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 .
Response to Amendment/Disposition of Claims
Applicant’s Amendment filed on 10 December 2025 has been received and entered. Claims 1-19 were pending. Claims 1, 6-8, 10-15, 17, and 19 have been amended. Claims 2-3, 9, and 18 have been cancelled. No new claims have been added.
Accordingly, Claims 1, 4-8, 10-17, and 19 are currently pending and will be examined on their merits.
Examiner’s Note
All paragraph numbers (¶) throughout this office action, unless otherwise noted, are from the US PGPub of this application US 2023/0184763 A1, Published 15 June 2023. Applicant’s amended Specifications as presented on 10 December 2025 and 15 September 2022 are acknowledged and entered.
Applicant is encouraged to utilize the new web-based Automated Interview Request (AIR) tool for submitting interview requests; more information can be found at https://www.uspto.gov/patent/laws-and-regulations/interview-practice.
Response to Arguments
Applicant's arguments filed 10 December 2025 regarding the previous Office action dated 11 June 2025 have been fully considered. If they have been found to be persuasive, the objection/rejection has been withdrawn below. Likewise, if a rejection/objection has not been recited, said rejection/objection has been withdrawn. If the arguments have not been found to be persuasive, or if there are arguments presented over art that has been utilized in withdrawn rejections but utilized in new rejections, the arguments will be addressed fully with the objection/rejection below.
Drawings
(Objection withdrawn) – The objection to the Drawings for referring to color is withdrawn in light of Applicant’s Arguments.
Response to Arguments
Applicant’s arguments, filed 10 December 2025, with respect to the objection to the Drawings for referring to colors have been fully considered and are persuasive.
In their Response, Applicant argues that “all drawings filed with this application were black and white line drawings or grayscale photographs” (see Page 1 of Remarks, Paragraph 3) and that the figures which were objected to “merely describe fluorescence emission or chemiluminescence colors (Figs. 4-5) or depict intensities of the hydrolysis reaction of HE and resorufin acetate under various concentrations (Figs. 7-8)” (see Page 1, Paragraph 3). Applicant also confirmed “that color is not part of the disclosure and is not necessary for understanding the invention” (see Page 1, Paragraph 3). Examiner finds these arguments persuasive. As such, the objection to the Drawings for referring to colors has been withdrawn.
Specification
(Objection withdrawn) – The objection to the Abstract of the disclosure for containing implied language is withdrawn in light of the amendments to the Abstract.
(Objection withdrawn) – The objection to the disclosure for containing an embedded hyperlink and/or other form of browser-executable code is withdrawn in light of the amendments to the Specification.
(Objection withdrawn) – The objection to the disclosure for containing possible minor errors is withdrawn in light of the amendments to the Specification.
(New Objection) – The Abstract of the disclosure is objected to because of the following informalities: the Abstract contains a run-on sentence. It is suggested that it say “…and detecting activity of the enzyme[[,]]. T[[t]]he detection of the activity indicates…”. There should be a period between “enzyme” and “the”.
It is also suggested that the Abstract say “…detecting a virus having [[a]] hemagglutinin-esterase activity…”.
Appropriate correction is required.
(New Objection) – The Abstract of the disclosure is objected to because of the following informalities: the Abstract contains a sentence fragment. It is suggested that it say “A method of detecting a virus having hemagglutinin-esterase activity in a sample is provided,…”.
Appropriate correction is required.
Claim Objections
(Objection withdrawn) – The objection to Claims 1-2, 6-8, 10-15, and 17-18 is withdrawn in light of the cancellation of two of the claims and the amendments to the remainder of the claims.
(New Objection) – Claim 19 is objected to because of the following informalities: it is suggested that it say “A kit for detecting a virus having a hemagglutinin-esterase enzyme in a sample”.
Appropriate correction is required.
(New Objection) – Claim 1 is objected to because of the following informalities: it is suggested that it say “A method of detecting a virus having hemagglutinin-esterase activity in a sample, wherein the virus is SARS-CoV-2, comprising:…”.
Appropriate correction is required.
(New Objection) – Claim 17 is objected to because of the following informalities: it is suggested that it say “A method of detecting coronavirus in a sample, wherein the coronavirus is SARS-CoV-2, comprising:…”.
Appropriate correction is required.
(New Objection) – Claim 19 is objected to because of the following informalities: it is suggested that it say “A kit for detecting a virus having hemagglutinin-esterase enzyme in a sample, wherein the virus is SARS-CoV-2, comprising…”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b); Second Paragraph
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.
(Rejection withdrawn) – The rejection of Claim 3 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the cancellation of the claim.
(Rejection withdrawn) – The rejection of Claim 11 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of the amendments to the claim.
Claim Interpretation
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.
Claim Rejections - 35 USC § 112(a); First Paragraph
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.
(New Rejection – necessitated by amendment) – Claims 1, 4-8, 10-17, and 19 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. This is a new matter rejection.
The amendments to Claims 1, 17, and 19 all introduce new matter which is not supported by the original disclosure filed on 15 September 2022. Specifically, the recitation of detecting “SARS-CoV-2 or a variant thereof” is not supported by the originally-filed disclosure as the Specification simply discloses detection of HE activity in an enzyme from a generic and unspecified coronavirus. The original claims recite detecting the activity of a hemagglutinin-esterase as evidence of infection with a coronavirus. The specification does not provide any examples, in words or in the figures, that SARS-CoV-2 was specifically tested using the claimed methods and kit. The term “SARS” only appears in the Specification five times (see Paragraphs 0003-0004, 0010, 0014, and 0045), and none of these instances are in the context of the HE activity of SARS-CoV-2 being tested using the methods and/or kit of the instant application. In fact, no examples are provided in the Specification, so it is unclear exactly which coronavirus HE was tested and what kind of samples were used in the data provided. Additionally, there is no definition for the term “variant” provided in the Specification and this term is only mentioned in the context of the antibody against SARS-CoV-2 or a variant thereof (see Paragraphs 0010 and 0045 of PGPub), not in the context of detecting the enzymatic activity. These independent claims each recite a new, more specific embodiment of the claimed invention which is not explicitly disclosed in the original Specification. The original disclosure should teach, contemplate, and thus anticipate the instant claims. A genus does not anticipate a species. It is not sufficient that the instant Specification merely render the instant claims obvious. Therefore, Claims 1, 4-8, 10-17, and 19 do not meet the written description requirement as they contain new matter.
(New Rejection – necessitated by amendment) – Claims 1, 4-8, 10-17, and 19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for detecting a select few coronaviruses in a sample based on their hemagglutinin-esterase activity, does not reasonably provide enablement for detecting any and all coronaviruses, including SARS-CoV-2, in a sample based on their hemagglutinin-esterase activity. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). See also MPEP § 2164.01(a) and § 2164.04. Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including: the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention/Breadth of the claims. The claims are drawn to a method of detecting a virus having hemagglutinin-esterase activity in a sample, comprising: contacting the sample with a substrate the hemagglutinin-esterase (HE) enzyme of SARS-CoV-2 or a variant thereof; and detecting the activity of the enzyme, wherein the detection of activity indicates that the sample contains SARS-CoV-2 or a variant thereof, and wherein the substrate is selected from the group consisting of 4-methylumbelliferyl acetate, 3-(2-benzoxazolyl)umbelliferyl acetate, fluorescein diacetate, and resorufin acetate. There is no definition for the term “variant” provided in the instant Specification and this term is only mentioned in the context of the antibody against SARS-CoV-2 or a variant thereof (see Paragraphs 0010 and 0045 of PGPub), not in the context of detecting the enzymatic activity. As such, the breadth of the claims encompasses any and all possible “variants” of SARS-CoV-2, such as Omicron variants of the wild-type SARS-CoV-2, but also less related “variants”, such as SARS-CoV-1 and bovine coronavirus (BCoV), and any and all other distantly related coronaviruses, of which there are 45 species officially recognized, which are organized into four genera, Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus.
State of the prior art/Predictability of the art. The teachings of the art indicate that SARS-CoV-2 does not in fact encode a hemagglutinin-esterase and that only a small subset of coronaviruses encode this enzyme in their genomes. While Santacroce et al. (Santacroce L, Charitos IA, Carretta DM, De Nitto E, Lovero R. The human coronaviruses (HCoVs) and the molecular mechanisms of SARS-CoV-2 infection. J Mol Med (Berl). 2021 Jan; 99 (1): 93-106.) indicates the SARS-CoV-2 does possess an HE (see Page 98, Left Column, Paragraph 1; Figure 2), numerous other references argue against the existence of this gene in the SARS-CoV-2 genome. Wang et al. (US 2023/0109393 A1), for instance, explicitly states that unlike “other betacoronaviruses, SARS-CoV-2 does not possess a hemagglutinin-esterase glycoprotein (see Paragraphs 0005, 0050; Figure 1). Woo et al. (Woo PCY, Huang Y, Lau SKP, Yuen KY. Coronavirus genomics and bioinformatics analysis. Viruses. 2010 Aug; 2(8):1804-1820.) provides a breakdown of the four genera of coronaviruses, Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus, including the subgenera of Betacoronaviruses, which are further broken down into four subgenera or lineages, A, B, C, and D (see Table 1). As shown by Woo et al., viruses such as HCoV-229E and HCoV-NL63 are part of the Alphacoronavirus genus, while HCoV-OC43, HCoV-HKU1, and SARS-CoV-1 are part of the Betacoronavirus genus, with OC43 and HKU1 falling within Subgroup or Lineage A and SARS-CoV-1 falling within Subgroup or Lineage B. Woo et al. goes on to further explain that “all members of Betacoronavirus subgroup A” possess an HE gene and that the “presence of HE genes exclusively in members of Betacoronavirus subgroup A, but not members of Betacoronavirus subgroup B, C and D suggested that the recombination” which introduced it “probably occurred in the ancestor of members of Betacoronavirus subgroup A, after diverging from the ancestor of other subgroups of Betacoronavirus” (see Page 1809, Paragraph 2).
Bakkers et al. (Bakkers, Mark J.G. et al. Betacoronavirus Adaptation to Humans Involved Progressive Loss of Hemagglutinin-Esterase Lectin Activity. 2017. Cell Host & Microbe, Volume 21, Issue 3, 356-366.) go into further detail by stating that “HEs are found in toroviruses and in influenza C and D viruses, but among coronaviruses, only in lineage A betacoronaviruses” (see Page 357, Left Column, Paragraph 2). A similar point is made by Zeng et al. (Q. Zeng, M.A. Langereis, A.L.W. van Vliet, E.G. Huizinga, & R.J. de Groot, Structure of coronavirus hemagglutinin-esterase offers insight into corona and influenza virus evolution. (2008). Proc. Natl. Acad. Sci. U.S.A. 105 (26) 9065-9069.), who states that “among coronaviruses, HE is exclusive to member of phylogenetic subgroup 2a” but that “closely related proteins do occur in toroviruses and in orthomyxoviruses of mammals and fish” (see Page 9065, Right Column, Paragraph 1). Hasoksuz et al. (Hasoksuz M, Vlasova A, Saif LJ. Detection of group 2a coronaviruses with emphasis on bovine and wild ruminant strains. Virus isolation and detection of antibody, antigen, and nucleic acid. Methods Mol Biol. 2008; 454:43-59.) states that “Group 2a of the Coronaviridae family contains human and animal pathogens that include mouse hepatitis virus, rat coronavirus, human respiratory coronaviruses OC43 and the recently identified HKU1 strain, a newly recognized canine respiratory coronavirus, porcine hemagglutinating encephalomyelitis virus, equine coronavirus, bovine coronavirus (BCoV), and wild-ruminant coronaviruses) and that the “presence of a hemagglutinin-esterase (HE) surface glycoprotein in addition to the viral spike protein is a distinguishing characteristics of most group 2a coronaviruses” (see Abstract). While not in the context of the HE gene, Wang et al. (Wang M-Y, Zhao R, Gao L-J, Gao X-F, Wang D-P and Cao J-M (2020) SARS-CoV-2: Structure, Biology, and Structure-Based Therapeutics Development. Front. Cell. Infect. Microbiol. 10:587269.) mentions that SARS-CoV-2 is a group 2b betacoronavirus, same as SARS-CoV-1 (see Page 7, Left Column, Paragraph 1), meaning that neither virus would have an HE gene, based on the teachings of the art. While Hwang et al. (WO 2022/005214 A1) generally agree with the rest of the art, stating that some coronaviruses, such as HCOV-OC43 and BCoV possess an HE (see Page 3, Paragraph 6) and that SARS-CoV-1 and SARS-CoV-2 “do not have independent HE genes” (see Page 3, Paragraph 6), they also state that the Spike protein of SARS-CoV-2 possesses an esterase activity that hydrolyzes p-nitrophenol acetate (see Page 3, Paragraph 6).
Working examples. No working examples are disclosed in the specification. As noted above in the new matter rejection, the specification does not provide any examples, in words or in the figures, that SARS-CoV-2 was specifically tested using the claimed methods and/or kit.
Guidance in the specification. As noted above in the new matter rejection, the specification provides guidance towards detection of HE activity in an enzyme from a generic and unspecified coronavirus. The term “SARS” only appears in the Specification five times (see Paragraphs 0003-0004, 0010, 0014, and 0045), and none of these instances occur in the context of the HE activity of SARS-CoV-2 being tested using the methods and/or kit of the instant application. In fact, no examples are provided in the Specification, so it is unclear exactly which coronavirus HE was tested and what kind of samples were used in the data provided.
Amount of experimentation necessary. Additional research is required in order to determine how effective SARS-CoV-2 or a variant thereof which does not naturally possess an HE gene in its genome would perform in the disclosed assay.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed products and/or methods.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
(Rejection withdrawn) – The rejection of Claims 1-2, 4-9, and 15-16 under 35 U.S.C. 102(a)(1) as being anticipated by Klausegger et al. (Klausegger, A., Strobl, B., Regl, G., Kaser, A., Luytjes, W., & Vlasak, R. (1999). Identification of a Coronavirus Hemagglutinin-Esterase with a Substrate Specificity Different from Those of Influenza C Virus and Bovine Coronavirus. Journal of Virology, 73(5), 3737–3743.) (cited by Applicant on IDS filed on 15 September 2022) is withdrawn in light of the amendments to the claims and the cancellation of one of the claims.
(Rejection withdrawn) – The rejection of Claims 1-2, 4-8, 10-11, 15, and 17-19 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Noji and Tabata (US 2019/0194717 A1, Published 27 June 2019), as evidenced by Chait and Zaslavsky (US 2023/0088162 A1, earliest Priority Date 28 February 2020) is withdrawn in light of the amendments to the claims and the cancellation of two of the claims.
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.
(Rejection withdrawn) – The rejection of Claims 3 and 12-14 under 35 U.S.C. 103 as being unpatentable over Noji and Tabata (US 2019/0194717 A1, Published 27 June 2019) and Klausegger et al. ((Klausegger, A., Strobl, B., Regl, G., Kaser, A., Luytjes, W., & Vlasak, R. (1999). Identification of a Coronavirus Hemagglutinin-Esterase with a Substrate Specificity Different from Those of Influenza C Virus and Bovine Coronavirus. Journal of Virology, 73(5), 3737–3743.) (cited by Applicant on IDS filed on 15 September 2022) as applied to claims 1-2, 4-11, and 15-19 previously, and further in view of Chait and Zaslavsky (US 2023/0088162 A1, earliest Priority Date 28 February 2020), Liav et al. (U.S. Patent No. 5,252,458, Issued 12 October 1993) (cited by Applicant on IDS filed on 15 September 2022), and Shimasaki et al. (U.S. Patent No. 7.081,352 B2, Issued 25 July 2006) (cited by Applicant on IDS filed on 15 September 2022) is withdrawn in light of the amendments to the claims and the cancellation of some of the claims.
(New Rejection – necessitated by amendment) – Claims 1, 4-8, 10-17, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Klausegger et al. ((Klausegger, A., Strobl, B., Regl, G., Kaser, A., Luytjes, W., & Vlasak, R. (1999). Identification of a Coronavirus Hemagglutinin-Esterase with a Substrate Specificity Different from Those of Influenza C Virus and Bovine Coronavirus. Journal of Virology, 73(5), 3737–3743.) (cited by Applicant on IDS filed on 15 September 2022) (cited in a previous Office Action), Noji and Tabata (US 2019/0194717 A1, Published 27 June 2019) (cited in a previous Office Action), Chait and Zaslavsky (US 2023/0088162 A1, earliest Priority Date 28 February 2020) (cited in a previous Office Action), Witcher et al. (US 2020/0385776 A1, earliest Priority Date 19 December 2017), Swiss et al. (US 2018/0113128 A1, Published 26 April 2018), and Caron and Trowell (US 2021/0018497 A1, earliest Priority Date 24 August 2017).
Klausegger et al. teach a method of detecting a coronavirus in a sample by determining the presence of a viral hemagglutinin-esterase enzyme in said sample and detecting the activity of the enzyme which is indicative of the presence of a coronavirus in said sample by contacting the sample with a substrate of the enzyme (see Abstract; Page 3738, Right Column, Last Paragraph; Page 3739, Left Column, First Paragraph). Klausegger et al. also teach wherein said method comprises the viral hemagglutinin-esterase catalyzing hydrolysis of the enzyme substrate, wherein the substrate is 4-methylumbelliferyl acetate, and wherein said hydrolysis reaction emits a detectable fluorescent signal (see Abstract; Figure 2; Page 3738, Right Column, Last Paragraph; Page 3739, Left Column, First Paragraph; Page 3739, Right Column, First Paragraph, Page 3740, Right Column, First Paragraph; Page 3741, Left Column, First Paragraph). Additionally, Klausegger et al. teach a method wherein the readings of the enzymatic activity are taken as a function of reaction time and a method wherein the mixture of the sample and the substrate has a pH between 7.4 and 7.8 (see Page 3738, Left Column, Paragraph 6; Page 3739, Left Column, Last Paragraph and Right Column, First Paragraph; Figure 6).
Noji and Tabata teach a method and a kit for detecting a virus having hemagglutinin-esterase activity in a sample, wherein said virus is a coronavirus and wherein said sample is a biological sample taken from a subject infected with or a subject suspected of being infected with a pathogenic microorganism, such as a coronavirus (see Paragraphs 0012, 0024-0028), and wherein said biological is specifically a saliva sample, a nasopharyngeal sample, or a sputum sample (see Abstract; Paragraphs 0003, 0026-0028, 0074, 0080-0090, 0122, 0147, 0197). Noji and Tabata also teach an antibody against the HE of coronaviruses (see Paragraph 0183).
Neither teaches detection of variants of SARS-CoV-2 by similar methods.
Chait and Zaslavsky teach that some coronaviruses encode an HE enzyme in their genomes (see Paragraph 0090) as well as antibodies which bind to the HE dimers present on the virus as part of a method for detecting a coronavirus, such as SARS-CoV-2 (see Paragraph 0316), in a sample, such as a human biological sample (see Paragraphs 0087-0088).
None of the references above provides incubation temperatures of times as in claim 12.
Witcher et al. teach compositions and methods for detecting microorganisms (see Paragraph 0002), wherein the composition can comprise a plurality of enzymes, such as an esterase, and an indicator compound (see Paragraphs 0013, 0034) and wherein the indicator compound can be 4-methylumbelliferyl acetate or fluorescein diacetate (see Paragraph 0035).
Swiss et al. teach compositions, methods, and kits for detecting urease and/or esterase activity from bacteria using a fluorescent compound, wherein the sample and the substrate are incubated at room temperature for approximately 10 minutes (see Paragraphs 0132, 0177-0181), wherein the substrate can be fluorescein diacetate (see Paragraphs 0182-0185).
Caron and Trowell teach bioluminescence resonance energy transfer (BRET) sensor molecules wherein the sensors comprise luciferase and fluorescein diacetate, which is hydrolyzed by an esterase (see Abstract; Paragraph 0169) and sensor and methods for detecting hydrolases, such as phosphatases, glycosidases, esterases, exopeptidases, and lipases (see Paragraph 0001). Caron et al. teach a method of measuring esterase activity using fluorescein diacetate as the substrate wherein the incubation is carried out at room temperature for 10-60 minutes (see Example 5; Paragraphs 0286-0287; Table 6).
Taken all together, it would have been obvious to a PHOSITA before the filing of the instant application that the methods of detection using HE activity taught by Klausegger and Noji and Tabata could be used to detect coronaviruses which encode an HE enzyme. This sensitive detection technique relying on enzyme amplification of signal would be very desirable to a PHOSITA. Additional steps could identify viral source of the HE using antibodies specific to the HE of those coronaviruses which possess the enzyme, as taught by Chait above. This obvious method would predictably detect a coronavirus possessing HE activity in a patient sample such as those above.
A person having ordinary skill in the art would have been motivated to combine the teachings of Klausegger et al., Noji and Tabata, Chait and Zaslavsky, Witcher et al., Swiss et al., and Caron and Trowell in order to develop methods of and kit for detecting a coronavirus with an HE in a sample from its HE activity. While the HE antibody disclosed by Noji and Tabata is in the context of determining inhibitors of viral activity, the same principle is used as recited in the instant claims as it relates to using a fluorescent assay to measure the level of HE enzymatic activity. While the teachings of Witcher et al., Swiss et al., and Caron and Trowell are not specifically geared towards hemagglutinin-esterases or viral esterases, their teachings clearly demonstrate that substrates for esterases have been known in the prior art for a long time and that methods for measuring and/or determining the esterase activity of a cell or microorganism have also been known in the prior art for a long time. Additionally, Klausegger et al. teach that several coronaviruses possess an HE protein and a specificity for 4-methylumbelliferyl acetate as a substrate. As such, it would have been obvious to try the same substrate for other newer, related coronaviruses possessing an HE which emerged after the publication of this prior art reference to see if this specificity carried over to other coronaviruses. Furthermore, given that there is a small and finite number of hemagglutinin-esterase or esterase substrates known in the prior art, it would have been obvious to try the recited substrates with coronaviruses possessing an HE as there would have been a reasonable expectation of success given that HE assays have been known a long time in the prior art and using a panel of substrates on new HE-expressing coronaviruses is also known. The claimed invention in Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 82 USPQ2d 1321 (Fed. Cir. 2007), was directed to the amlodipine besylate drug product, which was sold in tablet form in the United States under the trademark Norvasc®. Amlodipine and the use of besylate anions were both known at the time of the invention. Amlodipine was known to have the same therapeutic properties as were being claimed for the amlodipine besylate, but Pfizer discovered that the besylate form had better manufacturing properties (e.g., reduced "stickiness"). Pfizer argued that the results of forming amlodipine besylate would have been unpredictable and therefore nonobvious. The court rejected the notion that unpredictability could be equated with nonobviousness here, because there were only a finite number (53) of pharmaceutically acceptable salts to be tested for improved properties. The court found that one of ordinary skill in the art having problems with the machinability of amlodipine would have looked to forming a salt of the compound and would have been able to narrow the group of potential salt-formers to a group of 53 anions known to form pharmaceutically acceptable salts, which would be an acceptable number to form "a reasonable expectation of success."
Finally, optimized result effect variables of the instant claims to include pH, incubation time, and incubation temperature do not obviate this rejection and will be arrived at by routine experimentation. “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) (see MPEP 2144.05(II)(A)). Therefore, the combined teachings of the prior art render obvious the inventions encompassed by the instant claims.
Such modifications, combining prior art elements according to known methods to yield predictable results, would have had a reasonable expectation of success and arrived at the claimed invention prior to the effective filing date of the instant application. For at least these reasons, instant Claims 1, 4-8, 10-17, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over the prior art.
Response to Arguments
Applicant’s arguments, filed on 10 December 2025, with respect to the rejection of the claims under 35 U.S.C. 103 as being unpatentable over the prior art have been fully considered and are persuasive. While the original rejection has been withdrawn, a new rejection was warranted that utilizes the teachings of Klausegger et al., Noji and Tabata, and Chait and Zaslavsky, and the arguments presented regarding these teachings will be addressed as applicable herein in the interest of compact prosecution.
In their Response, Applicant argues that Claims 12-14 variously depend on claim 1 and thus, incorporate all the elements of claim 1, i.e., “[a] method of detecting a virus having hemagglutinin-esterase activity in a sample, comprising…contacting the sample with a substrate for the hemagglutinin-esterase (HE) enzyme of SARS-CoV-2 or a variant thereof; and detecting the activity of the enzyme, wherein the detection of the activity indicates that the sample contains SARS-CoV-2 or a variant thereof, and wherein the substrate is selected from the group consisting of 4-methylumbelliferyl acetate, 3-(2-benzoxazolyl)umbelliferyl acetate, fluorescein diacetate, and resorufin acetate” (see Page 4 of Remarks, Paragraph 3”. Applicant also argues that “Liav and Shimasaki cannot cure the deficiencies of the combined teachings of Noji, Chait and Klausegger, as Liav and Shimasaki also fail to teach or suggest the above-identified features of claim 1” and that because “the combined teachings of Noji, Chait, Klausegger, Liav and Shimasaki fail to teach or suggest each and every feature of claim 1, they cannot render claim 1 and dependent claims 12-14 obvious” (see Page 4, Paragraph 4). Examiner disagrees with the argument and conclusion that the prior art of record fails to render the instant claims obvious. Also, Liav and Shimasaki have not been used in the new obviousness rejection, rendering moot the argument with respect to those references. While it is true that no single reference teaches each and every limitation of the amended independent claims, the combination of the prior art references teaches methods and a kit for detecting a coronavirus possessing an HE in a sample from its HE activity using at least one of the recited substrates, as noted in the obviousness rejection raised above. It has been held that one cannot show non-obviousness by attacking references individually where, as here, the rejections are based on combinations of references. In re Keller, 208 USPQ 871 (CCPA 1981). For at least these reasons, Applicant’s Arguments are not persuasive.
Conclusion
No claims are allowed.
The prior art made of record, but not relied upon, and considered pertinent to applicant's disclosure is listed below:
Arad and Ezra (US 2009/0220941 A1, Published 03 September 2009)
Arad and Ezra teach a method for detecting Influenza virus by detecting the enzymatic activity of the neuraminidase protein. This reference has not been utilized, as rejection would have been redundant to those set forth above.
Barnhizer and Faro (U.S. Patent No. 11,066,712 B1, Issued 20 July 2021)
Barnhizer and Faro teach that Betacoronaviruses of lineage A possess a hemagglutinin-esterase. This reference has not been utilized, as rejection would have been redundant to those set forth above.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/CAREY ALEXANDER STUART/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671