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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/24/2025 has been entered.
Status of Claims
Claims 1-3, 5-7 and 9-14 are pending and under examination. Claims 4 and 8 are canceled.
Claim Objections
Claims 1, 5 and 9 are objected to because of the following informalities:
Claims 1, 5, 9 recite the phrase “Flour” should be – Fluor –, as Alexa Flour is not a fluorophore.
Additionally, Europium Cryptate should be – europium cryptate –, as it is a generic name for the compound. For claims 5 and 9, the phrase “Azid” is incorrect and it appears to be – Azide – (also see Table 1).
Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities: The phrase “Azid” is incorrect and it appears to be – Azide – (see Table 1). Additionally, the phrase “Flour” should be – Fluor – (see Table 1). Appropriate corrections are 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 1-3, 5-7 and 9-14 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.” MPEP 2163.
MPEP § 2163 further 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 nature of claims 1, 5, and 9 relate to a wide dynamic range two-part biological probe comprising a first probe that has a single strand DNA sequence attached to a competitive ligand and a second probe with a cDNA that has at least two fluorescent signaling molecules and the fluorescent signaling molecules are either high, medium, or low sensitivity.
The claims are broad and generic to having a two-part biological probe comprising ssDNA with at least two fluorescent molecules of different sensitivities, as required. Implicit in the claims is that such fluorescent signaling molecules attached to the ssDNA as a whole must possess certain functional characteristics; namely the claimed fluorescent molecules attached to the ssDNA would each represent a distinguishable and measurable sensitivity when attached to said ssDNA.
Simeonov et al. (“Interference with Fluorescence and Absorbance”, Assay Guidance Manual: Eli Lilly & Company and the National Center for Advancing Translational Sciences, pgs. 1-12, published 2015, of record) teach there are many fluorophores available that span of a wide energy spectrum, and it is important to select the appropriate fluorophore and assay conditions for a given assay to minimize assay interference and similarly, for absorbance assays, colored compounds can interfere with the detection (see abstract). Simeonov further teaches Alexa dyes have higher charge, which can limit the formation of these dimers and dimer formation results in a decreased assay performance due to self-quenching of the fluorescence, spurious changes in fluorescence polarization as a function of probe concentration, and solubility issues (see page 3, para. 2).
Kurata et al. (“Fluorescent quenching-based quantitative detection of specific DNA/RNA using a BODIPY-FL-labeled probe or primer”, Nucleic Acids Research, vol. 29, no 6 e34, published 2001, pgs. 1-5, of record) teach BODIPY FL fluorescence was quenched by its interaction with a uniquely positioned guanine (G) of DNA or RNA (see abstract; and Table 1). Kurata further teaches in the abstract that when such a probe was hybridized with a target DNA, its fluorescence was quenched by the guanine (G) in the target, complementary to the modified cytosine, and the quench rate was proportional to the amount of target DNA (also see pg. 1, left col., para. 2).
Tomita et al. (“A Multi-Fluorescent DNA/Graphene Oxide Conjugate Sensor for Signature-Based Protein Discrimination”, Sensors, vol. 17, 2194, pgs. 1-12, published 09/23/2017, of record) teach ssDNAs labeled with carboxyfluorescein (FAM) at the 3’ terminus (P1-FAM), with carboxytetramethylrhodamine (TAMRA) at the 3’ terminus (P2-TAMRA), or with indodicarbocyanine (Cy5) at the 5’ terminus (P3-Cy5) were synthesized (see pg. 3, section 2.1 Materials). Tomita further teaches P1-FAM, P2-TAMRA, and P3-Cy5 have different wavelengths but similar absorbance or fluorescence (see Fig. 2). Tomita further teaches that P1-FAM and P3-CY5 showed a similar pronounced decreased in fluorescence emission, the corresponding quenching efficacies were lower than that of P2-TAMRA and this may be attribute to the shielding of nucleobases in P1-FAM and P3-Cy5, caused by the DNA folding (see pg. 4, last para.).
Peeters et al. (“Impact of spacers on the hybridization efficiency of mixed self-assembled DNA/alkanethiol films”, Biosensors and Bioelectronics, vol. 24, pgs. 72-77, published 2008) teach immobilization of DNA strands is an essential step in the development of any DNA biosensor and evaluating spacers to assess their impact on sensitivity and reproducibility (see abstract). Peeters further teaches that there is a considerable and clear impact of spacers on the biosensor performance (see abstract and conclusion). Peeters teaches dynamic range was negatively affected and the maximum hybridization signal dropped from spacers (see pg. 76, last para. right col., section 3.3).
Meanwhile, the instant specification has only provided a single example having a specific spacer and linker to conjugate the claimed fluorophores and competitive ligand to the claimed DNA lengths (see Fig. 4 and pages 19 and 21-23, as filed) for the claimed sensitivities. The disclosed fluorophores are Europium Cryptate, Alexa Flour 350, and DT-6’-FAM Azid conjugated with a specific hydrocarbon and PEG spacers/linkers (see Fig. 4, as filed) while attached to 14-22 nucleotide sequences at a phosphate group of a particular nucleotide base to produce the claimed functions. The specification lacks guidance to a wide range of DNA structures coupled to the claimed fluorophores to provide specific sensitivities as a two-part probe in competitive assay. The courts have stated that “tossing out the mere germ of an idea does not constitute enabling disclosure.” Genentech, 108 F.3d at 1366 (quoting Brenner v. Manson, 383 U.S. 519, 536 (1966) (stating, in context of the utility requirement, that “a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion”)). “[R]easonable detail must be provided in order to enable members of the public to understand and carry out the invention.” Id.
In this instant case, such reasonable detail is lacking in these claims. For example, chemical sensitivities would encompass a wide range of chemical structures which has not been described in the instant specification. There is nothing in the application, as filed, to suggest that, for example, the DNA sequences between 14-22 nucleotides would be able to produce specific sensitivities from the claimed fluorophores and competitive ligand.
Meanwhile, Peeters teaches that there is a considerable and clear impact of spacers on the biosensor performance (see abstract and conclusion). Peeters teaches dynamic range was negatively affected and the maximum hybridization signal dropped from spacers (see pg. 76, last para. right col., section 3.3). Tomita teaches that fluorescence emission may be shielded by nucleobases which is caused by the DNA sequence. In addition, Simeonov teaches that interferences occur in assays. Likewise, Kurata teaches specific DNA or RNA molecules quenched fluorophores by simply the position of guanine and these are short DNA sequence (see abstract; and Table 1). Therefore, based from the prior art and the instant disclosure, there would be undue experimentations to determine the attachments of the claimed fluorophores and competitive ligand to produce the claimed sensitivities and effectiveness of the probe.
As stated above, the state of the art teaches the unpredictability associated with attaching fluorophore signaling to DNA sequences. However, in this particular case, the DNA sequence also contains a competitive ligand. Thus, the fluorescent signaling as claimed would be unpredictable, as spacers clearly impact hybridization and sensitivity of DNA. In summary, due to the state of the prior art and the lack of the instant specification in not disclosing a representative number of attaching DNA probes with fluorophores and competitive ligands, as well as the lack of direction/guidance or working examples, the specification fails to teach the skilled artisan how to make the claimed invention without undue experimentations. Therefore, the claims fail to comply with the written description requirement of a representative number species.
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 1-3, 5-7, and 9-14 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.
In particular, claims 1, 5, and 9 contain the trademark/trade name Alexa Fluor 350. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe a chemical structure of fluorophore and, accordingly, the identification/description is indefinite. In this particular, an IUPAC name of Alexa Fluor 350 would be appropriate to name the chemical structure of said fluorophore.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5-7, and 9-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of copending Application No. 18906231 (reference application).
With respect to instant claims 1, 5, 9, Although the claims at issue are not identical, they are not patentably distinct from each other because A biological probe configured to competitively assay small molecules, the probe comprising: a first probe part comprising a single strand DNA sequence, the first probe part attached to at least one competitive ligand competitive to a target small molecule; a second probe part comprising the single strand cDNA complement of the single strand DNA sequence of the first probe part, the second probe part comprising first and second fluorescent signaling molecules each conjugated to a particular base in the single strand cDNA complement; wherein the first signaling molecule has a higher sensitivity than the second signaling molecule; wherein the first signaling molecule is conjugated proximate the 5’-end of the cDNA complement, and the second signaling molecule is conjugated proximate the 3’-end of the cDNA complement; and wherein the first signaling molecule is Europium Cryptate, and the second signaling molecule is Alexa Flour 350. Although the copending Application does not explicitly recite the probes are from 14 to 22 nucleotides in length. However, copending claim 4 recites that the single strand DNA sequence of the first probe has sequences that are within the range of the claimed invention. Therefore, it would have been obvious for the first and second probes to have the claimed nucleotide length.
With respect to claims 2-3, 6-7, and 10-14, the copending claims 2-3, 8-9 and 14 read on the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 03/24/2025 have been fully considered but they are not persuasive under 35 U.S.C. 112(a) rejection. In light of the amendments, the rejection has been modified.
Applicant argues on page 7 that the claims have been amended in accordance with the Office Action to recite “wherein the first probe part and the second probe part are from 14- to 22 nucleotides in length”. Applicant argues that the amendments satisfy the written description requirement.
The arguments are not found persuasive. As stated in the above written description, Peeters teaches immobilization of DNA strands is an essential step in the development of any DNA biosensor and there is a considerable and clear impact of spacers on the biosensor performance Peeters teaches dynamic range was negatively affected and the maximum hybridization signal dropped from spacers.
The state of the art teaches the unpredictability associated with attaching fluorophore signaling to DNA sequences. In this particular case, the DNA sequence also contains a competitive ligand. Thus, the fluorescent signaling as claimed would be unpredictable, as spacers clearly impact hybridization and sensitivity of DNA. In summary, due to the state of the prior art and the lack of the instant specification in not disclosing a representative number of attaching DNA probes with fluorophores and competitive ligands, as well as the lack of direction/guidance or working examples, the specification fails to teach the skilled artisan how to make the claimed invention without undue experimentations.
Conclusion
No claim is allowed.
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/N.P.N/Examiner, Art Unit 1678
/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678