DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of Group I, claims 15-23, drawn to a method for detection and/or quantification of hCMV virion mRNA in a sample obtained from a patient treated with an antiviral drug capable of interfering with cleavage and encapsidation of hCMV DNA. in the reply filed on 12/19/2025 is acknowledged.
Claims 24-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected Groups II and III, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/19/2023.
Claims Status
Claims 15-28 are pending.
Claims 24-28 are withdrawn.
Claims 15-23 are currently under examination.
Priority
This application 17995642 is a 371 national phase of PCT/EP2021/058497 filed on 03/31/2021, which claims priority of IT102020000007357 filed on 04/07/2020.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of IT102020000007357 has been submitted of the record on 10/06/2022.
An English translation of the foreign application IT102020000007357 is required for the record to be considered for the priority date of 04/07/2020. Accordingly, the priority date of instant claims is determined to be 03/31/2021, the filing date of PCT/EP2021/058497.
Specification
The following guidelines illustrate the preferred layout for the specification of a utility application. These guidelines are suggested for the applicant’s use.
Arrangement of the Specification
As provided in 37 CFR 1.77(b), the specification of a utility application should include the following sections in order. Each of the lettered items should appear in upper case, without underlining or bold type, as a section heading. If no text follows the section heading, the phrase “Not Applicable” should follow the section heading:
(a) TITLE OF THE INVENTION.
(b) CROSS-REFERENCE TO RELATED APPLICATIONS.
(c) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT.
(d) THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT.
(e) INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A READ-ONLY OPTICAL DISC, AS A TEXT FILE OR AN XML FILE VIA THE PATENT ELECTRONIC SYSTEM.
(f) STATEMENT REGARDING PRIOR DISCLOSURES BY THE INVENTOR OR A JOINT INVENTOR.
(g) BACKGROUND OF THE INVENTION.
(1) Field of the Invention.
(2) Description of Related Art including information disclosed under 37 CFR 1.97 and 1.98.
(h) BRIEF SUMMARY OF THE INVENTION.
(i) BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S).
(j) DETAILED DESCRIPTION OF THE INVENTION.
(k) CLAIM OR CLAIMS (commencing on a separate sheet).
(l) ABSTRACT OF THE DISCLOSURE (commencing on a separate sheet).
(m) SEQUENCE LISTING. (See MPEP § 2422.03 and 37 CFR 1.821 - 1.825). A “Sequence Listing” is required on paper if the application discloses a nucleotide or amino acid sequence as defined in 37 CFR 1.821(a) and if the required “Sequence Listing” is not submitted as an electronic document either on read-only optical disc or as a text file via the patent electronic system.
The disclosure is objected to because of the following informalities: section arrangement and absence of section headings.
Appropriate correction is required.
Claim Objections
Claims 16 and 21 are objected to because of the following informalities:
Regarding claim 16, there is improper punctuation around the following set numbers:
(“set 1)”) (ln 3), (“set 2)”) (ln 6), and (“set 3)”) (ln 9).
Regarding claim 21, “eye swab supernatant, fecal supernatant” (ln 6) is missing “or”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 (b)
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 15-23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 is indefinite over the limitation “i) optionally removing from the sample obtained from the patient any cellular component that might be present, obtaining a cell-free sample”. It is unclear how step “ii) extracting RNA from a cell-free sample obtained from the patient or from the cell-free sample obtained in step i)” can be performed when step “i) optionally removing from the sample obtained from the patient any cellular component that might be present, obtaining a cell-free sample” is not performed as step i) is optional. Claims 16-23 depend from claim 15.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 22 recites the broad recitation of a gene e.g., UL21.5, and the claim also recites a SEQ ID No., e.g., SEQ ID No:117, which is the narrower statement of the range/limitation. UL21.5 reads on a genus (broad) of sequences of this gene, depending on the date of disclosure, whereas SEQ ID NO: 117 is a specific sequence segment of a specific specie of UL21.5 (narrow). The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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 19-20 is 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. Claim 19 depends on claim 15, which does not specifically claim an antiviral drug. Claim 20 depends on claim 19. 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.
Improper Markush Rejection
Claims 16-17 and 22 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
A Markush claim contains an “improper Markush grouping” if:
(1) the species of the Markush group do not share a “single structural similarity,” or (2) the species do not share a common use. Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the specification or known in the art to be functionally equivalent. See MPEP § 2117.
The Markush groupings of primers listed in Claims 16-17 and genes listed in claim 22 are improper because the alternatives defined by the Markush groupings do not share both a single structural similarity and a common use for the following reasons:
The recited alternative species in the groups set forth here do not share a single structural similarity, as each different primer/gene that could be detected is itself located in a separate region of the genome and has its own structure. The primers/genes recited in the instant claims, do not share a single structural similarity since each consists of a different nucleotide sequences with different expression patterns. The only structural similarity present is that all detected positions are part of nucleic acid molecules. The fact that the markers comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being correlated with hCMV. Accordingly, while the different markers are asserted to have the property of being expressed in with HCMV, they do not share a single structural similarity.
MPEP 2117 (II)(A) provides the following guidance as to what constitutes a physical, chemical, or art recognized class:
A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved”
The recited primers/genes do not belong to a recognized chemical class because there is no expectation from the knowledge in the art that the primers/genes will behave in the same manner and can be substituted for one another with the same intended result achieved. In other words, there is no expectation from the knowledge in the art that each of the recited primers/genes would function in the same way in the claimed method; it is only in the context of this specification that it was disclosed that all members of this group may behave in the same way in the context of the claimed invention. Further there is no evidence of record to establish that it is clear from their very nature that each of the recited primers/genes possess the common property of being associated with HCMV.
MPEP 2117 (II) further states the following:
Where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the compounds do not appear to be members of a recognized physical or chemical class or members of an art-recognized class, the members are considered to share a "single structural similarity" and common use when the alternatively usable compounds share a substantial structural feature that is essential to a common use. Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
The recited alternative species do not share a substantial common structure just because they all have a sugar phosphate backbone. The sugar phosphate backbone of a nucleic acid chain is not considered to be a substantial common structural feature to the group of primers/genes being claimed because it is shared by ALL nucleic acids. Further, the fact that the primers/genes all have a sugar phosphate backbone does not support a conclusion that they have a common single structural similarity because the structure of comprising a sugar phosphate backbone alone is not essential to the asserted common use of being associated with HCMV.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
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 15, 18 and 21-23 are rejected under 35 U.S.C. 103 as being unpatentable over Boriskin et al. (“Boriskin”; (2002). Early detection of cytomegalovirus (CMV) infection in bone marrow transplant patients by reverse transcription-PCR for CMV spliced late gene UL21.5: a two site evaluation. Journal of Clinical Virology, 24(1-2), 13–23.).
Claim interpretation: Regarding claim 15, the limitation “i) optionally removing from the sample obtained from the patient any cellular component that might be present, obtaining a cell-free sample” is not a required step. It is noted that “A method for detection and/or quantification of a human cytomegalovirus (hCMV) virion mRNA in a sample obtained from a patient treated with an antiviral drug capable of interfering with cleavage and encapsidation of hCMV DNA” recited in the preamble is considered as the result of performing the required steps ii) to vi).
Boriskin discloses “Background: Bone marrow transplant (BMT) patients at risk of developing cytomegalovirus (CMV) pneumonitis are identified routinely by the early detection of virus in blood. For early diagnosis of CMV infection, the RNA-based approach demonstrates advantages when compared with the current CMV antigen and DNA detection methods. Objectives: We have evaluated our previously developed reverse transcription-polymerase chain reaction (RT-PCR) to a spliced late CMV gene (SLG; J. Virol. Methods 56 (1996), 139) to monitor CMV infection in BMT patients at two clinical sites. The diagnostic value of the SLG RT-PCR was compared with the routine CMV antigen and DNA detection methods. Study design: Weekly blood samples from BMT patients were tested for CMV during the first 3 months post-transplant. The qualitative SLG RT-PCR, semiquantitative DNA PCR, and viral antigen tests were compared. The RNA and DNA PCR results were analyzed in terms of their temporal relationship and consistency of CMV detection and compared with CMV infection diagnosed by viral antigen tests. Results: Of the 101 BMT recipients studied, 25 developed CMV antigenemia and/or DNAemia resulting in symptomatic infection in two patients. All CMV PCR-positive patients were either CMV seropositive pretransplant or received marrow from seropositive donor. The highest incidence of CMV infection was seen in seropositive recipients (R+) irrespective of the donor's status. Detection of CMV infection by SLG RNA preceded CMV DNA detection by 0–2 weeks (median 1 week) and CMV antigen detection by 0–8 weeks (median 3 weeks). Once detected, the SLG RNA remained consistently positive before antiviral treatment was commenced. Both the SLG RNA and CMV DNA detection methods had the same clinical sensitivity, specificity, positive and negative predictive values of 100, 94, 80 and 100%, respectively. Conclusions: The RT-PCR for SLG RNA proved to be the earliest indicator of CMV infection in BMT patients demonstrating a sustained pattern of CMV detection during the 3 months post-transplant period. Although very similar in its diagnostic performance to CMV DNA PCR the SLG RNA RT-PCR does not require quantitation and provides an efficient and ongoing indication of active CMV infection.” (Abstract).
Regarding claim 15, Boriskin teaches a method comprising “we examined the clinical utility of the RT-PCR for one of the CMV SLG glycoproteins, the UL21.5 … as part of the surveillance protocol for CMV infection” (Pg. 14, Introduction, last Para.). Boriskin teaches a comprising “UL21.5 mRNA” (Pg. 20, Col 2, Para. 1). Boriskin teaches a method comprising “Anticoagulated blood (0.5–10 ml) was separated… extracted for RNA” (Pg. 15, Col. 2, 2.3. Blood specimen processing for PCR, Para. 1). Boriskin teaches a method comprising “RT reaction mixture” (Pg. 16, 2.4. DNA PCR and RT PCR for CMV, Para. 2). Boriskin teaches a method comprising “SLG primers” (Pg. 20, Col. 2, Para. 1). “… CMV RNA … dropped to undetectable levels within 2 weeks after initiation of anti-CMV treatment…” (Pg. 18. Col 1., Para. 1; Fig. 2). Thus, Boriskin teaches A method for detection and/or quantification of a human cytomegalovirus (hCMV) virion mRNA in a sample obtained from a patient treated with an antiviral drug, comprising the steps of: i) optionally removing from the sample obtained from the patient any cellular component that might be present, obtaining a cell-free sample; ii) extracting RNA from a cell-free sample obtained from the patient or from the cell- free sample obtained in step i); iii) forming a reaction mixture by contacting said RNA extracted in step ii) with a solution comprising: a) one or more primer pairs specific for said hCMV virion mRNA; b) an RNA-dependent DNA polymerase; c) a DNA polymerase; iv) subjecting said reaction mixture to a reverse transcription process under conditions suitable to generate a cDNA corresponding to said hCMV virion mRNA; v) subjecting said cDNA to an amplification process under conditions adapted to generate an amplification product constituted by DNA; vi) detecting a presence and/or quantifying the quantity of said amplification product constituted by DNA, as an indication of the presence and/or of the quantity of hCMV virion mRNA in the sample obtained from the patient.
The teachings of Boriskin are documented above in the rejection of claim 15 under 35 U.S.C. 103. Claims 18 and 21-23 depend on claim 15.
Regarding claim 18, Boriskin teaches a method wherein “RT-PCR” (Pg. 14, Introduction, last Para.). Thus, Boriskin teaches a method wherein said amplification process is polymerase chain reaction (PCR).
Regarding claim 21, Boriskin teaches a method wherein “Anticoagulated blood (0.5–10 ml) was separated on a Histopaque gradient” (Para.). “Anticoagulated blood (0.5–10 ml) was separated on a Histopaque gradient” reads on plasma optionally containing an anticoagulant. Thus, Boriskin teaches a method wherein said sample obtained from the patient is selected from a group consisting of plasma optionally containing an anticoagulant, serum, urine, saliva, oral swab supernatant, cerebrospinal fluid (CSF), bronchoalveolar lavages (BAL), nasopharyngeal lavages, nasopharyngeal aspirates, pharyngeal swab supernatant, tear fluid, vitreous humor, eye swab supernatant, fecal supernatant.
Regarding claims 22-23, Boriskin teaches a method wherein “CMV RNA UL21.5” (Pg. 20, Col. 1, Para. 3). Thus, Boriskin teaches a method wherein said hCMV virion mRNA is an mRNA of a gene.
Therefore, the invention as recited in claims 15, 18 and 21-23 are prima facie obvious over the prior art Boriskin et al. One of ordinary skill in the art would have had a reasonable expectation of success given the lack of novelty. It would have been obvious to provide a method for detection and/or quantification of a human cytomegalovirus (hCMV) virion mRNA in a sample according to the limitations of the instant application claims 15, 18 and 21-23 based on Boriskin.
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Boriskin et al. (“Boriskin”; (2001). Human cytomegalovirus UL21.5 gene is expressed as an "early-late" gene in cultured human fibroblasts. Acta virologica, 45(3), 185–189.), as applied to claim 15, and further in view of Bentwich et al. (“Bentwich”; US Patent No. US 7696334 B1, Apr. 13, 2010), Tarnowski et al. (“Tarnowski”; US Patent No. US 5202239 A, Apr. 13, 1993), Diffenbach et al. (“Diffenbach”; PCR methods and Applications (1993) volume 3, pages S30-S37) and Kenneth Roux (“Roux”; PCR Methods and Applications (1995) volume 4, pages s185-s194).
The teachings of Boriskin are documented above in the rejection of claims 15, 18 and 21-23 under 35 U.S.C. 103. Claim 16 depends on claim 15.
Regarding claim 16, Boriskin teaches a method wherein the primers are “SLG primers” (Pg. 20, Col. 2, Para. 1).
However, Boriskin does not explicitly teach the recited primer i) SEQ ID No: 52 and ii) SEQ ID No. 75.
Bentwich discloses “The present invention relates to a group of novel viral RNA regulatory genes, here identified as "viral genomic address messenger genes" or "VGAM genes", and as "genomic record" or "GR" genes. VGAM genes selectively inhibit translation of known host target genes, and are believed to represent a novel pervasive viral attack mechanism. GR genes encode an operon-like cluster of VGAM genes. VGAM and viral GR genes may therefore be useful in diagnosing, preventing and treating viral disease. Several nucleic acid molecules are provided respectively encoding several VGAM genes, as are vectors and probes, both comprising the nucleic acid molecules, and methods and systems for detecting VGAM genes, and for counteracting their activity.” (Abstract)
Regarding claim 16, SEQ ID No: 52, Bentwich teaches a sequence comprising 100% identity to 20 nt of Human herpesvirus 5 (see alignment below, Result 14). Human herpesvirus 5 reads on hCMV.
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Tarnowski discloses “Methods and compositions are provided for oligonucleotides that bind target biomarkers and allow characterization of a phenotype. The target biomarkers may include microvesicle antigens, including microvesicles derived from various diseases. The characterization may comprise detection, diagnosis, prognosis, theranosis or other characterization of a disease or disorder.” (Abstract)
Regarding claim 16, SEQ ID No: 75, Tarnowski teaches a sequence comprising 100% identity to 18 nt (see alignment below, Sequence 12).
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Regarding claim 16, Diffenbach teaches parameters and principles of promoter design include primer length, terminal nucleotide, GC content, melting temperature, PCR product length and placement of target sequence (s30-s34). Diffenbach teaches PCR software was known (s35).
Regarding claim 16, Roux teaches optimization of PCR by the presence of enhancing agents, Mg2+, annealing temperature, primer design, cycle number, hot start PCR (s185-s194).
Designing oligonucleotides to hybridize to specific targets, which are equivalents to those taught in the art, is routine experimentation. The prior art teaches the parameters and objectives involved in the selection of oligonucleotides that function as primers, see Diffenbach and Roux. The prior art is replete with guidance and information necessary to permit the ordinary artisan in the field of nucleic acid detection to design primer. As discussed above, the ordinary artisan would be motivated to have designed and tested new primers to obtain additional oligonucleotides that function to detect hCMV and identify oligonucleotides with improved properties for such detection. Thus, for the reasons provided above, the ordinary artisan would have designed additional oligonucleotides using the teachings in the art at the time the invention was made. The claimed primer sequences are obvious over the cited prior art, absent secondary considerations.
Boriskin, Bentwich and Tarnowski, are considered to be analogous to the claimed invention because they are in the same field of disease detection, in particular viral disease. Boriskin, Bentwich, Tarnowski, Diffenbach and Roux are considered to be analogous to the claimed invention because they are in the same field of designing primers to a target sequence. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detection of human cytomegalovirus (hCMV) virion mRNA in a sample obtained from a patient treated with an antiviral as taught by Boriskin to incorporate the method wherein the primer selected has sequence selected from SEQ ID No: 52 as taught by Bentwich, wherein the primer selected has sequence selected from SEQ ID No: 75 as taught by Tarnowski, and wherein the primer is designed to hybridize to specific targets as taught by Diffenbach and Roux and provide limitations according to claim 16. Doing so would allow for detection of hCMV using primers designed to a specific regions the hCMV genome.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Boriskin et al. (“Boriskin”; (2001). Human cytomegalovirus UL21.5 gene is expressed as an "early-late" gene in cultured human fibroblasts. Acta virologica, 45(3), 185–189.), in view of Bentwich et al. (“Bentwich”; US Patent No. US 7696334 B1, Apr. 13, 2010), Tarnowski et al. (“Tarnowski”; US Patent No. US 5202239 A, Apr. 13, 1993), Diffenbach et al. (“Diffenbach”; PCR methods and Applications (1993) volume 3, pages S30-S37) and Kenneth Roux (“Roux”; PCR Methods and Applications (1995) volume 4, pages s185-s194). as applied to claim 16, and further in view of Liu et al. (“Liu”; US Patent No. US 7407744 B2, Aug. 5, 2008).
The teachings of Boriskin, Bentwich, Tarnowski, Diffenbach and Roux are documented above in the rejection of claim 16 under 35 U.S.C. 103. The teachings of Boriskin are documented above in the rejection of claim 15 under 35 U.S.C. 103. Claim 17 depends on claim 16, which depends on claim 15.
However, Boriskin, Bentwich, Tarnowski, Diffenbach and Roux do not explicitly teach further comprising the recited primer SEQ ID No: 87.
Liu discloses “A global functional analysis of HCMV genes is performed by constructing virus gene-deletion mutants and examining their growth phenotypes in different natural HCMV host cells. This systematic analysis of the HCMV genome identified 45 viral ORFs essential for viral replication and characterizes of 115 growth-dispensable viral genes. Of particular interest is the finding that HCMV encodes genes (temperance factors) that repress its own replication on a cell type-specific basis. In addition to HCMV, pathogen temperance may be a strategy employed by other infectious agents to enhance their long-term survivability within their respective host population.” (Abstract)
Regarding claim 17, SEQ ID No: 87, Liu teaches a sequence comprising 100% identity to 24 nt of cytomegalovirus (see alignment below, Result 5). Cytomegalovirus reads on hCMV.
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Designing oligonucleotides to hybridize to specific targets, which are equivalents to those taught in the art, is routine experimentation. The prior art teaches the parameters and objectives involved in the selection of oligonucleotides that function as primers, see Diffenbach and Roux. The prior art is replete with guidance and information necessary to permit the ordinary artisan in the field of nucleic acid detection to design primer. As discussed above, the ordinary artisan would be motivated to have designed and tested new primers to obtain additional oligonucleotides that function to detect hCMV and identify oligonucleotides with improved properties for such detection. Thus, for the reasons provided above, the ordinary artisan would have designed additional oligonucleotides using the teachings in the art at the time the invention was made. The claimed primer sequences are obvious over the cited prior art, absent secondary considerations.
Boriskin, Bentwich, Tarnowski and Liu are considered to be analogous to the claimed invention because they are in the same field of disease detection, in particular viral disease. Boriskin, Bentwich, Tarnowski, Liu, Diffenbach and Roux are considered to be analogous to the claimed invention because they are in the same field of designing primers to a target sequence. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detection of human cytomegalovirus (hCMV) virion mRNA in a sample obtained from a patient treated with an antiviral as taught by Boriskin to incorporate the method wherein the primer selected has sequence selected from SEQ ID No: 52 as taught by Bentwich, wherein the primer selected has sequence selected from SEQ ID No: 75 as taught by Tarnowski, further comprises a primer selected has sequence selected from SEQ ID No: 87 as taught by Liu, and wherein the primer is designed to hybridize to specific targets as taught by Diffenbach and Roux and provide limitations according to claim 17. Doing so would allow for detection of hCMV using primers designed to a specific regions the hCMV genome.
Claims 19-20 is rejected under 35 U.S.C. 103 as being unpatentable over Boriskin et al. (“Boriskin”; (2001). Human cytomegalovirus UL21.5 gene is expressed as an "early-late" gene in cultured human fibroblasts. Acta virologica, 45(3), 185–189.) as applied to claim 15, and further in view of Morgan Hakki (“Hakki”; (2020). Moving Past Ganciclovir and Foscarnet: Advances in CMV Therapy. Current hematologic malignancy reports, 15(2), 90–102.).
The teachings of Boriskin are documented above in the rejection of claims 15, 18, and 21-23 under 35 U.S.C. 103. Claim 20 depends on claim 19, which depends on claim 15. Claim 15 does not specifically claim an antiviral drug capable of interfering with the cleavage and encapsidation see U.S.C. 112 (d) rejection above. However, Boriskin does not explicitly teach antiviral drug capable of interfering with the cleavage and encapsidation of hCMV DNA is a viral terminase complex inhibitor.
Hakki discloses “CMV DNA polymerase inhibitors such as ganciclovir and foscarnet have dramatically reduced the burden of CMV infection in the HCT recipient. However, their use is often limited by toxicities and resistance. Agents with novel mechanisms and favorable toxicity profiles are critically needed. We review recent developments in CMV antivirals and immune-based approaches to mitigating CMV infection. Letermovir, an inhibitor of the CMV terminase complex, was approved in 2017 for primary CMV prophylaxis in adult seropositive allogeneic HCT recipients...” (Abstract).
Regarding claims 19-20, Hakki teaches a method wherein “letermovir’s mechanism of action involved targeting the terminase complex” (Mechanism of Action and Pharmacology, Para. 2; Table 1). Thus, Boriskin and Hakki teaches a method wherein said antiviral drug capable of interfering with the cleavage and encapsidation of hCMV DNA is a viral terminase complex inhibitor.
Boriskin and Hakki are both considered to be analogous to the claimed invention because they are in the same field of Human Cytomegalovirus treatment. Therefore, it would have been obvious to someone of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of detection of human cytomegalovirus (hCMV) virion mRNA in a sample obtained from a patient treated with an antiviral as taught by Boriskin to incorporate the method wherein the antiviral drug is capable of interfering with cleavage as taught by Hakki and provide limitations according to claim 19-20. Doing so would allow for detection of hCMV using a newer approved antiviral with no major toxicities and decreased resistance.
Conclusion
No claims are in condition for allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KENDRA R VANN-OJUEKAIYE whose telephone number is (571)270-7529. The examiner can normally be reached M-F 9:00 AM- 5:00 PM.
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/KENDRA R VANN-OJUEKAIYE/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682