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
The instant claims are entitled to an effective filing date of 12/20/2018.
DETAILED ACTION
Claims 2-19 and 28 are canceled. Claims 1, 20-27, and 29-34 are pending and under consideration in this action.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites “SEQ ID No.” in line 7, which should be replaced with “SEQ ID NO:” so that the sequence identifiers are consistent throughout the claim. MPEP 608.01(m) states that periods may not be used elsewhere in the claims except for abbreviations. Although “No.” is an abbreviation for number, claim 1 also uses “NO” as an abbreviation for number. Therefore, the sequences should be consistently identified with their corresponding “SEQ ID NO:”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 25-27 and 32-33 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 25-27 broaden the scope of the composition required in claim 1. Claim 1, as amended, requires a “composition consisting of” (line 5) the recited elements. Claim 1 requires the composition to contain a mutated glycine/glyphosate oxidase from marine bacteria Bacillus licheniformis BliGO-SCF-4 having the sequence SEQ ID No. 4, or a tagged BliGO-SCF-4 selected from: GST-BliGO-SCF-4 (SEQ ID NOs: 7 or 8) or SUMO-BliGO-SCF-4 (SEQ ID NO: 11 or 12). Claim 25 recites “wherein said glycine/glyphosate oxidase BliGO-SCF-4 comprises a tag which is fused to the glycine/glyphosate oxidase enzyme”. Claim 25 broadens the scope of the composition required in claim 1, because claim 25 recites the open-ended term “comprises”, and because claim 25 does not require the tagged BliGO-SCF-4 to be GST-BliGO-SCF-4 or SUMO-BliGO-SCF-4. Claims 26-27 depends from claim 25, which in turn depends upon claim 1. Claim 26 does not further limit the composition of claim 1, because claim 26 encompasses composition embodiments with additional tags. Specifically, claim 26 encompasses the following tags: maltose-binding protein, chitin binding protein, GST, thioredoxin, NUS A, ubiquitin, or SUMO tags. Claim 27 recites “the tag is a SUMO or a GST tag”. However, claim 27 does not limit the SUMO or GST tagged BliGO-SCF-4 to the GST-BliGO-SCF-4 (SEQ ID NOs: 7 or 8) or SUMO-BliGO-SCF-4 (SEQ ID NO: 11 or 12) of claim 1. Accordingly, claims 25-27 fail to further limit the subject matter of claim 1, from which claims 25-27 depend.
Claims 32-33 broaden the scope of the composition required in claim 1. Claim 1 recites a “composition consisting of” in line 5. Claim 1 requires the composition to contain “encapsulated in a vesicle, a peroxidase and a substrate of said peroxidase which can be oxidized” (line 16). Claims 32 recites “wherein the vesicle is trapped in a porous polymeric gel”, which broadens the scope of the required composition in claim 1 because the porous polymeric gel is an additional element. Claim 33 depends from claim 32 and requires the porous polymeric gel to be selected from alginate, chitosan, PVP, PVA, agarose, gel or mixture thereof. As such, claims 32-33 fail to further limit the composition of claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 1, 20-23, 25-27, 29-31 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Molina (WO 2017/178896) in view of Zhang (Enzyme and Microbial Technology, 2016 85, 12-18; in IDS 03/21/2024) and Rosini (The FEBS Journal, 2014, 281(15), 3460-3472.) with evidence from Gillezeau (Environ Health. 2019 Jan 7;18(1):2), Dunstan (Nutr J. 2017 Mar 23;16(1):19), Uniprot.org, accessed 8/26/2024 (hereafter Uniprot, as relied upon in the action mailed 09/13/2024), and Ding (The Journal of Physical Chemistry B 2015 119 (49), 15263-15274).
Regarding claims 1 and 34, Molina teaches a method for the identification and/or the quantification of a compound in a sample, comprising the steps of: a) bringing into contact a micro/nanoscale biosynthetic device with a sample susceptible to contain said compound to generate a mixture, b) incubating said mixture in conditions adapted for the performance of at least one biochemical reaction to generate at least said readable/measurable physiochemical output signal, wherein said output signal being indicative of the presence and/or the level of the compound to be analyzed in said sample, c) detecting or measuring the output signal. See claim 9. The device comprises at least two compatible biomolecular elements, for instance two compatible enzymes. See claim 5. Said device comprises at least two different microenvironments, this device being capable of biosensing at least two different biomolecular signals. See claim 6. The biomolecular elements are spatially encapsulated within a liposome (e.g. a vesicle). See claim 7. Molina teaches encapsulated biochemical elements selected from the group consisting of enzymes and/or metabolites preferably selected from a list that includes a horse radish-peroxidase enzyme and metabolites including NADH and ABTS (peroxidase substrates). See claim 15. In table 2, Molina teaches horseradish peroxidase and its substrates NADH, ABTS and amplex red (peroxidase substrates). Molina teaches samples selected from urine, serum, blood, foods, raw materials and environmental sample. See page 11 lines 20-21.
Evidentiary reference Gillezeau discloses that glyphosate may be present in the urine of individuals from the general public. See the abstract, table 1 and figure 3. Evidentiary reference Dustan discloses that the amino acid glycine is present as a urinary amino acid. See the abstract, the first full paragraph on page 5, and table 2. Thus, the urine samples of Molina are inherently susceptible to containing glyphosate and glycine, as evidenced by Gillezeau and Dunstan respectively.
Molina does not teach BliGO-SCF-4 that has the sequence of SEQ ID NO: 4 or a tagged BliGO-SCF-4 selected from: the GST-BliGO-SCF-4 having the DNA sequence SEQ ID NO: 7 or the amino acid sequence SEQ ID NO:8; or the SUMO-BliGO-SCF-4 having the DNA sequence SEQ ID NO: 11 or the amino acid sequence SEQ ID NO: 12; and a glycine oxidase H244K from Bacillus subtilis.
Zhang teaches a BliGO mutant, SCF-4, with six amino acid substitutions. See section 3.2 and table 2. The amino acid substitutions include G51S, A54R, K81R, S202C, I332V and M342V. See table 2. Zhang discloses that the nucleotide sequence of the BliGO gene [wild type] is submitted under the GenBank accession number KCB831746. See section 3.1. As evidenced by UniProt, the corresponding protein sequence of KCB831746 is S5FMM4. The S5MM4 protein sequence is a 98.4% best local similarity match with instant SEQ ID NO:4. The only mismatched amino acid residues correspond to the G51S, A54R, K81R, S202C, I332V and M342V substitutions described for the SCF-4 mutant of Zhang. See the alignment between instant SEQ ID NO:4 (top) and the wild-type BliGO protein sequence S5FMM4 described below, where the boxed residues represent the point mutations for the SCF-4 mutant. Zhang discloses that SCF-4 shows a 7.1-fold increase in substrate affinity and an 8-fold improvement of catalytic efficiency towards glyphosate. See the sentence spanning the left and right columns on page 15. Therefore, Zhang’s SCF-4 mutant (Table 2) is the
PNG
media_image1.png
576
640
media_image1.png
Greyscale
same as the claimed BliGO-SCF-4 that has the sequence of SEQ ID NO: 4.
Molina and Zhang do not teach the glycine oxidase H244K from Bacillus subtilis.
Rosini teaches engineering glycine oxidase from Bacillus subtilis (GO) to improve its kinetic efficiency on glycine and sarcosine in biological fluids. See the first 5 lines on page 3461. Rosini discloses that the kinetic efficiency on glycine increased from 860 M-1·S-1 for the wild-type to 9650 M-1·S-1 -for the H244K GO variant. See the first full paragraph on page 3462, table 2 and figure 2a. Rosini teaches a schematic representation of the biosensor for fluorometric determination of glycine and sarcosine, where the yellow working cuvette contains 0.1 µM GO variants (e.g. H244K variant) and the substrate glycine/sarcosine. See figures 4a, 4c and the left column on page 3467.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to substitute the SCF-4 of Zhang and the H244K GO of Rosini for the at least two compatible biomolecular elements (e.g. enzymes) in the device of Molina. One would be motivated to use the SCF-4 of Zhang as a biomolecular element in the device of Molina because Zhang discloses that the SCF-4 shows an 8-fold improvement of catalytic efficiency towards glyphosate. There would be a reasonable expectation of success because Molina teaches identifying and/or the quantifying a compound in a sample, such as a urine sample, which is inherently susceptible to containing glyphosate as evidenced by Gillezeau. One would be further motivated to use the H244K GO of Rosini as a biomolecular element in the device of Molina because Rosini indicates that the H244K GO variant exhibits increased kinetic efficiency on glycine compared to the wild-type GO. There would be a reasonable expectation of success because Rosini demonstrates detecting glycine in a yellow working cuvette (i.e. a yellow dyed liquid) via fluorimetric determination, and Molina teaches using the device to identify and/or quantify a compound in a sample, such as a urine sample (e.g. a yellow liquid).
Regarding claim 20, Molina teaches encapsulated biochemical elements selected from the group consisting of enzymes and/or metabolites preferably selected from a list that includes a horse radish-peroxidase enzyme (e.g. a peroxidase) and metabolites including NADH and ABTS (e.g. peroxidase substrates). See claim 15. In table 2, Molina teaches horseradish peroxidase and its substrates NADH, ABTS and amplex red (e.g. peroxidase substrates). The full name for ABTS is 2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid). The full name for the Amplex Red substrate is 10-acetyl-3,7-dihydroxyphenoxazine.
Molina does not explicitly teach encapsulated in a vesicle, a peroxidase and a 10-Acetyl-3,7-dihydroxyphenoxaxine (i.e. Amplex™ Red) substrate.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to select the amplex™ red (in table 2) of Molina as the horse radish-peroxidase enzyme metabolite within the encapsulant. Doing so is merely pursuing the known options. A person of ordinary skill in the art has good reason to pursue the known options within his/her technical grasp. There would be a reasonable expectation of success because Molina suggests encapsulating metabolites such as NADH and ABTS, and Molina also suggests that amplex™ red, NADH and ABTS are all interchangeable as substrates for horseradish peroxidase.
Regarding claims 21 and 22, Molina teaches a sample selected from a list that includes a urine sample (e.g. a fluid sample and a physiologic fluid). See page 11 lines 20-21.
Regarding claim 23, Molina teaches an output signal that is a chemical, biological, electronic or photonic signal, or a physicochemical output signal, capable of carrying out a mechanical action or the synthesis and/or output secretion of a compound of interest. See claim 18. A signal which can be used as an output signal includes, for example colorimetric, fluorescent, luminescent or electrochemical signal. See page 7 lines 21-28. In example 6, Molina teaches performing multiple experiments and measuring the generation of output signals, fluorescence or absorbance. See lines 11-14 on page 44.
Zhang teaches screening evolved mutants (e.g. SCF-4) using an enzyme-coupled colorimetric assay. See section 2.4. Zhang teaches evaluating enzyme activity by monitoring the absorbance change with a Multiskan™ Spectrum spectrophotometer (e.g. spectroscopy). See section 2.5.
Rosini teaches using a fluorimeter to record the fluorescence intensity emission of a dye transducer, which is modulated by the different intensity of light absorbed by the GO enzyme in the free (oxidized) and substrate bound (reduced state). See the first full paragraph on page 3467 and figures 4a-4c.
Regarding claim 25-27, Zhang teaches tagging wild type BliGO genes with GST. See section 2.5. Specifically, plasmids carrying the wild type BliGO gene and its resulting mutants (e.g. SCF-4) are transformed into E. coli for protein expression. The transformants are cultured, and harvested to obtain a supernatant that is mixed with FAD and 2-mercaptoethanol to gain GST-tagged enzymes. See section 2.5. Thus, Zhang indicates that a GST tag is fused to the SCF-4 enzyme of Zhang.
Regarding claim 29, Molina teaches biomolecular elements that are spatially encapsulated within a liposome (e.g. a vesicle). See claim 7. Molina discloses that the encapsulation of biochemical networks can be achieved using natural bilayer membranes, e.g. phospholipid bilayers, liposomes. See page 61 lines 23-24.
Regarding claim 30, Molina teaches encapsulating biochemical networks using natural bilayer membranes, e.g. phospholipid bilayers, liposomes. See page 61 lines 23-24.
Evidentiary reference Ding discloses that bilayer membranes typically contain varying amounts of lamellar (e.g. unilamellar or multilamellar) and nonlamellar lipids. See the abstract. Thus, the natural bilayer membrane of Molina is considered to be a unilamellar or multilamellar vesicle, which is a lipid vesicle.
Regarding claim 31, Molina teaches a micro/nanoscale biosynthetic device preferably having a size diameter comprised between 5 nm (i.e. 0.005 µm) and 20 µm. See page 6 lines 1-4. Molina teaches phospholipidic protocells encapsulating biochemical species. See page 21 lines 4-5 and page 48 line 19. Molina teaches a protocell diameter of 10 µm. See page 23 line 24. Molina teaches a 10 µm diameter vesicle. See page 28 line 22. Thus, Molina teaches an average vesicle diameter within the instantly claimed 0.05 µm to 500 µm and 0.1 µm and 100 µm ranges.
Claim 24 is rejected under 35 U.S.C. 103 as being unpatentable over Molina (WO 2017/178896) in view of Zhang (Enzyme and Microbial Technology, 2016 85, 12-18; in IDS 03/21/2024) and Rosini (The FEBS Journal, 2014, 281(15), 3460-3472.), as applied to claims 1 and 20-23, 25-27, and 29-31 above, and further in view of De Góes (Sensors, 2017 17(5), 954, hereafter Góes).
The teachings of Molina, Zhang, and Rosini with respect to instant claim 1 and 23 are discussed above.
Regarding claim 24, Molina discloses that examples of readable/measurable signals can include colorimetric measurement, mass spectroscopy or another signal well known by the skilled person. See the paragraph spanning pages 13-14.
Molina, Zhang and Rosini do not teach infa-red or raman spectroscopy.
Góes suggests that glyphosate water analyses of drinking water can demand expensive equipment and labored process. See the paragraph spanning pages 1-2. Góes teaches investigating two transduction principles: colorimetric, using UV-Vis, and Surface Enhanced Raman Spectroscopy (SERS) that carries information not only about the analyte concentration but also about the interaction between the analyte and colloid silver substrate. See the first full paragraph on page 3. Góes suggests using SERS for transduction with higher specificity. Moreover, Góes suggests that the proposed approach of simultaneously evaluating chemometric data from UV-Vis and SERS can be useful for a pre-qualification of samples regarding the presence of glyphosate. See the conclusion section.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to apply the SERS technique of Góes to the sample of Molina (e.g. urine sample) in the identification and/or quantification method of Molina as modified by Zhang and Rosini. One would be motivated to use the SERS technique of Góes because Góes suggests that the SERS technique can be useful for pre-qualifying samples regarding the presence of glyphosate. Furthermore, Góes suggests that the SERS technique may be less expensive and labor intensive compared to other techniques. There would be a reasonable expectation of success because Molina suggests reading colorimetric measurement signals and Góes suggests that SERS can be simultaneously with a colorimetric UV-Vis technique.
Claims 32 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Molina (WO 2017/178896) in view of Zhang (Enzyme and Microbial Technology, 2016 85, 12-18; in IDS 03/21/2024) and Rosini (The FEBS Journal, 2014, 281(15), 3460-3472), as applied to claims 1 and 20-23, 25-27, and 29-31 above, and further in view of Bianco-Peled (WO 2017/221251).
The teachings of Molina, Zhang, and Rosini with respect to instant claim 1 are discussed above.
Regarding claims 32 and 33, Molina teaches spatially encapsulating biochemical elements, such as horse radish-peroxidase and metabolites within a liposome. See claims 7 and 15. Molina teaches encapsulation within the pores of a gel. See page 4 lines 7-8. Molina teaches a preferred biosynthetic device in which the synthetic biochemical network is compartmentalized or encapsulated in for example a porous gel, a porous polymetric bead, and a liposome. See page 5 lines 19-25. Molina teaches biomolecular elements that are spatially confined with a synthetic, semi-synthetic or naturally occurring membrane or polymeric support. See claim 8.
Molina, Zhang and Rosini do not teach vesicles trapped in a porous polymeric gel (relevant to instant claim 32).
Molina, Zhang and Rosini do not teach a porous polymeric gel selected from alginate, chitosan, PVP (polyvinylpyrrolidone), PVA (polyvinyl-alcohol), agarose, gel or mixture thereof (relevant to instant claim 33).
Bianco-Peled teaches a composition comprising one or more nano-carriers entrapped within a muco-adhesive polymer and said one or more nano-carriers comprise at least one therapeutic or diagnostic agent. See claim 1 on page 62. Bianco-Peled indicates that the one or more nano-carriers are entrapped within the internal pores of the muco-adhesive matrix. See claims 2-3. The muco-adhesive polymer is selected from a group that consists of alginate, chitosan, or any derivative or a combination thereof. See claim 12. Bianco-Peled teaches one or more nano-carriers that are lipid-based particles, wherein the lipid-based particles are liposomes or micelles. See claims 15 and 16. Bianco-Peled teaches examples of therapeutically active agents including an enzyme. See paragraph [0126] and [0127]. Bianco-Peled suggests that combining mucoadhesion with the advantages of liposomal drug delivery allows the pharmaceuticals to be protected against degradation and improves the drug bioavailability. See [074]. In example 10, Bianco-Peled teaches encapsulating proteins into liposomes. See [0382].
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to combine the alginate or chitosan muco-adhesive matrix of Bianco-Peled with the liposome of Molina containing the horseradish peroxidase and metabolite. One would be motivated to do so because Bianco-Peled suggests that combining mucoadhesion with liposomes may protect the contents within the liposome from degradation. There would be a reasonable expectation of success because Bianco-Peled teaches a composition in which liposomal nano-carriers containing enzyme therapeutic agents are entrapped within alginate or chitosan muco-adhesive matrixes.
Response to Arguments
Applicant's arguments filed 06/04/2026 have been fully considered but they are unpersuasive. To the rejections under 35 U.S.C. 103, Applicant argues that the rationale for combining the references lacks a rational underpinning and relies on impermissible hindsight. See the remarks p. 8 heading. Applicant argues that Molina’s disclosure presents a vast array of sample possibilities, with no teaching that directs a person of ordinary skill in the art to single out urine from a long list of samples, and further to specifically target glyphosate and glycine from the countless other compounds present. See the remarks p. 8 para. 3. Applicant argues that the path from Molina’s general disclosure to the specific invention of amended claim 1 is a path that was obvious only in retrospect. There is no teaching in Molina that directs a person of ordinary skill in the art to single out urine, and even within urine, to specifically target glyphosate and glycine over countless other metabolites. See the remarks p. 8 para. 4.
This argument is not persuasive because Molina, in example 1, teaches collecting glycosuric urine samples from diabetic patients. See p. 22 lines 22-23. Molina also teaches urine amongst a list. For example, on p. 11 in lines 20-21, Molina teaches samples selected from urine, serum, blood, foods, raw materials and environmental sample. However, independent claim 1 and dependent claims 20, 23, 24-27, 29-34 do not limit the required sample to urine. Claim 21 requires the sample to be susceptible to contain the glyphosate and glycine in a fluid or solid material sample. Claim 22 requires the fluid or solid material sample to be an environmental material sample, vegetal material, water, beverage, food products, soil extracts, industrial material, food production, plant extract, physiologic fluid or tissue from living organism. Therefore, the argument that Molina does not single out urine from a list of other samples is unpersuasive, because it is not commensurate in scope with the instant claims. In response to Applicant's argument that the Examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, every limitation is accounted for in the prior art, so nothing is gleaned from the instant disclosure.
Applicant argues that Rosini and Molina are not in the same field of endeavor, and that Examiner defined the field of endeavor too broadly. See the remarks p. 8 last paragraph. Molina is directed to clinical diagnostics for diabetes. The reference describes a biosensor platform for the differential classification of acute metabolic complications of diabetes (Molina p. 4) by detecting biomarkers such as glucose, ketones and lactate (Molina, p. 41). A person of ordinary skill in the art would be motivated to improve the detection of these specific clinical biomarkers. See the remarks p. 9 first bullet. Furthermore, Zhang is directed to agricultural biotechnology. The objective is to engineer an enzyme to degrade glyphosate for the purpose of creating “new generation glyphosate-resistant crops”(Zhang introduction; discussion). The technical problem is purely agronomic and environmental. See the remarks p.9 second bullet. Rosini is directed to neurological and oncological diagnostics. The document aims to develop biosensors for glycine as a neurotransmitter and sarcosine as a prostate cancer biomarker (abstract). See the remarks p. 9 third bullet.
This argument is not persuasive because MPEP 2141.01(a)(I) states that “[w]hen more than one prior art reference is used as the basis of an obviousness rejection, it is not required that the references be analogous art to each other”. See Sanofi-Aventis Deutschland GMbH v. Mylan Pharms. Inc., 66 F.4th 1373, 1380, 2023 USPQ2d 552 (Fed. Cir. 2023). Molina is not limited to clinical diagnostics for diabetes. Molina in the abstract states “[p]referably, said device is used as an assay diagnostic, or to predict the risk, of a disease, or for the classification of mammal, preferably human pathologies. The invention also relates to a method for the identification and/or the quantification of a compound in a sample”. Molina teaches environmental sample. See p. 11 line 21. Furthermore, Molina suggests that the device is “preferably in the field of health, agronomic food or environment diagnostic”. See p. 10 lines 17-19.
Applicant argues that MPEP 2145, as referenced by Examiner in the previous action, does not eliminate the requirement for motivation altogether. See the remarks p. 9 second to last paragraph. Applicant argues that A logical reason why a person of ordinary skill in the art would have combined them must be provided. See the remarks p. 9 last paragraph.
This argument is not persuasive because motivation is and was provided in all rationales. For example, with respect to instant claim 1, the rationale states that “[o]ne would be motivated to use the SCF-4 of Zhang as a biomolecular element in the device of Molina because Zhang discloses that the SCF-4 shows an 8-fold improvement of catalytic efficiency towards glyphosate…One would be further motivated to use the H244K GO of Rosini as a biomolecular element in the device of Molina because Rosini indicates that the H244K GO variant exhibits increased kinetic efficiency on glycine compared to the wild-type GO”. See the rationale paragraph above spanning pages 8-9 of this action.
Applicant argues that the prior art teaches away from the claimed method. Applicant argues that the prior art actively discourages the path taken by the present inventors. Examiner suggests that it would have been obvious to combine an enzyme effective for glyphosate from Zhang with an enzyme effective for glycine from Rosini. However, Zhang’s data teaches that such an approach is counterproductive. See the remarks p. 9 first paragraph. Zhang demonstrates that engineering the BliGO enzyme to improve its affinity for glyphosate results in near-total destruction of its activity on glycine. Table 3 of Zhang. This is a clear and direct teaching away. Optimizing for glyphosate comes at the direct and severe expense of glycine activity. Faced with this data, a person of ordinary skill in the art seeking to develop a biosensor for both analytes would have been actively discouraged from pursuing this engineering path, concluding that this enzyme family is unsuitable for a dual analyte system. See the remarks p. 10 second paragraph. Applicant argues that Zhang and Rosini exemplify that the prevailing paradigm in the art is to engineer a single enzyme to alter its substrate specificity. The shift to a single-enzyme approach to a complex, multi-component system where different enzymes are spatially segregated is a conceptual leap, not an obvious incremental step. See the remarks p. 10 last full paragraph.
This argument is not persuasive because Molina is relied upon for teaching a device that comprises two compatible enzymes. See claim 5 of Molina. Therefore, the argument that it would have been a conceptual leap to shift from the single-enzyme systems of Zhang and Rosini to a multi-component system is not persuasive. Moreover, Applicant argues that Zhang teaches away from the instant invention because Zhang teaches decreasing BliGO-SCF-4’s affinity for glycine. This argument is not persuasive for two reasons. The first reason is that Zhang does not teach completely abolishing BliGO-SCF-4’s affinity for glycine, which is the natural substrate of glycine oxidase. Therefore, to the extent that Applicant is arguing that Zhang’s BliGO-SCF-4 serves a different function compared to the instant invention, it is unpersuasive. The second reason is that MPEP 2144 (IV) states that “[o]ne of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings.”
Applicant argues that the claimed architecture requires a functional interaction between enzymes in free solution and an encapsulated reaction. A skilled artisan would have had to address critical challenges such as (a) establishing a proper stoichiometric balance between the free enzymes and the encapsulated peroxidase to ensure a linear and reliable signal response; (b) managing the diffusion kinetics of the H2O2 intermediate; and (c) avoiding unpredictable interferences where components of the sample or the free enzymes might inhibit the encapsulated reaction or vice versa. See the remarks the paragraph spanning pages 10-11.
This argument is not persuasive because it is not commensurate in scope with the instant claims. The claims do not require a stoichiometric balance, or diffusion kinetics; and the claims do not limit the components of the samples as to avoid unpredictable interferences. Furthermore, Applicant has not pointed to evidence, and arguments of counsel cannot take the place of factually supported objective evidence (MPEP 2145 or 716.01(c)).
Applicant argues that the unexpected results disclosed in figure 12 are not merely the magnitude of the signal, but the functional viability of the integrated, spatially-segregated system. Given the explicit teaching away from Zhang and the well-known technical challenges of creating a functional network with both free and encapsulated components, achieving a stable and specific dual-analyte detection system is a non-trivial, technical accomplishment. The claimed system is not a simple sum of its parts; it is a functional, integrated system that solves a problem the prior art suggested was difficult. See the remarks p. 11 second to last paragraph.
This argument is not persuasive because to establish unexpected results, the evidence relied upon should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). Applicant has not pointed to evidence besides figure 12 of the instant disclosure. As discussed previously, the data set forth in figure 12 appear to show the additive effect of the glycine and glyphosate on the fluorescence output.
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 KIMBERLY C BREEN whose telephone number is (571)272-0980. The examiner can normally be reached M-Th 7:30-4:30, F 8:30-1:30 (EDT/EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, LOUISE HUMPHREY can be reached at (571)272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/K.C.B./Examiner, Art Unit 1657
Prosecution Insights