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 .
Claim Status and Formal Matters
The instant action is in response to papers filed 6/11/2026.
The instant response in non-compliant with 37 CFR 1121 as the claims have been amended, but do not provide the required markings. For example claim 1 stepc) previously recited:
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However the instant claims recite:
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Thus the amendment has added the limitation of “specifically binding” while the claim previously recited,”binding.” However to promote compact proscuteion and customer service the instant response will be examined. However, future amendments which are not compliant with 37 CFR 1.121 may not be entered or examined.
Claims 2, 17, 21 has been amended to add limitations, but does not provide the required markings.
Further claims 3-4 have limitations which have been deleted but they are not correctly marked.
Claims 1-21 are pending.
Claims 1-21 have been amended.
The previous objection to the claims has been withdrawn.
Priority
The instant application was filed 06/13/2024 Claims Priority from Provisional Application 63508309 , filed 06/15/2023.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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 - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete.
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 incorporation by reference paragraph, 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.
Response to Arguments
The response has not addressed the issue. Future response which do not address the issue may not be entered or examined.
Specification
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: Claim 7 has been amended to recite, “polvethylene oxide-polypropvlene oxide-polyethylene oxide (PEO-PPO-PEO) triblock copolymer having an average molecular weight between approximately 7,500 and 9,000 Daltons.” Review and searching of the specification did not reveal antecedent basis for this limitation in the specification as.originally filed.
Response to Arguments
This is a new ground of rejection necessitated by amendment.
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 1-16 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.
MPEP 2163 IB New or amended claims section II
With respect to newly added or amended claims, applicant should show support in the original disclosure for the new or amended claims. See, e.g., Hyatt v. Dudas, 492 F.3d 1365, 1370, n.4 (Fed. Cir. 2007) (citing MPEP § 2163.04 which provides that a "simple statement such as ‘applicant has not pointed out where the new (or amended) claim is supported, nor does there appear to be a written description of the claim limitation ‘___’ in the application as filed’ may be sufficient where the claim is a new or amended claim, the support for the limitation is not apparent, and applicant has not pointed out where the limitation is supported."); see also MPEP §§ 714.02 and 2163.06 ("Applicant should ... specifically point out the support for any amendments made to the disclosure."); and MPEP § 2163.04
Claim 1 has been amended to recite, “(c) providing a plurality of detectable nanoparticles either pre-coated onto the test strip or added to the mixture of step (a) or added to the mixture of step (b), wherein the plurality of detectable nanoparticles have their surfaces coated with a receptor capable of specifically binding either the first affinity tag or the second affinity tag but not both, and wherein the test strip comprises a test line containing a surface- immobilized receptor capable of specifically binding either the first affinity tag or the second affinity tag but not both, and d_(d causing the mixture of step (b) to flow along the test strip to reach the test line. The response provides no indication where support for the amendment can be founds. Review and searching of the specification revealed a single recitation of “pre-coated” and it was not with respect to pre-coated onto the test strip. Further review of the specification did not reveal explicit support for the order of steps or step (d) being limited to the mixture of step (b). Thus the amendment appears to be new matter.
Claim 7 has been amended to recite, “wherein the block copolymer surfactant is a polvethylene oxide-polypropvlene oxide-polyethylene oxide (PEO-PPO-PEO) triblock copolymer having an average molecular weight between approximately 7,500 and 9,000 Daltons” The response with respect to 112(b) issues asserts this is the same Pluronic F68 and is supported by 0051. However the specification does not provide antecedent basis for this limitation. Further the response has provide no evidence a polvethylene oxide-polypropvlene oxide-polyethylene oxide (PEO-PPO-PEO) triblock copolymer having an average molecular weight between approximately 7,500 and 9,000 Daltons is Pluronic F68. Thus the amendment appears to be new matter.
Response to Arguments
The is a new ground of rejection necessitated by amendment.
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 1-21 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.
Claim 1 has been amended to recite, “ with a receptor capable of specifically binding either the first affinity tag or the second affinity tag but not both, and wherein the test strip comprises a test line containing a surface- immobilized receptor capable of specifically binding either the first affinity tag or the second affinity tag but not both,.” The recitation of “capable of specifically binding” suggests there is non-specifically binds. Review and searching of the specification did not provide a standard to differentiate capable of specifically binding from capable of non-specifically binding. Thus the metes and bounds are unclear.
Claim 1 has been amended to recite, “ relative to a negative control sample lacking ribonuclease.” The claim is confusing and unclear how to compare to a negative control when the claim does not provide any limitations requiring a negative control sample. Thus the metes and bounds are ulcer.
Claim 1 has been amended to recite, “ detecting the presence or absence of ribonuclease in the test sample based on the signal intensity at the test line..” The recitation of “based on” is not an art accepted term and it is not defined by the specification. Thus the metes and bounds are vague and unclear how detecting is determined.
Claim 2 has been amended to recites wherein in step (c) the test strip further contains a control line distal to the test line, wherein the control line contains an immobilized receptor capable of binding the plurality of detectable nanoparticles regardless of the presence of ribonuclease in the test sample, wherein the control line contains an immobilized receptor capable of binding the plurality of detectable nanoparticles regardless the presence of ribonuclease in the test fluid of step (g).” The metes and bounds are unclear as claim 1 does not provide a step (g). Further the claim is confusing how the immobilized receptor capable of binding the plurality of detectable nanoparticles regardless the presence of ribonuclease in the test fluid. The claim provides functional language about a receptor for immobilize the nanoparticles, but does not provide a structure for how this is done. Further it is unclear how what the duplication of limitations encompasses or required. Thus the metes and bounds are unclear.
It is noted claim 4 has been amended to delete reference to step (g) and replace regardless with independently. However, the response does not follow the rules of 37 CFR 1.121.Claim 4 has been amended to recite, “wherein the control line contains an immobilized receptor capable of binding the plurality of detectable nanoparticles independently of the presence of ribonuclease in the test sample.” The metes and bounds are unclear as claims 1-3, do not provide a step (g). Further the claim is confusing how the immobilized receptor capable of binding the plurality of detectable nanoparticles independently of the presence of ribonuclease in the test fluid. The claim provides functional language about a linker compound configured to bind both to the control line and to the plurality of detectable nanoparticles, but does not provide a structure for how this is done. Thus the metes and bounds are unclear.
Claim 17 has been amended to recite, “ with a receptor capable of specifically binding either the first affinity tag or the second affinity tag but not both, and wherein the test strip comprises a test line containing a surface- immobilized receptor capable of specifically binding either the first affinity tag or the second affinity tag but not both,.” The recitation of “capable of specifically binding” suggests there is non-specifically binds. Review and searching of the specification did not provide a standard to differentiate capable of specifically binding from capable of non-specifically binding. Thus the metes and bounds are unclear.
Claim 17 has been amended to recite, “ relative to a negative control sample lacking ribonuclease.” The claim is confusing and unclear how to compare to a negative control when the claim does not provide any limitations requiring a negative control sample. Thus the metes and bounds are ulcer.
Claim 17 has been amended to recite, “ detecting the presence or absence of ribonuclease in the test sample based on the signal intensity at the test line..” The recitation of “based on” is not an art accepted term and it is not defined by the specification. Thus the metes and bounds are vague and unclear how detecting is determined.
Claim 21 has been amended, but does not provide the markings required of 37 CFR 1.121.Claim 21 has been amended to recite, “ (b) a plurality of detectable nanoparticles with their surfaces coated with a receptor capable of specifically binding either the first affinity tag or the second affinity tag but not both; (c) a test strip having a test line containing a surface-immobilized receptor capable of specifically binding either the first affinity tag or the second affinity tag but not both;,.” The recitation of “capable of specifically binding” suggests there is non-specifically binds. Review and searching of the specification did not provide a standard to differentiate capable of specifically binding from capable of non-specifically binding. Thus the metes and bounds are unclear.
Response to Arguments
The amendment has overcome the previous issues, but the amendment has raised new issues as addressed in the rejection above.
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.
Claim(s) 1-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Palsoke (Methods in Molecular Biology (2001) vol 160,pages 105-111), Green ( from the Molecular Cloning collection, edited by Michael R. Green and Joseph Sambrook. ©2019 Cold Spring Harbor Laboratory Press Cite this introduction as Cold Spring Harb Protoc; doi:10.1101/pdb.top101857), Sharma (Biosensors 2015, 5, 577-601; doi:10.3390/bios5030577 ), Kemble (US 20220010386), Bohannon (20050255608), Chou (WO 2022093211 A1 ), Khambhati (J Cell Biochem (2019) volume 120, pages 2721-2725) and Wei (Analyst,2021,146,558–564)
This rejection is set forth in view of the 112 issues and the breadth of the claims.
The prior art exemplified below demonstrates the use lateral flow technology to detect enzymes and RNA with two affinity reagents. The art exemplifies the use of buffers, double labeled nucleic acids, with nanoparticles for binding to a test strip for determination of activity or levels were known.
Palsoke teaches Rnases are difficult to remove and inactivate and can make RNA analysis difficult. (page 105)
Green teaches, “Autoclaving glassware and plasticware may not be sufficient to inactivate RNase. Bake glassware for 4 h at 300˚C. Treat plasticware either with DEPC or commercially available products that inactivate RNase upon contact (e.g., RNaseZap from Ambion).” (page 6)
Sharma teaches, “ Existing diagnostic instrumentation usually requires sophisticated infrastructure, stable electrical power, expensive reagents, long assay times, and highly trained personnel which is not often available in limited resource settings. This review will critically survey and analyse the current lateral flow-based point-of-care (POC) technologies, which have made a major impact on diagnostic testing in developing countries over the last 50 years. The future of POC technologies including the applications of microfluidics, which allows miniaturisation and integration of complex functions that facilitate their usage in limited resource settings, is discussed The advantages offered by such systems, including low cost, ruggedness and the capacity to generate accurate and reliable results rapidly, are well suited to the clinical and social settings of the developing world.” (abstract).Sharma teaches, “Lateral flow or Lateral Flow Immunoassay (LFIA) technology is the most simple and successful rapid diagnostic testing platform derived from the latex agglutination test developed by Singer and Plotz in 1956” (579, last paragraph).
Sharma teaches, “Lateral flow immunoassay (LFIA) is based on the use of a nitrocellulose, polymer, paper, or other composite substrate membrane which facilitates the separation, capture, and detection of the target analyte(s) of interest. The various components of a LFIA have the capacity to transport fluid, including blood or serum, under capillary action, and thus no external pumps are required.” (page 583, 2nd paragraph) Sharma teaches, “In a simple capture format (Figure 1) the target analyte from the sample interacts with a labelled antibody, already pre-loaded on the strip, and migrates up the strip until it encounters another target-specific antibody, which is immobilised on the strip. The capture antibody-antigen-labelled antibody is then evident as a line which can be seen by eye or can be measured using a detector. A control is also present which uses a non-specific antibody and the presence of the associated line clearly demonstrates that the assay is working correctly.” page 583, 1st paragraph)
Sharma teaches, “The mobile phase contains the antibody bound with a label, e.g., enzymes, fluorescent tags, gold nanoparticles, quantum dots, or latex beads, which first interact with the target analyte in a direct or sandwich immunoassay format and then come in contact with the immobilised capture antibodies. Recently, the potential of using recombinant antibodies is being explored.” (2.2.1, page 585). Sharma teaches, “Single-stranded DNA or RNA (ssDNA or ssRNA) molecules can bind to selected targets, including proteins and peptides, with high affinity and specificity.” (586). Sharma teaches, “The choice of a label used for detection normally depends on the application of the LFIA system. Labels such as latex beads, colloidal carbon, colloidal gold, fluorescent tags, enzymes, streptavidin, or gold nanoparticles, are conjugated with an antibody or an antigen depending on the format of the LFIA system [“ (2.2.7)Sharma teaches, “The use of colloidal gold, paramagnetic particles, and fluorescent dyes as labels in lateral flow formats has opened up new horizons for LFIA technology by allowing true quantitative testing. The development of quantitative assays in lateral flow formats requires an additional fluorescence or optical strip reader which allows measurement of the intensity produced at the test and control lines of the strip.” (2.2.8)
Kemble teaches, “[0005] Aspects of the disclosure relate to compositions and methods for amplifying and/or detecting target analytes (e.g., nucleic acids) in a sample. The disclosure is based, in part, on methods and compositions that produce amplification products that result in high contrast, visible, colored bands when bound to certain immunoassay devices (e.g., lateral flow immunoassays). In some embodiments, compositions and methods described herein allow for direct application of the amplicons to immunoassay devices without any intervening fluid transfer or dilution step.” Kemble teaches, “0017] In some embodiments, a 5′ portion of a first single stranded polynucleotide comprises a digoxigenin (DIG). [0018] In some embodiments, a single stranded reporter oligonucleotide comprises a FITC on its 5′ portion or 3′ portion. “ Kemble teaches, “[0052] In some embodiments, a target nucleic acid comprises DNA or RNA.”
Kemble teaches, “An RNase generally refers to an enzyme that catalyzes the degradation of RNA. In some cases, an RNase may be used to digest RNA from an RNA-DNA hybrid.”
Bohannon teaches, “[0002] Numerous analytical methods have been developed for determining the presence or absence and/or quantifying the amount of various analytes in tissues and fluids of organisms, such as blood, urine, fecal material, or tissue biopsy. Lateral flow chromatography is, perhaps, one of the more common of these analytical methods. [0003] Lateral flow chromatography assays and devices are well known to those of skill in the art (see, e.g., U.S. Pat. Nos. 5,569,608, 5,120,643, 5,656,503, 4,855,240, and 5,591,645, British Patent GB 2204398A, and European patent EP 0323605 B1) and such assays are commercially available on a retail or OEM basis for numerous analytes”. Bohanon teaches “[0014] t has been discovered that, surprisingly, bulking materials having a starch reagent effectively enhance chromatographic detection methods by providing component stability and controlled release. Thus, the novel components and methods disclosed herein provide a completely new modality of chromatographic analyte detection. “Bohannon teaches, “[0110] Surfactants are useful as additional reagents in the bulking material. Exemplary surfactants include, for example, non-ionic surfactants and ionic surfactants. Non-ionic surfactants do not ionize in aqueous solutions. Exemplary non-ionic surfactants include sodium deoxycholate, octylglucoside, digitonin, octaethyleneglycol mono n-dodecyl ether (C12E8), lubrol, polyoxyethylated octyl phenol (Triton X-100), ethylphenolpoly-(ethyleneglycolether) (Nonidet P-40), [Octylphenoxy]polyethoxyethanol (Nonidet P-40 substitute), Polyoxyethylene Sorbitan Monooleate (polyoxyethylenesorbitanmonooleat) (Tween 80), polyoxyethylene sorbitan monolaureate (Tween-20), BRIG 35, dodecyl maltopyranoside, heptyl thioglucopyranoside, ethylenoxide and propylenoxide block-copolymer surfactants such as Pluronic and Tetronic surfactants available from BASF (e.g. Pluronic F-127 and Tetronic T1307), Isotridecyl(PEG-ether)8 (also referred to as Genapol X-080), N-alkanoyl-N-methylglucamide surfactants (e.g. the MEGA series surfactant including MEGA 9 AND MEGA 10), and the like. Ionic surfactants include anionic surfactants, cationic surfactants, and amphoteric surfactants. Useful anionic surfactants include, for example, sodium dodecyl sulfate, cholate and deoxycholate, and the like. Exemplary cation surfactants include cetyltrimethyl-ammonium bromide (CTAB) and the like. Amphoteric surfactants useful in the present invention include, for example, LysoPC, CHAPS, Zwittergent 3-14, and the like.” Bohannon teaches, “[0133] Surfactants are useful as additional reagents in the bulking material. Exemplary surfactants include, for example, non-ionic surfactants and ionic surfactants. Non-ionic surfactants do not ionize in aqueous solutions. Exemplary non-ionic surfactants include sodium deoxycholate, octylglucoside, digitonin, octaethyleneglycol mono n-dodecyl ether (C12E8), lubrol, polyoxyethylated octyl phenol (Triton X-100), Ethylphenolpoly-(ethyleneglycolether) (Nonidet P-40), [Octylphenoxy]polyethoxyethanol (Nonidet P-40 substitute), polyoxyethylene sorbitan monooleate (polyoxyethylenesorbitanmonooleate) (Tween 80), polyoxyethylene sorbitan monolaureate (Tween-20), BRIG 35, dodecyl maltopyranoside, heptyl thioglucopyranoside, block-copolymer surfactants such as Pluronic and Tetronic surfactants available from BASF (e.g. Pluronic F127, Pluronic F98, Tetronic 904 and Tetronic T1307), Isotridecyl(PEG-ether).sub.8 (also referred to as Genapol X-080), N-alkanoyl-N-methylglucamide surfactants (e.g. the MEGA series surfactant including MEGA 9 AND MEGA 10), and the like. Ionic surfactants include anionic surfactants, cationic surfactants, and amphoteric surfactants. Useful anionic surfactants include, for example, sodium dodecyl sulfate, cholate and deoxycholate, and the like. Exemplary cation surfactants include cetyltrimethyl-ammonium bromide (CTAB) and the like. Amphoteric surfactants useful in the present invention include, for example, LysoPC, CHAPS, Zwittergent 3-14, and the like.”
Chou teaches, “The present disclosure relates to self-wicking assay devices that can include a porous membrane for sequential flow of a sample fluid from a complexing region to a detecting region thereof. The complexing region can include a releasing compound to ameliorate binding between a porous membrane and an analyte introduced by the sample fluid and an analyte-complexing compound. The detecting region can be positioned downstream from the complexing region along the porous membrane. The detecting region can include an immobilized testing compound applied to the porous membrane at a first discrete location of the detecting region, and an immobilized control compound applied to the porous membrane at a second discrete location of the detecting region.” Chou teaches, “[0037] As one example, a membrane-modifying compound can be delivered in a fluid and can include a dual functioning copolymer with a modifiable functional portion that serves to block binding of the biomolecule, while another portion may have a stronger affinity to the hydrophobic substrate. The modifiable portion can include functionalities or moieties that can provide steric or electrostatic hindrance to binding, e.g., PEG moieties, primary amines to form amide linkages, etc., that may allow for binding of BSA, casein, or other biomolecules that act as blocking agents. As another example, a Pluronic block copolymer surfactant with terminal alcohols can be used to noncovalently bind to the surface of the hydrophobic membrane, while leaving hydrophilic portions available to change the membrane surface energy. A Pluronic block copolymer may include hydrophilic ethylene oxide (EO) and hydrophobic propylene oxide (PO) blocks arranged block copolymer structure, e.g., A-B-A structure. The terminal alcohols may also be transformed to primary amines/carboxylic acids, which then can attach further blocking agents. Thus, a portion with affinity to the porous substrate may be hydrophobic to enable noncovalent hydrophobic binding. Stated another way, one example of a membrane-modifying compound may be a dual functioning copolymer to non-covalent bind to the porous substrate and block biomolecule binding. The molecular weight of the copolymer can be dependent on the polymer composition, which may be dictated by feed ratio and reactivities of the monomers applied, but in some examples, the molecular weight may range from about 2,000 Daltons to about 1 ,000,000 Daltons, from about 2,000 Daltons to about 500,000 Daltons, or from about 4,000 Daltons to about 500,000 Daltons. In further detail, though hydrophobic non-covalent attraction is mentioned above, other mechanisms of attraction can likewise be used, depending on the porous membrane. In some examples, the burial of hydrophobic surfaces in protic-polar solvents may dominate the interaction, especially with hydrophobic surfaces. Multivalent hydrogen bonding may also aid in association of complimentary donor/acceptor pairs existing between the polymer and surface. In situ polymerization or polymerization followed by attraction or attachment can likewise be used for providing releasing compound at the complexing region. These compounds for polymerization can be applied by fluid jet ejection in some examples. [0038] Polymerizable free-radical or condensation monomers (including some which may act as crosslinking monomers) that can be used to prepare such polymers as releasing compounds may include the following: and/or where R represents a moiety that may provide functionality to the polymer system, with example structures including aliphatic or aromatic chemical groups to impart hydrophobicity; oxygen-, nitrogen-, or sulfur-containing moieties that generate polar bonds and impart hydrophilicity; pH sensitive moieties that form anionic or cationic species; surface bound crosslinking sites; etc. Notably, the surface of the porous membrane may also be chemically modified so as to provide acryloyl, condensable, or other functional groups that may incorporate into the growing polymer chain or initiate polymerization of monomers in solution, thereby providing a covalent link to the membrane surface, depending on the chemistry of the porous substrate being used.” Chou teaches, “, the hydrophobic membranes can be harder to wet, which means that any unbound biomolecules may have difficulty resolubilizing and may not be able to be released from the porous membrane while the sample fluid is being passed therethrough. Treatment with a membrane- modifying compound can provide a decrease in nonspecific binding of biomolecules to the porous membrane, particularly hydrophobic porous membranes.” (0036)
Khambhati teaches
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Wei teaches:
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Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to use RNA with two different affinity tags and nanoparticles with a sample and a block copolymer surfactant, adding to a running buffer, allowing the running buffer sample solution to flow along a test strip to detect the cleavage of the RNA, by binding one of the two affinities tags to a test line to allow determination of Rnase in the sample by comparison to a negative control sample. The artisan would be motivated to detect RNAse as the art demonstrates Rnase is a contaminant confounding RNA analysis. The artisan would be motivated to use a nonionic block copolymer as a bulking material as Bohannon teaches, “It has been discovered that, surprisingly, bulking materials having a starch reagent effectively enhance chromatographic detection methods by providing component stability and controlled release. Thus, the novel components and methods disclosed herein provide a completely new modality of chromatographic analyte detection.” Further Chou teaches, “, the hydrophobic membranes can be harder to wet, which means that any unbound biomolecules may have difficulty resolubilizing and may not be able to be released from the porous membrane while the sample fluid is being passed therethrough. Treatment with a membrane- modifying compound can provide a decrease in nonspecific binding of biomolecules to the porous membrane, particularly hydrophobic porous membranes. “The artisan would have a reasonable expectation of success as the artisan is merely using known methods. (claim 1 and 21)
With regards to claim 2, Sharma teaches, “This is followed by the presence of another zone, the control zone, which checks for assay functionality. Superfluous reagents, buffers, and assay fluids further migrate toward the absorbent pad and are absorbed as waste. The results are interpreted either by the naked eye or using a reader which evaluates the presence or absence of a test line along with the control line [2” 92.2, 584, bottom)
With regards to claim 3-4, Sharma teaches
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(figure 1, page 584)
With regards to claims 5-7 and 14, Bohannon teaches, “xemplary non-ionic surfactants include sodium deoxycholate, octylglucoside, digitonin, octaethyleneglycol mono n-dodecyl ether (C12E8), lubrol, polyoxyethylated octyl phenol (Triton X-100), ethylphenolpoly-(ethyleneglycolether) (Nonidet P-40), [Octylphenoxy]polyethoxyethanol (Nonidet P-40 substitute), Polyoxyethylene Sorbitan Monooleate (polyoxyethylenesorbitanmonooleat) (Tween 80), polyoxyethylene sorbitan monolaureate (Tween-20), BRIG 35, dodecyl maltopyranoside, heptyl thioglucopyranoside, ethylenoxide and propylenoxide block-copolymer surfactants such as Pluronic and Tetronic surfactants available from BASF “
With regards to claim 8, Sharma teaches nitrocellulose membrane (2.2.4)
With regards to claims 9, Sharma teaches, “The choice of a label used for detection normally depends on the application of the LFIA system. Labels such as latex beads, colloidal carbon, colloidal gold, fluorescent tags, enzymes, streptavidin, or gold nanoparticles, are conjugated with an antibody or an antigen depending on the format of the LFIA system.” (2.27)
MPEP 2144.05 III states:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997).
Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of “having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium” as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium.).
With regards to claim 10, Kemble teaches, “0025] In some embodiments, a first single stranded polynucleotide ranges from about 10 to about 50 nucleotides in length.”
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims the ranges of Kemble render the instant claims obvious. The artisan would be motivated as the prior art suggests a range which encompasses the claimed ranges. The artisan would have a reasonable expectation of success as the artisan is merely using known lengths of RNA.
With regards to claim 11, Kemble teaches Avidin and biotin (0223)
With regards to claim 12, Sharma teaches use of antibody and antigen (2.2.7)
With regards to Claim 13, Kemble teaches, “Non-limiting examples of suitable labels include biotin, streptavidin, fluorescein isothiocyanate (FITC), fluorescein amidite (FAM), fluorescein, and digoxigenin (DIG).” (0214)
With regards to claim 14, Bohannon teaches, “n an exemplary embodiment, the concentration of the surfactant is between 1% and 5%.” (0111)
With regards to claim 15-16, Kemble teaches nucleic acids with modifications at the 5’ end and 3’ end (0135). Kemble teaches nucleic acids can be RNA or DNA (0147)
Green teaches glassware can be contaminated with RNAses.
Kemble teaches the use of environmental swabs.(0179)
Therefor it would have been prima facie obvious to one of skill in the art prior to the effective filing date of the claims to swab glassware or other solid surface to practice the use RNA with two different affinity tags and nanoparticles with a sample, adding to a running buffer, allowing the running buffer sample solution to flow along a test strip to detect the cleavage of the RNA, by binding one of the two affinities tags to a test line to allow determination of Rnase in the sample. The artisan would be motivated to detect RNAse as the art demonstrates Rnase is a contaminant confounding RNA analysis. The artisan would have a reasonable expectation of success as the artisan is merely using known methods
With regards to claims 18-20, Kemble teaches the lysis of sample by time periods of 1 to 5 minutes or 1 to 15 minutes (0189)
Therefore it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claims to submerge the swab of glassware in the cell lysis or reagent fluid for 1 to 5 minutes to allow for detection of RNase on glassware or other hard surfaces. The artisan would be motivated to place the swab in solution to allow for examination of RNases on the hard surface or glassware. The artisan would have a reasonable expectation of success the artisan is merely using known reagents.
Response to Arguments
Ther response being traversing the rejection by asserting, “The claimed invention is not simply "using lateral flow to detect RNase." The claimed invention operates through a specific RNA molecular bridging mechanism: an intact RNA oligonucleotide bearing two different affinity tags simultaneously binds both (i) a receptor-coated nanoparticle via one tag, and (ii) a surface-immobilized receptor at the test line via the other tag.” This argument has been thoroughly reviewed but is not considered persuasive as the claims do not require a “specific RNA molecular bridging mechanism.” The claims merely require, “ mixing an aqueous test sample with the a reagent fluid to cause them to react together, wherein the reagent fluid comprises ribonucleic acid attached to a first affinity tag and a second affinity tag in a buffered aqueous solution containing a block copolymer surfactant;” This is of different scope than the assertion and is at least obvious over
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The response continues by arguing, “he Examiner relies on Kemble as the primary reference for the concept of dual-labeled nucleic acids in lateral flow detection. However, Kemble is directed to detecting specific pathogen nucleic acid sequences (e.g., SARS-CoV-2) by RT-LAMP amplification, followed by detection of the amplified products on a lateral flow strip. Kemble's labeled loop primers (LoopF-FITC/DIG, LoopB-biotin) function as primers that are enzymatically incorporated into amplicons during amplification. The labels are incorporated into the amplification product and the amplicon (not a pre-existing bridge) is the analyte detected.” This argument has been thoroughly reviewed but is not considered persuasive as Kemble teaches, “[0193] In some embodiments, reverse transcription is performed by exposing lysate (or nucleic acids within a lysate) to one or more reverse transcription reagents. In certain instances, the one or more reverse transcription reagents comprise a reverse transcriptase, a DNA-dependent polymerase, and/or a ribonuclease (RNase). A reverse transcriptase generally refers to an enzyme that transcribes RNA to complementary DNA (cDNA) by polymerizing deoxyribonucleotide triphosphates (dNTPs). An RNase generally refers to an enzyme that catalyzes the degradation of RNA. In some cases, an RNase may be used to digest RNA from an RNA-DNA hybrid.” Thus the teachings of Kemble are not limited to only the preferred embodiment of Kemble.
The response continues by asserting Sharma only provides general LFIA architecture, but not enzyme detection. This argument has been thoroughly reviewed but is not considered persuasive as the cited art of Khambhati and Wei teach assays including enzymes.
The response continues traversing the rejection by asserting, “The Examiner relies on Bohannon's §§ 0110-0111 for the disclosure of nonionic surfactants, including "ethylenoxide and propylenoxide block-copolymer surfactants such as Pluronic," and the statement that concentrations of 1-5% are exemplary. Respectfully, this reliance mischaracterizes Bohannon's teaching. Bohannon discloses these surfactants as components of a dry bulking material - specifically, a maltodextrin-based powder that is dried onto the sample pad or test zone of the lateral flow strip for the purpose of stabilizing antibodies and controlling analyte release during rehydration. The surfactants in Bohannon's disclosure are embedded in a dehydrated solid matrix on the strip, and their function is to maintain protein stability in the dry state and to control the kinetics of rehydration and analyte binding upon sample addition. This is a wholly different context from the present invention. In the present invention, the block copolymer surfactant (e.g., the PEO-PPO-PEO triblock copolymer described in amended Claim 7) is dissolved in the aqueous liquid reaction mixture that contains the RNA substrate, and it serves an entirely different purpose: dramatically enhancing the sensitivity of the RNase detection assay by increasing RNase enzymatic activity. The effect is related to improving enzyme activity and not to reagent stabilization or release onto the strip. Bohannon provides no teaching, explicit or implicit, that adding a block copolymer surfactant to a liquid enzyme reaction mixture would enhance the detection of enzymatic activity by a lateral flow bridging assay. Furthermore, the concentration range of 1-5% cited by the Examiner from Bohannon §0111 refers to the concentration of surfactant within the dry bulking material composition, not within an aqueous enzyme reaction. These are not comparable quantities. Applicants respectfully submit that the Examiner's reliance on Bohannon for the block copolymer surfactant element of the claims is misplaced.” This argument has been thoroughly reviewed but is not considered persuasive as the teachings of Bohannon are not limited to dried bluk reagents as Bohannon teaches “[0133] Surfactants are useful as additional reagents in the bulking material. Exemplary surfactants include, for example, non-ionic surfactants and ionic surfactants. Non-ionic surfactants do not ionize in aqueous solutions. Exemplary non-ionic surfactants include sodium deoxycholate, octylglucoside, digitonin, octaethyleneglycol mono n-dodecyl ether (C12E8), lubrol, polyoxyethylated octyl phenol (Triton X-100), Ethylphenolpoly-(ethyleneglycolether) (Nonidet P-40), [Octylphenoxy]polyethoxyethanol (Nonidet P-40 substitute), polyoxyethylene sorbitan monooleate (polyoxyethylenesorbitanmonooleate) (Tween 80), polyoxyethylene sorbitan monolaureate (Tween-20), BRIG 35, dodecyl maltopyranoside, heptyl thioglucopyranoside, block-copolymer surfactants such as Pluronic and Tetronic surfactants available from BASF (e.g. Pluronic F127, Pluronic F98, Tetronic 904 and Tetronic T1307), Isotridecyl(PEG-ether).sub.8 (also referred to as Genapol X-080), N-alkanoyl-N-methylglucamide surfactants (e.g. the MEGA series surfactant including MEGA 9 AND MEGA 10), and the like. Ionic surfactants include anionic surfactants, cationic surfactants, and amphoteric surfactants. Useful anionic surfactants include, for example, sodium dodecyl sulfate, cholate and deoxycholate, and the like. Exemplary cation surfactants include cetyltrimethyl-ammonium bromide (CTAB) and the like. Amphoteric surfactants useful in the present invention include, for example, LysoPC, CHAPS, Zwittergent 3-14, and the like.” Thus the teachings are not limited to dried surfancants. Further Chou teaches specifically envisions pluronic solutions.
The response traverses the rejection by conceding Palsoske and Green identify the problem.
The response continues by asserting, “that the Examiner had established a prima facie case of obviousness (which Applicants deny) the specification provides compelling experimental evidence of unexpected results that rebuts any such showing. Examples 6a and 6b of the specification (paragraphs 0061-0063) demonstrate that adding a PEO-PPO-PEO block copolymer surfactant to the aqueous RNA reaction mixture at concentrations of 0.5-1% (v/v) produced a dramatically unexpected enhancement in assay sensitivity. Specifically, without surfactant (using only Tween-20),” This argument has been thoroughly reviewed but is not considered persuasive as the alleged unexpected result is not commensurate in scope with the claimed invention. Specifically the independent claim is not limited to PEO-PPO-PEO block copolymer surfactant or any specific concentration of surfactant. Further the independent claim encompasses any RNA and any affinity tags, not those specific to example 6. Thus the rejection is maintained.
The response traverses the rejection asserting there is no reasonable expectation of success. The response specifically alleges, “skilled artisan would face substantial uncertainty as to whether: (i) an RNA oligonucleotide bearing two different affinity tags would function as a stable molecular bridge between nanoparticles and a test line at nanomolar concentrations; (ii) RNase cleavage of the RNA would produce a measurable, reproducible signal change in the specific format claimed; and (iii) a block copolymer surfactant in the liquid reaction mixture would enhance rather than disrupt nanoparticle-RNA-test line binding kinetics. The extensive optimization experiments described in the specification, including evaluating RNA lengths of 6 to 30 nucleotides (Example 5), multiple buffer systems (Examples 1-4), and a dose-response series for the surfactant (Examples 6a and 6b), demonstrate that this was not a trivial combination achievable by routine experimentation. “ This argument has been thoroughly reviewed but is not considered persuasive as the response concedes the experiments are optimization. Further 2143.02(II) states:
Obviousness does not require absolute predictability, however, at least some degree of predictability is required.
Obviousness cannot be avoided simply by a showing of some degree of unpredictability in the art so long as there was a reasonable probability of success. See In re Corkill, 771 F.2d 1496, 1500 (Fed.Cir.1985) ("Although [the inventor] declared that it cannot be predicted how any candidate will work in a detergent composition, but that it must be tested, this does not overcome [the prior art's] teaching that hydrated zeolites will work."); see also Brown & Williamson Tobacco Corp. v. Philip Morris Inc., 229 F.3d 1120, 1125 (Fed.Cir.2000); Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 809 (Fed.Cir.1989); In re Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed.Cir. 1986). Indeed, a rule of law equating optimization with patentability is in consistent with obviousness standards. This cannot be the proper standard since the expectation of success need only be reasonable, not absolute. Merck, 874 F.2d at 809; In re O'Farrell, 853 F.2d 894, 903 (Fed.Cir. 1988). The evidence would convince a reasonable finder of fact that the skilled artisan would have had a reasonable expectation of success of performing an LFIA to detect RNase by use of an RNA with two affinity tags and would work for its intended purpose. See In re Rinehart, 531 F.2d 1048, 1053-54 (C.C.P.A.1976).
Office personnel should not withdraw any rejection solely on the basis that the invention lies in a technological area ordinarily considered to be unpredictable. See MPEP § 2145(X)(E).
Summary
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEVEN C POHNERT PhD whose telephone number is (571)272-3803. The examiner can normally be reached Monday- Friday about 6:00 AM-5:00 PM, every second Friday off.
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/Steven Pohnert/Primary Examiner, Art Unit 1683
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