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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application claims benefit of Foreign Application ITALY 102021000000533 filed 01/13/2021. Based on the filing receipt, the effective filing date of this application is January 13, 2021, which is the filing date of Foreign Application ITALY 102021000000533 from which the benefit of priority is claimed.
Information Disclosure Statement
The information disclosure statement filed 07/10/2023 has been considered by the examiner.
Status of Claims
Claims 26-27 are cancelled.
Claims 1-25 and 28-33 are pending and examined herein.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that use the word “means,” and are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitations uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitations are:
A “means for processing an electric signal produced by said one or more biosensors, configured to detect said electric signal and to process it in output data comprising information about the presence of viral particles in said biological sample” in claim 22; and
A “means for transmitting said information associated to said processing means” in claim 24.
Because these claim limitations are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, they are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
The “means for processing an electric signal produced by said one or more biosensors, configured to detect said electric signal and to process it in output data comprising information about the presence of viral particles in said biological sample” in claim 22 is interpreted as “amplifying systems, filter, electric meters, multipliers and/or any other processing means known in the art” from p. 16-17 of the applicant’s specification.
The “means for transmitting said information associated to said processing means” in claim 24 is interpreted as “at least one between displaying unit of said output data, for example a screen, and/or radio frequency transmission unit, for example a unit for transmitting by Wi-Fi, Bluetooth or infrared; and/or serial transfer unit, for example a USB port” from p. 17 of the applicant’s specification.
If applicant does not intend to have these limitations interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitations to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitations recite sufficient structure to perform the claimed function so as to avoid them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claim Objections
Claim 18 is objected to because of the following informalities:
Claim 18 recites, “said protein is the ACE2 enzyme having sequence SEQ ID Nr. 1”. The claim should recite, “said protein is the ACE2 enzyme having sequence SEQ ID NO: 1”.
Claim 21 recites, “a biological sample to be analysed”. The claim should recite, “a biological sample to be analyzed”. British spellings should be removed.
Claim 29 recites, “said biological sample to be analysed”. The claim should recite, “said biological sample to be analyzed”. British spellings should be removed.
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 1-25 and 28-33 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 claims 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 inventors, 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: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. See MPEP 2163.
Claims 1 and 32 are directed to a protein capable of specifically binding a viral particle and/or a fragment thereof. Claim 2 is directed to a protein capable of specifically binding a viral particle of SARS-CoV-2 and/or a fragment thereof. Claims 13 and 31 are directed to a protein that binds to the S1 subunit of the SARS-CoV-2 Spike protein.
The scope of the claims therefore cover proteins for detecting a large genus of analytes characterized by substantial variability; and further uses a large genus of proteins that bind the analytes.
Regarding the predictability or unpredictability in the art, Sahni (“Challenges in predicting protein-protein interactions of understudied viruses: Arenavirus-human interactions”, published 2025-11-21) teaches that predicting protein-protein interactions across understudied viruses presents a significant challenge (see, e.g., p. 5401, under “ABSTRACT”). Sahni continues, “Our findings underscore the importance of employing rigorous evaluation methods, such as viral protein specific evaluation in conjunction with independent testing, particularly for minority classes” (see, p. 5410, col. 2, para. 2). Sahni gives evidence that protein binding of viruses has a low level of predictability.
The specification discloses the actual reduction to practice of only a few proteins capable of specifically binding a viral particle, the angiotensin-converting enzyme 2 (ACE2) receptor and nanobodies (see, e.g., under “Example 3 – Functionalization of the graphene substrate”, p. 23-24). The number of proteins reduced to practice is insufficient to properly describe the entire genus of proteins capable of binding viral particles or, even more narrowly, the entire genus of proteins capable of binding the S1 subunit of the SARS-CoV-2 Spike protein.
On p. 11, the applicant’s specification incorporates by reference nanobodies capable of binding to a viral particle of SARS-CoV-2: “Not limiting examples of nanobodies which can be used for implementing a biosensor according to the present invention are nanobodies as described in the following scientific publications herein integrally incorporated by reference Hanke L et al. "An alpaca nanobody neutralizes SARS-CoV-2 by blocking receptor interaction" Nat. Comm. 11, N. 4420 (2020); Huo J. et al. "Neutralizing nanobodies bind SARS-CoV-2 spike RBD and block interaction with ACE2" Nat. Structural & Molec.15Biol., 27, 846-854 (20); Schoof M. et al. "An ultrapotent synthetic nanobody neutralizes SARS- CoV-2 by stabilizing inactive Spike", Science, Vol. 370, Issue 6523, pages 1473-1479 (2020); Xiang Y. et al. "Versatile and multivalent nanobodies efficiently neutralize SARS-CoV-2", Science, Vol. 370, Issue 6523, pages 1479-1484 (2020)”. While the nanobodies incorporated by reference describe the limitations of claim 16, the proteins of claims 1-2, 13, and 31-32 are larger in scope than nanobodies alone.
The specification’s disclosure of general methods that might be used to make proteins capable of specifically binding viral particles is insufficient to describe the claimed genus of proteins. See p. 10 of the applicant’s specification: “Viral receptors suitable to be used for the functionalization of a biosensor according to the present invention are recombinant viral receptors, that is produced in recombinant way within host cells by using standard methods known in the art”. The Federal Circuit addressed an analogous situation in University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004), finding that disclosure of “assays for screening compounds, including peptides, polynucleotides, and small organic molecules to identify those that inhibit the expression or activity of the PGHS-2 gene product,” did not satisfy the written description requirement for claims requiring administration of a “compound that selectively inhibits PGHS-2.” Rochester, 119 F.3d at 918, 927; see also Ariad Pharmaceuticals, Inc., v. Eli Lilly and Company, 598 F.3d 1336, 1344 (Fed. Cir. 2010) (recognizing distinction between requirements for written description and enablement).
Furthermore, there is also no disclosure of any partial structure common to the members of the genus of proteins that would correlate with function (in this case, the claimed function of selectively binding to the “binding agent-analyte complex”). The applicant’s specification on p. 8-9, merely discloses, “Under the term "protein capable of specifically binding a viral particle and/or a fragment thereof" a protein is meant which has a specific affinity for a virus portion, for example it is capable of binding a viral protein with a dissociation constant lower than 10 mM, preferably lower than 100 nM, measured for example by means of an in-vitro binding assay”. The specification is only further describing the functional characteristics of the broad genus of proteins.
The importance of structure/function correlations was recently highlighted by the courts (Abbvie Deutschland v. Janssen Biotech and Centocor Biologics, App. No. 2013-1338, -1346 (Fed. Cir., July 1, 2014)). The Abbvie case involved antibodies and written description. The court stated: “We have held that “a sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id. at 1350 (quoting Eli Lilly, 119 F.3d at 1568– 69).”. The courts then further stated: “With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus.” and then state: " Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein). It is true that functionally defined claims can meet the written description requirement if a reasonable structure-function correlation is established, whether by the inventor as described in the specification or known in the art at the time of the filing date. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 964 (Fed. Cir. 2002).
There is no partial structure or other identifying characteristics disclosed, common to the members of the genus of proteins having sufficiently high binding affinity, that would allow one skilled in the art to envision that Appellant has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus.
For all of these reasons, the specification does not demonstrate possession of the entire genus of proteins having the claimed functional characteristics.
Claims 3-12, 14-25, 28-30, and 33 are rejected for failing to meet the written description requirement because they depend on independent claim 1.
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 15-16 and 33 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 recites the limitation "The biosensor according to claim 1, wherein said graphene-based chip consists of” in the body of the claim. However, no “graphene-based chip” was set forth in independent claim 1. Therefore, there is insufficient antecedent basis for this limitation in the claim.
Claim 16 contains the trademark/trade name nanobodyTM. 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 describe a protein and, accordingly, the description is indefinite.
Claim 33 recites the limitation "The kit for the detection of a viral particle and/or a fragment thereof and/or for the diagnosis of a viral infection comprising a biosensor according to claim 1” in the preamble of the claim. However, no “kit” was set forth in independent claim 1. Therefore, there is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4, 12, and 28-30 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Seo. (“Rapid Detection of COVID-19 Causative Virus (SARS-CoV-2) in Human Nasopharyngeal Swab Specimens Using Field-Effect Transistor Based Biosensor”, published 2020-04-15, cited in IDS filed 07/10/2023).
With respect to claim 1, Seo teaches a field-effect transistor (FET) biosensor for the detection of viral particles comprising a substrate and a protein capable of specifically binding a viral particle, immobilized on the surface of said substrate, wherein said protein is immobilized so that the binding of a viral particle thereof to said protein determines the emission of a detectable electrical signal (see, e.g., p. 5136, under “Figure 1.”).
With respect to claim 2, Seo teaches the protein is a protein capable of specifically binding a viral particle of SARS-CoV-2 (see, e.g., p. 5136, under “Figure 1.”).
With respect to claim 3, Seo teaches the substrate is graphene (see, e.g., p. 5136, under “Figure 1.”).
With respect to claim 4, Seo teaches the protein is immobilized on the substrate surface through binding of the protein with a linker molecule conjugated to the surface of said substrate (see, e.g., p. 5136, under “Figure 1.”).
With respect to claim 12, Seo teaches the linker molecule is 1-pyrenebutyric acid N-hydroxy succinimide ester (see, e.g., p. 5137, col. 2, para. 1).
With respect to claim 28, Seo teaches a method for detecting the presence of a viral particle within a biological sample comprising the following steps: i. contacting a biological sample to be analyzed with a biosensor of claim 1; and ii. detecting binding reactions with a viral particle means of an electrical signal emitted by said biosensor (see, e.g., p. 5136, under “Figure 1.”).
With respect to claim 29, Seo teaches the biological sample to be analyzed is a nasopharynx and pharyngeal mucosa sample of the subject (see, e.g., p. 5136, under “Figure 1.”, and p. 5141, col. 1, under “Clinical Sample Preparation.”).
With respect to claim 30, Seo teaches a method comprising diagnosing a viral infection when the biosensor produces a detectable signal in response to binding of viral particles (see, e.g., p. 5140, col. 2, para. 1: “Taken together, our findings show that our COVID-19 FET sensor successfully detected SARS-CoV-2 virus from clinical samples without any preprocessing and with a large dynamic range”, and p. 5136, under “Figure 1.”).
Claims 1-3, 13, and 16-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang (“Electrical probing of COVID-19 spike protein receptor binding domain via a graphene field-effect transistor”, published 2020-03, cited in IDS filed 07/10/2023).
With respect to claim 1, Zhang teaches a field-effect transistor (FET) biosensor for the detection of viral particles comprising a substrate and a protein capable of specifically binding a viral particle, immobilized on the surface of said substrate, wherein said protein is immobilized so that the binding of a viral particle thereof to said protein determines the emission of a detectable electrical signal (see, e.g., p. 6, under “Figure 1.”).
With respect to claim 2, Zhang teaches the protein is a protein capable of specifically binding a viral particle of SARS-CoV-2 (see, e.g., p. 9, under “Figure 2.”).
With respect to claim 3, Zhang teaches the substrate is graphene (see, e.g., p. 6, under “Figure 1.”, and p. 9, under “Figure 2.”).
With respect to claim 13, Zhang teaches the protein is capable of binding the S1 subunit of the SARS-CoV-2 spike protein (see, e.g., p. 6, under “Figure 1.”).
With respect to claims 16-17, Zhang teaches the protein is angiotensin-converting enzyme 2 (ACE2), a viral receptor (see, e.g., p. 6, under “Figure 1.”, and p. 7, para. 2: “ACE2 is an integral membrane protein served as functional receptor for the spike glycoprotein of human coronaviruses SARS and COVID-19 infections”).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 5-8, 10, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Seo (cited above), as applied to claims 1-4, 12, and 28-30 above, and further in view of Koussa (“Protocol for sortase-mediated construction of DNA-protein hybrids and functional nanostructure”, published 2014-05-15, cited in IDS filed 07/10/2023) and Boozer (“DNA Directed Protein Immobilization on Mixed ssDNA/Oligo(ethylene glycol) Self-Assembled Monolayers for Sensitive Biosensors”, published 2004-10-22).
Seo teaches as set forth above, in addition to teaching the process for the preparation of a field-effect transistor biosensor for the detection of viral particles comprising the steps of i. Arranging a FET biosensor comprising a substrate and ii. Functionalizing the substrate with a linker, as in claim 32 (see, e.g., p. 5140, under “MATERIALS AND METHODS”, under “Fabrication of Graphene-based Sensing Devices.”, and under “Immobilization of SARS-CoV-2 Antibody on the Graphene Surface.”). But, Seo fails to teach the second oligonucleotide is immobilized on a substrate, as in claim 6. Seo fails to teach the sortase-mediated conjugation of a first oligonucleotide to a protein then hybridizing the first oligonucleotide to a second oligonucleotide immobilized on a substrate through a linker, wherein the 5’ end of the first oligonucleotide is conjugated to the C-terminal portion of the protein, as in claims 5-8. Seo fails to teach the steps of the process for the preparation of a field-effect transistor biosensor comprising a linker binding a first single-stranded oligonucleotide, binding a protein to a second single-stranded oligonucleotide that is complementary to the first single-stranded oligonucleotide, and hybridizing the first and second single-stranded oligonucleotides, as in claim 32.
However, Boozer teaches a first oligonucleotide conjugated to a protein then hybridizing the first oligonucleotide to a second oligonucleotide immobilized on a substrate, as in claim 6 (see, e.g., p. 6968, under “Figure 1”).
Boozer teaches the steps of the process for the preparation of a field-effect transistor biosensor comprising a linker binding a first single-stranded oligonucleotide, binding a protein to a second single-stranded oligonucleotide that is complementary to the first single-stranded oligonucleotide, and hybridizing the first and second single-stranded oligonucleotides, as in claim 32 (see, e.g., p. 6968, under “Figure 1”).
In addition, Koussa teaches the sortase-mediated conjugation of a first oligonucleotide to a protein then hybridizing the first oligonucleotide to a second oligonucleotide, wherein the 5’ end of the first oligonucleotide is conjugated to the C-terminal portion of the protein, as in claims 5-8 (see, e.g., sortase mediated conjugation – p. 3, para. 2: “In this in vitro system Sortase covalently links the N-terminus of one protein to a location near (within ~100 amino acids of) the C-terminus of another protein. Sortase recognizes an N-terminal GGG and a C-terminal LPX1TGX2, where X1 can be any amino acid, and X2 can be any string of amino acids of length 1-99”; conjugation of the first oligonucleotide to a protein – p. 4, under “2.1 Protocol for the formation of oligonucleotides with sortase-compatible GGG peptide”, and p. 5-6, under “2.2 Protocol for sortase coupling LPETG-tagged proteins to GGG-oligonucleotides”; hybridizing the first oligonucleotide to a second oligonucleotide – p. 7, under “2.3 Protocol for hybridization of DNA-protein hybrid to scaffold (Thermostable Proteins)”, and p. 7-9, under “2.4 Protocol for hybridization of DNA-protein hybrid to scaffold (Non-thermostable Proteins)”; wherein the 5’ end of the first oligonucleotide is conjugated to the C-terminal portion of the protein – p. 4, under “2. Methods”: “We ordered oligo 1 with a 3′-azide and oligo 2 was ordered with a 5′ azide”, and p. 3, para. 2: “Sortase recognizes an N-terminal GGG and a C-terminal LPX1TGX2, where X1 can be any amino acid, and X2 can be any string of amino acids of length 1-99”).
Seo and Boozer are analogous to the field of the claimed invention because they are both in the field of bioconjugation. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use the DNA-directed protein immobilization of Boozer in the biosensor of Seo. An artisan would have been motivated to do so because Boozer discloses, “Compared to standard antibody immobilization techniques, this approach offers many advantages. The exceptional specificity of DNA hybridization combined with the diversity of potential sequences makes this platform perfect for multichannel sensors. Once a surface is patterned with the appropriate probe sequences, sequence-specific hybridization will sort out the target conjugates and direct them to the appropriate spots on the surface. In addition, the DNA SAMs are very stable and well suited to recycling by dehybdridization of the conjugates from the surface-bound probes. In this work, we demonstrate the specificity, sensitivity, and convenience of using protein-DNA conjugates to convert a DNA/ OEG SAM surface into a biosensor surface” (see, p. 6967, under abstract). An artisan would have been motivated to use the DNA-directed protein immobilization of Boozer in the biosensor of Seo because of all of the “many advantages” disclosed by Boozer. An artisan would have had a reasonable expectation of success based on the given disclosures.
Seo, Boozer, and Koussa are analogous to the field of the claimed invention because they are all in the field of bioconjugation. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate the technique of Koussa into the biosensor of Seo modified by Boozer. With the technique of Koussa, an artisan would have been able to immobilize the antibody of Seo onto the substrate of Seo modified by Boozer. An artisan would have been motivated to do so because Koussa discloses their technique allows for “covalently coupling proteins to DNA with minimal disturbance to protein function. […] Our protocol allows for the simple coupling and purification of a functional DNA-protein hybrid” (see, p. 1, under “Abstract”). An artisan would have had a reasonable expectation of success based on the given disclosures.
With regards to claim 7, when binding the 5’-end of the first oligonucleotide to the C-terminal portion of the protein, Koussa does not explicitly teach using the 5’-end, but they disclose, “We ordered oligo 1 with a 3′-azide and oligo 2 was ordered with a 5′ azide” (see p. 4, under “2. Methods”). Koussa discloses, “For this system selective coupling was achieved using the Flag-tag as a protecting group. That is, Oligo 1 was processed fully, resulting in a GGG-oligo, while Oligo 2 did not undergo TEV cleavage of its Flag tag” (see, p. 7, under “2.4 Protocol for hybridization of DNA-protein hybrid to scaffold (Non-thermostable Proteins)”). While Koussa uses oligo 1 with the 3’-end for the sortase-compatible GGG-oligo, Koussa had the 5’-end oligo 2 available to use. An artisan with ordinary skill in the art would have recognized that using the 5’-end for the sortase-mediated conjugation would have been obvious to try, given that there were only two options for which end to use for conjugation, the 3’-end or the 5’-end. An artisan would have had a reasonable expectation of success based on the given disclosures.
With regards to claim 10, Seo, Boozer, and Koussa does not explicitly disclose the first and second oligonucleotides consist of a number of bases comprised between 6 to 8. Boozer discloses the sequences with 21 bases (see, e.g., p. 6969, under “Table 1. DNA Sequencesa”). However, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to perform routine optimization of the components in the claimed invention to make and use the claimed invention. As noted in In re Aller, 105 USPQ 233 at 235, more particularly, where 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. Routine optimization is not considered inventive and no evidence has been presented that arriving at the claimed number of bases was anything other than routine, that the properties of the number of bases from the optimization has any unexpected properties, or that the results should be considered unexpected in any way as compared to the closest prior art. Optimization of parameters is a routine practice that would be obvious for the artisan to employ. See MPEP § 2144.05. The artisan would have had a reasonable expectation of success based on the cumulative disclosure of Seo, Boozer, and Koussa.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Seo (cited above), Boozer (cited above), and Koussa (cited above), as applied to claims 5-8, 10, and 32 above, and further in view of Meyer (“Advances in DNA-directed immobilization”, published 2013-11-21).
Seo, Boozer, and Koussa teaches as set forth above. In addition, Boozer teaches that the 5’-end of the second oligonucleotide comprises a thiol group (see, e.g., p. 6969, under “Table 1. DNA Sequencesa”).
However, Seo, Boozer, and Koussa fail to teach the second oligonucleotide comprises an amino group at the 5’-end capable of binding the linker molecule conjugated to the surface of the substrate, as in claim 9. However, Meyer teaches oligonucleotides comprising amino groups for conjugations in DNA-directed immobilization, as in claim 9 (see, e.g., p. 9, under “Table 1”, under “DNA modification”, “alkylamino”).
Seo, Boozer, Koussa, and Meyer are analogous to the field of the claimed invention because they are all in the field of bioconjugation. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to substitute the thiol group of Seo as modified by Boozer and Koussa with the amino group listed in Meyer. An artisan would have recognized that the amino group would be obvious to try when choosing from the finite number of identified, predictable solutions disclosed by “Table 1” of Meyer. An artisan would have had a reasonable expectation of success based on the given disclosures.
Claims 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Seo (cited above), as applied to claims 1-4, 12, and 28-30 above, and further in view of Hayashi (“High On-Off Ratio Graphene Switch via Electrical Double Layer Gating”, publication 2020-05-14) and Graphenea (“Reinforcing Ceramics with Graphene for Increased Strength and Conductivity”, published 2018-09-07) as evidenced by the Technical Datasheet for Graphenea’s Graphene Field-Effect Transistor Chip: GFET S-20 (published 2024).
Seo teaches as set forth above, but fails to teach the biosensor is a graphene-based chip having dimensions equal to 10 mm x 10 mm consisting of 12 graphene-based field-effect transistors, as in claims 14-15.
However, Hayashi teaches using a commercial biosensor from Graphenea, a graphene-based chip having dimensions equal to 10 mm x 10 mm and consisting of 12 graphene-based field-effect transistors, as in claims 14-15 (see, e.g., p. 92315, col. 1, under “II. METHODS”, para. 1). GFET S-20 gives evidence that the Hayashi graphene field-effect transistors are from a graphene-based chip having dimensions equal to 10 mm x 10 mm consisting of 12 graphene-based field-effect transistors, as in claims 14-15 (see, e.g., p. 1, under “Typical Specification”).
Seo, Hayashi, and Graphenea are analogous to the field of the claimed invention because they are all in the field of field-effect transistors. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use the commercial field-effect transistor biosensors referenced by Hayashi in the biosensor of Seo. An artisan would have been motivated to do so because Graphenea teaches that “Graphenea is a leading graphene producer for industrial and research needs. Graphenea has developed a leading synthesis and transfer process to obtain high uniformity monolayer graphene films on any substrate” (see, p. 3, under “About Graphenea”). An artisan would have recognized the benefits offered by the field-effect transistors of Graphenea when making/using the biosensor of Seo. An artisan would have had a reasonable expectation of success based on the given disclosures.
Claims 19-25 are rejected under 35 U.S.C. 103 as being unpatentable over Seo (cited above), as applied to claims 1-4, 12, and 28-30 above, and further in view of Ke (“An accurate, high-speed, portable bifunctional electrical detector for COVID-19”, published 2020-12-29), Sinha (“An integrated microfluidic system with field-effect-transistor sensor arrays for detecting multiple cardiovascular biomarkers from clinical samples”, published 2019-03-15), and Voitsekhivska (“CMOS Multiplexer for Portable Biosensing System with Integrated Microfluidic Interface”, published 2014).
Seo teaches as set forth above, but fails to teach a portable device comprising a biosensor according to claim 1 in an antechamber configured to hold a biological sample to be analyzed and capable of processing an electrical signal to output data comprising information about the presence of viral particles in the biological sample, as in claims 19 and 21-22. Seo fails to teach the device comprises a multiplexer and/or one or more filters, as in claim 23. Seo fails to teach means for transmitting the information associated to the processing means, as in claim 24. Seo fails to teach a displaying unit of the output data, as in claim 25.
However, Ke teaches a portable device comprising a field-effect transistor biosensor in an antechamber to hold a biological sample, and capable of processing an electrical signal to output data comprising information about the presence of viral particles in the biological sample then transmitting that data, as in claims 19, 21-22, and 24 (see, e.g., p. portable device comprising antechamber and transmitting data – p. 741, under “Figure 1” (see below); capable of processing an electrical signal to output data comprising information about the presence of viral particles in the biological sample – p. 740, col. 2, para. 1: “As shown in Fig. 1, the detection system mainly consists of two parts: a plug-and play packaged biosensor chip and a home-developed electrical measurement machine”). It is understood that the electrical measurement machine of Ke meets the 35 U.S.C. 112(f) interpretation of claim 22 as discussed above. It is understood that the display of Ke meets the 35 U.S.C. 112(f) interpretation of claim 24 as discussed above. Ke teaches a displaying unit of the output data, as in claim 25 (see, e.g., p. 741, under “Figure 1” – see below).
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Seo and Ke fail to teach an array of biosensors with processing means comprising a multiplexer, as in claims 20.
However, Sinha teaches a device with an array of field-effect transistors, as in claim 20 (see, e.g., p. 156, under “Fig. 1.”, panel “(d)”, and p. 161, under “Fig. 5.”). It is understood that array of biosensors is a series of biosensors based on p. 16, lines 7-8 of the applicant’s specification.
Seo, Ke, and Sinha fail to teach the processing means comprises a multiplexer, as in claim 23.
However, Voitsekhivska teaches a portable biosensing system with processing means comprising a multiplexer to connect each sensor-FETs on the biochip individually, as in claim 23 (see, e.g., p. 173, under “Abstract”).
Seo and Ke are analogous to the field of the claimed invention because they are both in the field of field-effect transistors. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to integrate the portable device of Ke into the biosensor of Seo. An artisan would have been motivated to do so because Ke discloses the portable device “enable[s] high-throughput point-of-care testing, which may facilitate management of the current severe public health crisis. We are firmly of the opinion that this detection system offers a universal methodology that is ready for immediate application and rapid detection of various biomolecules and viruses, such as nucleic acids, proteins, biomarkers, SARS, swine flu, Ebola, and MERS” (see, p. 746, col. 1, para. 1). An artisan would have had a reasonable expectation of success based on the given disclosures.
Seo, Ke, and Sinha are analogous to the field of the claimed invention because they are all in the field of field-effect transistors. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate the array of field-effect transistors of Sinha into the device of Seo modified by Ke. An artisan would have been motivated to do so because Sinha discloses, “To the best of our knowledge, this is the only reported setup capable of detecting four CVDs protein biomarkers from a single clinical sample in an area of only 4.0×3.3cm. Given the high demand for POC systems (Chin et al., 2012), this type of multiple-analyte detector could play an important role, either alongside, or in place of, more traditional, commercial systems (Table 1: De Moraes and Kubota, 2016) for CVDs diagnostics. Furthermore, it could be readily modified to feature immobilized aptamer probes specific to biomarkers diagnostic of other life-threatening illnesses”. An artisan would have had a reasonable expectation of success based on the given disclosures.
Seo, Ke, Sinha, and Voitsekhivska are analogous to the field of the claimed invention because they are all in the field of field-effect transistors. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to incorporate the multiplexer of Voitsekhivska into the device of Seo as modified by Ke and Sinha. An artisan would have been motivated to do because Voitsekhivska discloses, “Employing the proposed CMOS multiplexer allows simpler, more rapid and more accurate measurements comparing with the previous lab-scale setup” (see, p. 173, under “Abstract”, para. 2). An artisan would have had a reasonable expectation of success based on the given disclosures.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Seo (cited above) as applied to claims 1-4, 12, and 28-30 above, and further in view of Zhang (cited above).
Seo teaches as set forth above, but fails to teach the protein binds to the S1 subunit of the SARS-CoV-2 Spike protein, as in claim 31.
However, Zhang teaches a field-effect transistor biosensor with a protein that binds to the S1 subunit of the SARS-CoV-2 Spike protein, as in claim 31 (see, e.g., p. 6, under “Figure 1.”).
Seo and Zhang are analogous to the field of the claimed invention because they are both in the field of field-effect transistor biosensors for SARS-CoV-2. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to use the protein that binds to the S1 subunit of the SARS-CoV-2 Spike protein of Zhang into the biosensor of Seo. An artisan would have been motivated to do so because Zhang disclose, “Further studies confirms [sic] that COVID-19 infects the human respiratory epithelial cells through the S1 subunit protein, which mainly contains a receptor binding domain (RBD) interacting with the human angiotensin-converting enzyme 2 (ACE2)” (see, p. 4, para. 1). An artisan would have had a reasonable expectation of success based on the given disclosures.
Claim 33 is rejected under 35 U.S.C. 103 as being unpatentable over Seo (cited above) as applied to claims 1-4, 12, and 28-30 above, and further in view of Zuk (US Patent Number 4,208,479, published 1980-06-17).
Seo teaches as set forth above, in addition to teaching a control reagent, specifically Graphene-based FET without SARS-CoV-2 antibody is presented as negative control, as in claim 33 (see, e.g., p. 5138, under “Figure 4.”). But, Seo fails explicitly disclose the biosensor as a “kit”.
However, Zuk teaches that in performing assays, it is convenient and to combine the necessary reagents together in a kit (see, e.g., col. 22, lines 20-68). Zuk further teaches that this may improve assay accuracy (see, e.g., col. 22, lines 20-68).
Seo and Zuk are analogous to the field of the claimed invention because they are all in the field of immunoassays. One of ordinary skill in the art before the effective filing date of the application would have found it obvious to provide the reagents of Seo together in kit form for convenience and accuracy as taught by Zuk. An artisan would have had a reasonable expectation of success based on the given disclosures.
Conclusion
Claims 11 and 18 are free of the prior art, but are rejected on the grounds of 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 closest prior art to claims 11 and 18 is Seo (cited above). Seo teaches a field-effect transistor (FET) biosensor for the detection of viral particles comprising a substrate and a protein capable of specifically binding a viral particle, immobilized on the surface of said substrate, wherein said protein is immobilized so that the binding of a viral particle thereof to said protein determines the emission of a detectable electrical signal (see, e.g., p. 5136, under “Figure 1.”). Seo teaches the protein is a protein capable of specifically binding a viral particle of SARS-CoV-2 (see, e.g., p. 5136, under “Figure 1.”). Seo teaches the substrate is graphene (see, e.g., p. 5136, under “Figure 1.”). Seo teaches the protein is immobilized on the substrate surface through binding of the protein with a linker molecule conjugated to the surface of said substrate (see, e.g., p. 5136, under “Figure 1.”). Seo teaches the linker molecule is 1-pyrenebutyric acid N-hydroxy succinimide ester (see, e.g., p. 5137, col. 2, para. 1).
However, Seo fails to teach wherein said first oligonucleotide has the sequence 5'-GCACTG-3' and said second oligonucleotide has the sequence 5'-CAGTGC-3', wherein said second oligonucleotide comprises an amino group at the 5'-end, as in claim 11.
Seo fails to teach said protein is the ACE2 enzyme having sequence SEQ ID NO: 1, wherein one or more of the following mutations are inserted in the sequence of said enzyme: T27Y, L79T, N330Y, as in claim 18.
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/MICHAEL CAMERON SVEIVEN/ Examiner, Art Unit 1678
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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