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, 15-21 and 25-40 are pending and under examination. Claims 25-40 are new. Claims 5-12, 14 and 22-24 are cancelled.
Withdrawn Objection/Rejections
In light of the Specification filed 07/28/2026, the objection to the specification is hereby withdrawn.
In light of the amendments and cancelations, the objections are hereby withdrawn.
In light of the amendments, the 35 U.S.C. 112(b) rejections are hereby withdrawn.
In light of the amendments, the 35 U.S.C. 112(d) rejection to claim 15 is hereby withdrawn.
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 15-21, 25-27 and 29-40 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, of record).
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, of record).
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(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 26 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.
Claim 26 does not further limit and has broadened the scopes of claims 1-2 because claims 1-2 require the claimed compound to be intact with functional recitations. Meanwhile, claim 26 no longer requires the compound to retain X1 and X2. Thus, claim 26 does not further limit and has broadened the scopes of claims 1-2.
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.
Response to Arguments
Applicant's arguments filed 07/28/2026 have been fully considered but they are not persuasive.
35 U.S.C. 112(a), written description:
Applicant argues on pages 9-10 that the claims have been amended to recite “wherein each of C1 and C2 has a molecular weight of less than 500 g/mol”. Thus, these small molecules do not exhibit the complex folding or macromolecular steric bulk that Waugh and Wu identify as problematic for protease accessibility. Applicant further argues that these compounds are well-known to those skilled in the art and their structures are easily visualized.
The arguments are not found persuasive for the following reasons. The amendments of “wherein each of C1 and C2 has a molecular weight of less than 500 g/mol” do not satisfy the written description requirements for these claims because (1) even though the claims recite the claimed formula 1, the formula 1 may contain other structural features coupling to X1 and X2 and (2) the instant specification only provided two examples to produce the claimed function (i.e., detectable signal and retain SEQ ID NO: 1). As stated above in the rejection, Waugh discloses that every affinity tag, whether large or small, has the potential to interfere with the structure and function (at abstract) Meanwhile, the hydrolysis including the method claims are generic proteases and must be cleaved at one site and certain claims do not even have general structures associated to the function. Thus, the rejection is maintained for these claims.
Allowable Subject Matter
Claim 28 is objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. This claim meets the written description requirement.
As previously stated in the Office Action dated 03/31/2026, Gruba is the closest prior reference of record.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/N.P.N/Examiner, Art Unit 1678
/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678
