be – X1-Trp-Glu-Gly-Asn-X2 (formula 1) –. It appears that there is a gap between X1- and Trp.
Claims 4 and 23-24 recite Markush languages, therefore, “TAM/DANSYL, ABZ/Tyr(3-NO2) “ should be – TAM/DANSYL, and ABZ/Tyr(3-NO2) –.
Additionally, claims 4 and 23-24 recite abbreviated recitations of C1 and C4 but the claims must be accompanied (at least once) by unabbreviated forms are not typical abbreviations or overlap with other abbreviations in the art.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 13 and 15-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP § 2163 states that, for a claimed genus, the written description requirement may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
The claims are drawn to a compound and methods that are characterized by formula 1: X1-Trp-Glu-Gly-Asn-X2 (formula 1), wherein X1 and X2 are a pair of a fluorescence donor and acceptor wherein cleavage of the compound into fragments 1 and 2 generates an optical detectable signal and the detectable signal is generated upon spatial separation of C1 and C2 by hydrolytic cleaving the peptide Trp-Glu-Gly-Asn.
The claims as a whole cover a genus of chemical structures of X1 and X2 to generate optical detectable signals through hydrolytic cleaving of peptide Trp-Glu-Gly-Asn--OH. Explicit in the claims is that such peptide is retained from the hydrolytic cleaving and the releasing of X1 or X2 would possess certain functional characteristics; namely, the ability to produce an optical detectable signal or unquenched.
Level of skill and knowledge in the art:
Wu et al. disclose the fusion protein with intein tag could not be cleaved, even under stringent conditions, possibly due to steric hindrance (at abstract). Wu further discloses that they failed to observe sufficient intein cleavage of the model proteins, even though the adjacent amino acids were suitable for facilitating the release of target protein according to the reported protocols and steric hinderance in the chemical cleavage thus appears to be an important parameter, which might be improved through employment of suitable linker regions (at pg. 184, left col. last para. – right col. para. 1). (Wu et al., “High-level expression and rapid purification of rare-codon genes from hyperthermophilic archaea by the GST gene fusion system”, Journal of Chromatography B, vol. 786 (2003), pgs. 177-185).
Additionally, Waugh et al. disclose that every affinity tag, whether large or small, has the potential to interfere with the structure and function (at abstract). Waugh further teaches that the inability of a protease to cleave a fusion protein may also be caused by steric hindrance, which can be of several types. For example, the cleavage site may be too close to ordered structure in the target protein (at pg. 288, right col., para. 2). Waugh teaches intuitively obvious how the presence of a tag like the 42 kDa MBP on a multimeric protein might create steric problems for affinity tag removal, yet even a tag as small as polyhistidine can present similar difficulties (at pg. 288, right col., para. 3). Fig. 3 (caption) discloses that overcoming steric hindrance by inserting “spacer” residues between a protease recognition site and the N-terminus of the protein of interest (Waugh et al., “An overview of enzymatic reagents for the removal of affinity tags” Protein Expression and Purification, vol. 80, pgs. 283-293, published 2011).
The disclosure:
The specification only discloses the claimed sequence is coupled with 2-aminobenzoic acid (ABZ) and 5-amino-2-benzoic acid (ANB) to produce ABZ-Trp-Glu-Gly-Asn-ANB-NH2 (Example 1) or said sequence is coupled with ABZ and p-nitroaniline (pNA) to produce ABZ-Trp-Glu-Gly-Asn-pNA (Example 2) for producing the optical detectable signal by hydrolytic cleavage of the peptide. The claim requires direct covalent bonds between ABZ-Trp and ANB-Asn without spacers for hydrolytic cleavage in a sample.
In other words, the specification discloses only two specific chemical structures (i.e., 2-aminobenzoic acid (ABZ) paired with 5-amino-2-benzoic acid (ANB) and aminobenzoic acid (ABZ) paired with p-nitroaniline (pNA) which have specific conjugations to Trp and Asn residues for cleavage and detectable signal.
The instant disclosure, including the claims fail to disclose a representative number of species falling with the scope of the claimed genuses or structural common to the members of the genuses so the one of skill in the art can visualize or recognize that such enzyme in the sample is able to cleave covalent bonds from the peptide. The prior art references have indicated that even if the enzymes are known in the art, physical properties of certain compounds would interfere with the ability of enzyme hydrolysis to produce optical signals. In particular, claim 2 recites that such hydrolysis is engaged at Asn and X2 to produce Asn--OH. Thus the claims are specific to the specific cleavage of the compound.
Because the skilled artisan has to rely on the compound to be cleaved for optical detection, the artisan would not be able to determine whether the enzyme in the body fluid is present or absence, as the enzyme may be present but hindered by the structure of the claimed compounds.
Given the claimed broadly class of fluorescence donors or acceptors (big or small) and in the absence of sufficient disclosure of relevant identifying characteristics for said samples, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014) and the specification at best describes plan for making fusion proteins encompassed by the “limitations above” and then identifying those that satisfy claim limitations, but mere “wish or plan” for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011).
In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 43 USPQ2d 1398 (Fed Cir. 1997)). Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117). The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.).
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed in the specification. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only two species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).
In conclusion, there is nothing in the application as filed that discloses a representative of species of fluorescence donors and acceptors. As written, the claims encompass generic structures for desired functional properties, namely the ability to produce an optical signal from an enzyme of a body fluid. Because the specification only disclosed specific chemical structures of fluorescence donors and acceptors that have the ability to be cleaved from the claimed peptide by an enzyme at Asn position, a skilled artisan cannot, as one can do with a fully described genus, visualize or recognize the identity of the members of the claimed genus. The specification does not evidence the possession of these genuses that are undefined and uncharacterized falling within the potentially large genus to establish possession. Consequently, Applicant was not in possession of the instant claimed invention. The full breadth of the claims do not meet the written description provision of 35 U.S.C. 112, first paragraph.
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 2-4, 13 and 15-24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 2 recites the broad recitation “for a hydrolytic enzyme”, and the claim also recites “in particular a hydrolytic enzyme cleaving the compound into X1- Trp-Glu-Gly-Asn-- OH (fragment 1) and NH2-X2 (fragment 2)” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the present instance, claim 3 recites the broad recitation one of Cl and C2 is a chromophore having an absorption maximum 1 (AM1) at a wavelength 1, and the claim also recites “in particular C2, is a chromophore having an absorption maximum 1 (AM1) at a wavelength 1” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the present instance, claim 4 recites the broad recitation “ the pair of Cl and C2 is selected from the group consisting of 2-aminobenzoic acid (ABZ)/pNA, ABZ/ANB-NH2, ABZ/DNP, ABZ/EDDNP, EDANS/DABCYL, TAM/DANSYL, ABZ/Tyr(3-NO2)”, and the claim also recites “in particular the pair of Cl and C2 is selected from ABZ/pNA and ABZ/ANB-NH2” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the present instance, claim 15 recites the broad recitation “for which protease activity”, and the claim also recites “in particular increased protease activity has been detected in step a” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the present instance, claim 16 recites the broad recitation “a hydrolytic enzyme”, and the claim also recites “in particular a protease” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Claims 17-19 are rejected for being depend from claim 16.
In the present instance, claim 20 recites the broad recitation “a concentration of 0.1-10 mg/ml”, and the claim also recites “ particularly 0.25-7.5 mg/ml, more particularly 0.5-5 mg/ml, more particularly 0.75-2 mg/ml, even more particularly about 1 mg/ml, in a measurement buffer having neutral or alkaline pH, preferably physiological pH, and the body fluid sample is added to the compound at a ratio of 1:2 to 1:10, particularly 1:3 to 1:8, more particularly 1:4 to 1:6, even more particularly about 1:5” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the present instance, claim 21 recites the broad recitation “absorbance or fluorescence”, and the claim also recites “particularly measuring absorbance intensity at 300-500 nm, more particularly 380-430 nm, preferably for 40-60 min at 25-40°C, in particular at 36-38°C” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the present instance, claim 22 recites the broad recitation one of Cl and C2 is a chromophore having an absorption maximum 1 (AM1) at a wavelength 1, and the claim also recites “in particular C2, is a chromophore having an absorption maximum 1 (AM1) at a wavelength 1” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the present instance, claim 23 recites the broad recitation “ the pair of Cl and C2 is selected from the group consisting of 2-aminobenzoic acid (ABZ)/pNA, ABZ/ANB-NH2, ABZ/DNP, ABZ/EDDNP, EDANS/DABCYL, TAM/DANSYL, ABZ/Tyr(3-NO2)”, and the claim also recites “in particular the pair of Cl and C2 is selected from ABZ/pNA and ABZ/ANB-NH2” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
In the present instance, claim 24 recites the broad recitation “ the pair of Cl and C2 is selected from the group consisting of 2-aminobenzoic acid (ABZ)/pNA, ABZ/ANB-NH2, ABZ/DNP, ABZ/EDDNP, EDANS/DABCYL, TAM/DANSYL, ABZ/Tyr(3-NO2)”, and the claim also recites “in particular the pair of Cl and C2 is selected from ABZ/pNA and ABZ/ANB-NH2” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 15 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The currently recited claim does not refer to a preceding claim (see MPEP 608.01(n)) and, therefore, fail to further limit the subject matter of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Free of Prior Art
The closest prior art reference of record is Gruba et al. (892 dated 09/18/2025). The reference teaches the substrate with the consensus sequential motive ABZ-Val-Arg-Phe-Arg-ANB-NH2 (see abstract), which is a four amino acid sequence containing a fluorescence donor and acceptor (ABZ and ANB). However, the reference fails to teach or reasonably suggest the claimed peptide of formula 1.
Conclusion
No claim is allowed.
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/N.P.N/Examiner, Art Unit 1678
/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678