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 .
Status of Claims
Applicant's amendment filed 03/06/2026 is acknowledged. Claims 1 and 10 have been amended. Claims 15-20 have been added. Claims 1-20 are pending in the instant application and the subject of this final office action.
All of the amendments and arguments have been reviewed and considered. Any rejections or objections not reiterated herein have been withdrawn in light of amendments to the claims or as discussed in this office action.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Previous Rejection
Status of Prior Rejections/Objections:
The specification objection is withdrawn in view of the amendments.
The 112(b) rejections of claim(s) 10 is/are withdrawn in view of the amendments to the claims.
The 101 rejections of claims 1-14 are withdrawn in view of the amendments to claim 1 and the arguments.
The prior art rejection(s) under 35 USC 102 directed to claim(s) 1, 4, and 9 as being anticipated by Piepenburg is/are maintained and modified as necessitated by claim amendments.
The prior art rejection(s) under 35 USC 103 directed to claim(s) 1, 4, and 9-10 as being unpatentable over Piepenburg is/are maintained modified as necessitated by claim amendments; the corresponding rejections directed to claims 5-6 are withdrawn in view of the amendments.
The prior art rejection(s) under 35 USC 103 directed to claim(s) 1-10 as being unpatentable over Georgiou, as evidenced by Tanner are maintained and modified as necessitated by claim amendments. See also rejection of new claim 15 over the same.
The prior art rejection(s) under 35 USC 103 directed to claim(s) 11-14 as being unpatentable over Georgiou in view of Gnann, as evidenced by Tanner are maintained. See also rejection of new claim 20 over the same.
The double patenting rejections over 18/008,809 and 18/009,498 are maintained and modified as necessitated by amendments. See new double patenting rejections in view of the new claims.
New Ground(s) of Rejections
The new ground(s) of rejections were necessitated by applicant’s amendment of the claims.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Objections
Claims 10 and 15 are objected to because of the following informalities:
Claims 10 and 15 recite “the double-stranded elongated DNA sequence” in lines 1-2. These should be changed to “a double-stranded elongated DNA sequence”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
Claims 10, 17, and 19-20 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.
Regarding claim 10, the amended claim recites “the elongated strand”. There is insufficient antecedent basis for this limitation in the claim. It is further unclear how the artisan is to determine which strand is “the” elongated strand.
Regarding claims 17 and 19, the new claims recite “the primer sequences”. There is insufficient antecedent basis for this limitation in the claims. It is unclear whether the primer sequences are referring to all of or a subset of “the five DNA primers” of claim 16.
Regarding claim 20, the new claim recites “an efficient amount” in (f). The term “efficient” is a relative term which renders the claim indefinite. The term “efficient” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The specification defines “most efficient” in the context of detection on pg. 6; however, it is not clear what is meant by “efficient amount” in the context of treatment. For example, financial efficiency may mean small amount whereas time efficiency may be a large amount. Therefore, the metes and bounds cannot be understood by one of ordinary skill in the art.
Claim Rejections - 35 USC § 102
Claim(s) 1, 4, and 9 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Piepenburg (Piepenburg O, et al. DNA detection using recombination proteins. PLoS Biol. 2006 Jul;4(7):e204.).
Regarding claims 1, 4, and 9, Piepenburg teaches a method comprising:
Adding Bsu to human DNA [i.e., a sample from one or more human subjects] (pg. 1118, RPA conditions, para 1; pg. 1118, Proteins and DNA; pg. 1120, Figure S3, para 1; pg. 1115, Results/Discussion para 1; instant claim 4).
Adding at least six primers to the sample (pg. 1118, RPA conditions, para 1; Figure S3., para 1), wherein at least one primer is hybridizable to one strand, and the other is hybridizable to its reverse-complement (Fig. 1) and wherein any one of the targets may be considered the pre-determined the nucleic acid sequence
Incubating at a temperature for 120 min (pg. 1120, Figure S3, para 1; instant claim 9)
Determining whether an elongated DNA sequence is present in the sample wherein the elongated DNA sequence is indicative of the pre-determined nucleic acid in the sequence (Fig. 2), wherein any of the targeted genes (ApoB, Sry, or PBDG) may be considered the “pre-determined nucleic acid sequence”
F3 is not among the primers used in Piepenburg (pg. 1118, RPA conditions, para 1).
Piepenburg teaches that Bsu strand displacing activity (pg. 1115, Introduction, para 2) and that RP utilize a DNA polymerase (pg. 1115, Introduction, para 2). As Bsu is a functioning as DNA polymerase operating on a DNA substrate, it is thus interpreted to be a DNA-dependent DNA polymerase.
As amended, the claim recites that two or more of the DNA primers are loop primers. The specification defines the term loop primer as “a DNA primer comprising a sequence that is hybridisable to at least one loop region of an amplification product of the pre-determined RNA sequence” (pg. 7, para 1) and a loop region as a region “formed by the annealing of a strand of an amplification product to itself” (pg. 7, para 1).
Piepenburg teaches that the apoB 300 bp amplicons underwent hairpin-mediated product duplication (pg. 1120, Supporting Information, Fig. S2), wherein the ~300 bp product was chosen for the multiplex analysis (Fig. 2). Thus, the artisan would understand the apoB and apo300 primers to be loop primers as they are a sequence hybridisable to a region capable of participating in forming a stem of a hairpin once amplified if apoB is considered the pre-determined nucleic acid (see also pg. 1118, RPA conditions).
For at least these reasons, claims 1, 4, and 9 are anticipated by Piepenburg because they teach each and every element of the claims.
Claim Rejections - 35 USC § 103
Claim(s) 1, 4, and 9-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Piepenburg (Piepenburg O, et al. DNA detection using recombination proteins. PLoS Biol. 2006 Jul;4(7):e204.).
Regarding claims 1, 4, and 9, as cited and discussed in the 102 above, Piepenburg teaches adding a DNA-dependent DNA polymerase with SDA to a human DNA sample (pg. 1118, RPA conditions, para 1; pg. 1118, Proteins and DNA; pg. 1120, Figure S3, para 1; pg. 1115, Results/Discussion para 1; pg. 1115, Introduction, para 2; instant claim 4); adding at least six primers to the sample (pg. 1118, RPA conditions, para 1; Figure S3., para 1), wherein the pairs of primers are hybridizable to antiparallel strands of the DNA (Fig. 1) wherein any one of the targets may be considered the pre-determined the nucleic acid sequence; incubating at a temperature for 120 min (pg. 1120, Figure S3, para 1; instant claim 9); and determining whether an elongated DNA sequence is present in the sample wherein the elongated DNA sequence is indicative of the pre-determined nucleic acid in the sequence (Fig. 2), wherein any of the targeted genes may be considered the “pre-determined nucleic acid sequence”. F3 is not among the primers used in Piepenburg (pg. 1118, RPA conditions, para 1).
As amended, the claim requires two or more primers are loop primers, which have been interpreted according to the definition recited above. Piepenburg teaches that the apoB 300 bp amplicons underwent hairpin-mediated product duplication (pg. 1120, Supporting Information, Fig. S2), wherein the ~300 bp product was chosen for the multiplex analysis (Fig. 2). Thus, the artisan would understand the apoB and apo300 primers to be loop primers as they are a sequence hybridisable to a region capable of participating in forming a stem of a hairpin once amplified
Regarding claims 10, Piepenburg teaches detection of the RPA product using a probe-based method, including in a multiplex reaction (Fig. 3-5).
Piepenburg teaches that the RPA and nuclease sensitive fluorophore/quencher probes constitute a DNA amplification/detection system that would require no other equipment than a simple handheld fluorometer, thus making quantitative DNA testing potentially accessible in a non-laboratory point-of-care environment (pg. 1118, col 1, para 1).
Piepenburg fails to explicitly teach a method detecting apoB using a nucleic acid molecule that may hybridize to an elongated strand of the elongated DNA sequence.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective date of the claimed invention to substitute the intercalating molecule for the nuclease sensitivity probe, as they are taught as equivalents for the same purpose in a lab setting and/or motivated by the desire to further simplify for a non-clinical setting, as taught by Piepenburg. There would have been a strong expectation of success as all methods utilize the same amplification technology and represent the application of a known technique to a known method.
Claim(s) 1-10 and 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Georgiou (WO 2019/234251 A1; published 12/12/2019), as evidenced by Tanner (Tanner, N. Improved Reagents for Isothermal Amplification [Internet]. Ipswich (MA): New England Biolabs, Inc.; 2015 Apr [cited 2025 Aug 26]. Available from: https://www.neb-online.de/wp-content/uploads/2015/04/NEB_isothermal_amp.pdf).
Regarding claims 1, Georgiou teaches a method for determining presence of a pre-determined nucleic acid sequence in a sample (pg. 47), the method comprising the steps of:
(a) adding an enzyme to the sample to be analysed for the presence of the pre-determined nucleic acid sequence (pg. 47, lines 5-8), wherein the enzymes provide activities of RNA- and/or DNA-dependent DNA polymerase activity and strand-displacement activity (pg. 9, para 5-6; pg. 2, para 9);
(b) adding at least five DNA primers to the sample to be analysed for the presence of the pre-determined nucleic acid sequence, wherein at least one DNA primer comprises a sequence hybridisable to the nucleic acid sequence and at least one DNA primer comprises a sequence hybridisable to the DNA sequence reverse-complementary to the nucleic acid sequence (pg. 47: (iv): FIP, (v): BIP, (vi): forward blocking, (vii): backward blocking; pg. 23, lines 10-11: forward loop primer and backward loop primer; pg. 22, lines 22-23; pg. 22, lines 36-37)
(c) incubating the sample resulting from steps (a) and (b) at a fixed temperature (pg. 47, (a): “amplifying under isothermal conditions” [i.e., a fixed temperature]);
(d) determining whether an elongated DNA sequence is present in the sample, wherein presence of the elongated DNA sequence in the sample is indicative of the presence of the pre-determined nucleic acid sequence in the sample (pg. 47, (b))
Georgiou teaches a polymerase with strand-displacement activity at least by teaching that the DNA polymerase when the nucleic acid sequence is DNA may be Bst 2.0 DNA polymerase (pg. 9, para 5), evidenced by Tanner. While Georgiou does not explicitly teach that the polymerase itself has strand-displacement activity, it is inherently taught because Bst 2.0 has strand-displacement activity, evidenced by Tanner (pg. 4, para 1: “Bst 2.0 DNA polymerase possesses … strong strand-displacement activity”).
Georgiou teaches an embodiment without F3 (pg. 22, lines 22-23: “The reaction mixture may further comprise … F3 … and/or … B3 …” (emphasis added); pg. 22, lines 36-37: “The present inventors have determined that detectable amplification of the nucleic acid can occur in the absence of F3 and/or B3”). Georgiou teaches [traditional] LAMP uses four to six primers in the reaction (pg. 2, line 9), and that the efficiency of the reaction is enhanced by the addition of B3 (pg. 23, lines 6-7) and LF and LB (pg. 23, line 22).
Georgiou teaches that detection of genetic markers is still a major challenge for molecular-based diagnostic technologies, especially for those aiming to be deployed at point-of-care (PoC) (pg. 1, para 2).
Georgiou does not explicitly teach that the sample is from a human subject.
Georgiou rectifies this by teaching that the sample may be a clinical sample (pg. 24, line 1-2) from a patient (pg. 24, line 22). Georgiou teaches that the method is a method for the treatment of an infectious disease in a subject in need thereof (pg. 47, lines 1-2) and that infectious diseases can be spread from one person [i.e., human] to another (pg. 48, para 3). Georgiou teaches that the infectious disease may be selected from infectious diseases including Human Immunodeficiency Virus (HIV) and Human Papillomavirus (HPV) (pg. 48, line 38) or human-infective malaria (pg. 25, line 19).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized human samples in the method of Georgiou as evidenced by Tanner, motivated by the desire to detect and administer the drug to the subject who is in need thereof and/or to address treatment to the species of the human infectious diseases of Georgiou and address the threats to global public health, as taught by Georgiou.
It further would have been oblivious the POSITA before the EFD of the claimed invention to have added LF [instant LPF] and LB [instant LPB], i.e., loop primers, and/or B3 in the method of determining the presence of a sequence in a sample Georgiou evidenced by Tanner, motivated by the desire to increase the efficiency the reaction, as taught by Georgiou.
There would have been a strong expectation for success as the methods fall within the scope of Georgiou and are a combination of prior art elements according to known methods to yield predictable results.
Further, while Georgiou teaches embodiments with FIP, BIP, FB, BB, LF, LB, and B3 (at least 5 primers), the total number of primers utilized represents a matter for efficiency/optimization, as taught by Georgiou (e.g., typical number of LAMP primers, addition of LB and LF and/or B3).
It is noted that the courts have found that “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05 II. Thus, the claimed range of the number of primers merely represents routine optimization of the values of the cited prior art.
Regarding claim 2, in the method of Georgiou as evidenced by Tanner, as cited in the rejection of claim 1, Georgiou teaches primers including FIP and BIP in the method and an embodiment in which LF [instant LPF] and LB [LPB] are added to improve efficiency. The same motivations and expectations for success as above apply.
Regarding claim 3, in the method of Georgiou as evidenced by Tanner, as cited in the rejection of claim 1, Georgiou teaches a method with FIP, BIP, and forward and backward blocking primers and an embodiment in which B3 is added to improve efficiency. The same motivations and expectations for success as above apply.
Regarding claim 4, in the method of Georgiou as evidenced by Tanner, Georgiou teaches that the nucleic acid sequence may be DNA or RNA (pg. 9, line 30).
Regarding claim 5, in the method of Georgiou as evidenced by Tanner, Georgiou teaches that the nucleic acid may be from a pathogen (pg. 25, line 2).
Regarding claim 6, in the method of Georgiou as evidenced by Tanner, Georgiou teaches the pathogen [i.e., infectious disease; see also pg. 48, line 19] may be a virus, a bacterium, a fungus, or a parasite (pg. 25, lines 7-9; pg. 48, line 20).
Regarding claim 7, in the method of Georgiou as evidenced by Tanner, Georgiou teaches the pathogen [i.e., infectious disease] may be Herpes Zoster VZV [i.e., Human Herpesvirus 3] (pg. 48, line 38).
Regarding claim 8, in the method of Georgiou as evidenced by Tanner, Georgiou teaches that the temperature for the isothermal conditions may be around 50 C to 70 C (pg. 6, line 8).
Regarding claim 9, in the method of Georgiou as evidenced by Tanner, Georgiou teaches the amplifying duration may be around 1 to 150 minutes and ranges in between (pg. 6, para 2).
Regarding claims 10 and 15, in the method of Georgiou as evidenced by Tanner, Georgiou teaches determination of the presence of the double-stranded elongated DNA molecule by using a nucleic acid molecule hybridizable to an elongated strand of the elongated DNA sequence is present by teaching Georgiou teaches detection by turbidity and nucleic acid intercalating agents (pg. 7, line 8), as interpreted under the BRI. See, for example, instant pg. 16, para 1-2.
Claim(s) 11-14 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Georgiou (WO 2019/234251 A1; published 12/12/2019), as evidenced by Tanner (New England Biolabs, Inc. Isothermal Amplification [Internet]. Ipswich (MA): New England Biolabs, Inc.; 2015 Apr [cited 2025 Aug 26]. Available from: https://www.neb-online.de/wp-content/uploads/2015/04/NEB_isothermal_amp.pdf) as applied to claim 1 above, and further in view of Gnann (Gnann Jr. JW. Antiviral therapy of varicella-zoster virus infections. In: Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007. Chapter 65. Available from: https://www.ncbi.nlm.nih.gov/books/NBK47401/).
Regarding claims 11-14 and 20, in the method of Georgiou as evidenced by Tanner, Georgiou further teaches that the method is a method for the treatment of an infectious disease or a drug-resistant infection in a subject in need thereof (pg. 47, lines 1-2) and that it further comprises administering a drug to the subject in need thereof (pg. 47, (c)).
Georgiou teaches that treating the infectious disease comprises administration of a therapeutic agent to which the infection is not resistant [i.e., an anti-infective composition] (pg. 48, para 1).
As cited in claim 7, Georgiou teaches that the pathogen [i.e., infectious disease] may be Herpes Zoster VZV [i.e., Human Herpesvirus 3] (instant claims 12 and 14; for 12, see also the citations of claim 6 above).
Georgiou fails to explicitly teaches “an effective dose”.
Gnann rectifies this by teaching that oral acyclovir, dosed at 800 mg five times daily for 7 days, was capable of accelerating cutaneous healing and to reduce the severity of acute neuritis in immunocompetent adults with herpes zoster (pg. 7, Immunocompetent adults, para 2).
Thus, Gnann teaches an effective does of an anti-viral composition. (instant claims 13).
Gnann teaches that the outcomes of varicella and herpes zoster, especially in immunocompromised patients, have been dramatically improved by the development of safe and effective antiviral drugs with potent activity against VZV (pg. 1, Introduction, para 1).
Therefore, it would have been obvious to one of ordinary skill the art before the effective filing date of the claimed invention to have utilized the anti-viral and effective dose thereof of Gnann in the method of Georgiou as evidence by Tanner, motivated by the desire to improve the outcomes of at least immunocompromised patients, as taught by Georgiou. There would have been a strong expectation of success as both are directed toward treating infectious diseases and represent the application of a known technique/compound to a known method.
Claim(s) 15-17 and 19-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over in view of Gong (CN 103898222 B; published 09/09/2015) in view of Koliou (Koliou MG, et al. Mycoplasma pneumoniae as a cause of vulvar ulcers in a non-sexually active girl: a case report. J Med Case Rep. 2017 Jul 9;11(1):187).
This rejection is made only as necessitated by applicant’s amendment introducing claims 15-20. No inference should be drawn that claims 1-14 are not also rejectable under Koliou in view of Gong, as evidenced by Tanner.
Regarding claim 15-17 and 19-20, Gong teaches using LAMP as a detection method comprising designing 4-6 specific primers for regions of a target gene and using a strand displacement DNA polymerase to specifically amplify copies of the target sequence under isothermal conditions (para [0006]). Gong teaches that this method maintains the advantages of traditional PCR technology and further improves the specificity of the reactions and shortens detection time and further teaches the application to “various pathogenic microorganisms” (para [0006]).
Gong teaches that set of six DNA primers may comprise F3, B3, FIP, BIP, LF, and LB (e.g., claims 1-3; para [0068-0069]); incubating at a fixed temperature (claim 2, step 4; claim 2; Example 1); and detecting amplification with an intercalating dye (para [0025]) or turbidity measurement (para [0034]) (instant claim 15).
Gong teaches and embodiments where each of the outer and inner primers, including both of each, were sequentially left out, including where F3 is left out, that was performed as part of optimization (Fig. 3; para [0068]; instant claim 16). Gong teaches that a single outer primer can initiate the LAMP reaction (para [0069]). Gong also teaches optimizing the concentration of the ratio of outer primers to inner primers (para [0065]).
Gong teaches that its method can be used in primary healthcare units to screen and detect a bacterium and is rapid, efficient, easy to operate, highly specific, and highly sensitive (Abstract).
Gong fails to explicitly teach:
that the sample is from a human subject;
that the primer sequences target a sequence of M. pneumoniae (claim 17 and 20);
that the primer sequences target a sequence of human HSV-1 (claims 19 and 20); and
treating the human subject with an anti-infective after determining there had been a human herpesvirus of Mycoplasma infection (claim 20).
Koliou teaches performing PCR on tissue for HSV and M. pneumoniae (pg. 2, col 1, para 3 spanning col 2, para 1) and testing for antibodies against HSV1 and HSV2 (pg. 2, col 1, para 3) on a patient with genital ulcers and upper respiratory symptoms (Abstract; pg. 2, col 1, para 1-2).
Koliou teaches that the RT-PCR M. pneumoniae in nasopharyngeal secretions was positive and strongly positive in two consecutive sputum specimens, but the PCR for Mycoplasma in the tissue specimen from the genital lesions was found negative (pg. 2, col 1, para 3 spanning col 2, para 1). Koliou teaches that, when such ulcers develop in an adolescent, the differential diagnosis should include infections that may or may not be sexually transmitted such as an HSV and M. pneumoniae (pg. 3, col 1, para 3). Koliou teaches that direct detection of M. pneumoniae nucleotide sequences from clinical specimens has been proven to be a very sensitive and specific approach, which offers a rapid diagnosis of infection and the utilization of a combined approach with serology may surpass the limitations of either technique when used alone (pg. 3, col 1, para 1).
Koliou teaches administration of local antimicrobial treatment such as azithromycin significantly improved the skin lesions of the patient (pg. 3, col 2, lines 2-5).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized the LAMP method of Gong to the [human] clinical specimens of Koliou to detect M. pneumoniae (claims 17 and 20), either with or without a combination with serology techniques, motivated by the desire to expand the clinical applications of Gong to further targets/samples and/or to further improve the sensitivity and specificity of the of the nucleotide sequence detection of Koliou (e.g., to be able to improve detection in tissue in addition to sputum), as taught or suggested by Koliou and Gong, respectively. It further would have been obvious to the POSITA before the EFD of the claimed invention to have likewise adapted the LAMP method of Gong to detect HSV-1 (claims 19 and 20) for the same motivations as above and further because Koliou teaches HSV as a differential diagnosis, wherein HSV-1 is an obvious species of the genus of “an HSV” as taught by Koliou. It also would have been obvious to the POSITA before the EFD of the claimed invention to have treated the patient with at least local care using the antimicrobial treatment after detection of the infection with M. pneumoniae, as indicated by the presence of at least M. pneumoniae nucleic acid, motivated by the teachings of Koliou that such significantly improve patient skin lesions while the infection was still active.
In optimizing the combined method of Gong in view of Koliou, it would have been obvious to perform the same routine optimization of the number of primers of Gong to leave out each of the inner and outer primers and analyze the reaction for efficiency, where the artisan would have arrived at the solution to leave out F3 if efficiency were improved for the targets of M. pneumoniae and HSV-1, as demonstrated by Gong, and/or to save on material costs/complexity in a reaction, as Gong teaches that a single outer primer is sufficient to initiate the LAMP reaction.
There would have been a strong expectation of success as both Gong and Koliou are directed to the detection of pathogenic nucleic acids in a clinical setting, and such represents only the use of a known technique to improve a similar method in the same way. The removal of F3 would likewise be predictable as Gong teaches that LAMP functions without it.
Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over of Gong (CN 103898222 B; published 09/09/2015) in view of Koliou (Koliou MG, et al. Mycoplasma pneumoniae as a cause of vulvar ulcers in a non-sexually active girl: a case report. J Med Case Rep. 2017 Jul 9;11(1):187). as applied to claims 15-17 and 19-20 above, and further in view of Cai (CN 107630097 A; published 01/26/2018).
Regarding claim 18, Gong and Koliou fail to teach specific LAMP primers for M. pneumoniae or HSV-1.
Cai teaches a primer set for detection of common pathogens causing urogenital tract infections including HSV-1 that is suitable for primary care hospitals (Abstract).
Cai teaches:
SEQ ID NO: 21 (instant SEQ ID NO: 7, FIP);
SEQ ID NO: 22 (instant SEQ ID NO: 8, BIP);
SEQ ID NO: 23 (instant SEQ ID NO: 9, LPF);
SEQ ID NO: 24 (instant SEQ ID NO: 10, LPB);
SEQ ID NO: 20 (instant SEQ ID NO: 11, B3);
As all sequences of Cai are 100% identical to the instant sequence, they are interpreted to have the same functionality.
Cai teaches use of the primers in a method for such detection and that it is simple, accurate, and sensitive (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the nucleic acid sequences of set of Cai in the combined method to detect HSV-1, motivated by the teachings of Cai that they were art-recognized as suitable for the same purpose of urogenital tract detection of HSV-1 infections (see MPEP 2144.07) and/or in order to take advantage of a primer set taught to be accurate and sensitive as taught by Cai. As discussed above, it further would have been obvious to optimize the primer set in the method of Gong, including leaving out F3, for the same reasons as above with the same predictability. There would have been a strong expectation of success as Cai is likewise directed to nucleic amplification via LAMP and urogenital samples and such represents the application of a known product to a known technique.
Double Patenting
Claims 1-17 and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-11 and 16-17 of copending Application No. 18/008,809 in view of Cardinale (Cardinale F, et al. Macrolide-resistant Mycoplasma pneumoniae in paediatric pneumonia. Eur Respir J. 2011 Jun;37(6):1522-4.). This is a provisional nonstatutory double patenting rejection.
Both sets of claims are directed to a method of determining a presence of a pre-determined nucleic acid sequence in a sample comprising the steps of adding an RNA/DNA-dependent DNA polymerase with strand-displacement activity and at least five primers, incubating at a fixed sample, and determining whether an elongated DNA sequence is present in the sample, wherein the elongated DNA sequence is indicative of the pre-determined sequence in the sample and wherein no F3 primer is used.
‘809 claim 1 requires that the predetermined sequence be from Mollicutes, wherein ‘809 claim 5 recites that Mycoplasma is a bacterium of class Mollicutes. The incubation limitations of instant claims 8 and 9 are recited by ‘809 claims 10-11. The detection limitation of instant claim 10 and 15 is recited by ’809 claim 12 and 16.
‘809 claim 17 recites the five primer set.
Any additional limitations of the ‘809 claims are encompassed by the open claim language “comprising” found in the instant claims.
The claims of ‘809 fail to teach a method for treatment of a subject infected with a pathogen.
Cardinale rectifies this by teaching the importance of determining the prevalence of macrolide resistance among M. pneumoniae strains using molecular methods, and, in the case of macrolide failure during the course of treatment, optimizing the antibiotic strategy (pg. 1524, col 1, para 3), wherein ciprofloxacin treatment (40 mg*kg-^1*day^-1 in two doses) resulted in an improvement in condition of the patient [i.e., was effective] (pg. 1522, col 2, para 3). Cardinale teaches that an A-G transition at position 2,063 of the 23S rRNA gene of M. pneumoniae can be detected during adequate treatment with clarithromycin and seems to be associated with treatment failure (pg. 1524, col 1, para 3).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized the method of ‘809 to as the means of detecting the A-G transition at position 2,063 of the 23S rRNA gene indicative of macrolide resistance and to further choose an effective treatment, as taught by Cardinale, motivated by the desire to overcome the treatment failure and provide an effective (or “efficient amount of an”) antibiotic, as taught by Cardinale. There would be a strong expectation of success as both ‘809 and Cardinale are directed to molecular tests of Mollicutes including M. pneumoniae and the 23S rRNA gene, wherein such improvements represent the application of known techniques to known methods.
Claims 15-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-11 and 16-17 of copending Application No. 18/008,809 in view of Koliou (Koliou MG, et al. Mycoplasma pneumoniae as a cause of vulvar ulcers in a non-sexually active girl: a case report. J Med Case Rep. 2017 Jul 9;11(1):187) and further in view of Cai (CN 107630097 A; published 01/26/2018).
This rejection is made only as necessitated by applicant’s amendment introducing claims 15-20. No inference should be drawn that claims 1-14 are not also rejectable under ‘809 in view of Koliou in view of Cai.
Both sets of claims are directed to a method of determining a presence of a pre-determined nucleic acid sequence in a sample comprising the steps of adding an RNA/DNA-dependent DNA polymerase with strand-displacement activity and at least five primers, incubating at a fixed sample, and determining whether an elongated DNA sequence is present in the sample, wherein the elongated DNA sequence is indicative of the pre-determined sequence in the sample and wherein no F3 primer is used.
The detection limitation of instant claim 15 is recited by ’809 claim 16.
‘809 claim 17 recites the five primer set of instant claim 16
Any additional limitations of the ‘809 claims are encompassed by the open claim language “comprising” found in the instant claims.
‘809 fails to teach:
that the primers target M. pneumoniae or HSV-1;
specific primer sequences thereof; and
administering an “efficient amount” of an anti-infective composition to the human subject that was sampled when an infection has been determined.
As cited and discussed in the 103 rejections above, Koliou teaches:
detecting nucleic acids from M. pneumoniae and HSV;
that HSV-1 and HSV-2 are species of HSV; and
administering an anti-infective to a human subject from whom samples had been taken and from which samples it had been determined said subject was infected with a Mycoplasma species.
Koliou teaches that, when [urogenital] ulcers develop in an adolescent, the differential diagnosis should include infections that may or may not be sexually transmitted such as an HSV and M. pneumoniae (pg. 3, col 1, para 3). Koliou teaches that direct detection of M. pneumoniae nucleotide sequences from clinical specimens has been proven to be a very sensitive and specific approach, which offers a rapid diagnosis of infection and the utilization of a combined approach with serology may surpass the limitations of either technique when used alone (pg. 3, col 1, para 1).
Koliou teaches administration of local antimicrobial treatment such as azithromycin significantly improved the skin lesions of the patient (pg. 3, col 2, lines 2-5).
As cited and discussed in the 103 rejections above, Cai teaches:
the primer sequences SEQ ID NO: 7-11 for the detection of HSV-1 in urogenital samples.
Cai teaches use of the primers for detection of pathogens including HSV-1 for urogenital tract infections that a method of using them is simple, accurate, and sensitive (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized the method of ‘809 to detect at least M. pneumoniae and HSV of the differential diagnostic pathogens of Koliou, wherein HSV-1 is an obvious species of the genus of “an HSV” taught by Koliou, either with or without serology, motivated by the desire to perform a rapid diagnosis of infection of urogenital ulcers in adolescents, as taught by Koliou, where the combination would be obvious as a combination of equivalents for the same purpose of diagnostic assays for urogenital infections. It further would have been obvious to the POSITA before the EFD of the claimed invention to have treated the human subject diagnosed as positive with at least M. pneumoniae with an anti-infective, motivated by the teachings of Koliou that such local antimicrobial treatments significantly improved the skin lesions of such a patient. Additionally, it would have been obvious to the POSITA before the EFD of the claimed invention to select the a subset of the primers of Cai, which would be understood by the artisan as binding to the HSV-1 genome, to perform such an assay, motivated by the teachings of Cai their use in a method of detection enables simple, accurate, and sensitive detection, wherein omitting F3 is obvious, as discussed in MPEP 2144.04(II)(A) if not desired as in the method of ‘809.
There would have been as strong expectation for success as each is directed to the nucleic acid amplification of pathogens, and such represents the application of known methods/products to a known method.
Claims 1-17 and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-11, and 13-14 of copending Application No. 18/009,498 in view of Cardinale (Cardinale F, et al. Macrolide-resistant Mycoplasma pneumoniae in paediatric pneumonia. Eur Respir J. 2011 Jun;37(6):1522-4.). This is a provisional nonstatutory double patenting rejection.
Both sets of claims are directed to a method of determining a presence of a pre-determined nucleic acid sequence in a sample comprising the steps of adding an RNA/DNA-dependent DNA polymerase with strand-displacement activity and at least five primers, incubating at a fixed sample, and determining whether an elongated DNA sequence is present in the sample, wherein the elongated DNA sequence is indicative of the pre-determined sequence in the sample and wherein no F3 primer is used.
‘498 claim 1 requires that the sample is obtained from an animal. The incubation limitations of instant claims 8 and 9 are recited by ‘489 claims 8 and 9. The detection limitations of instant claims 10 and 15 are recited by ‘498 claim 10. The treatment instant claims 11, 12, and 13, and 20 are respectively recited, at least in part, by claims 11, 13, and 14 of ‘489.
‘489 fails to teach that the pathogen may be at least Mycoplasma (instant claim 7 and 14) and that the animal is a human.
Cardinale rectifies this by teaching that Mycoplasma pneumoniae is one of the most common causes of bacterial community-acquired pneumonia (CAP) in pediatrics [i.e., the medical care of human children] (pg. 1522, col 1, para 1). Cardinale further teaches the importance of determining the prevalence of macrolide resistance among M. pneumoniae strains using molecular methods, and, in the case of macrolide failure during the course of treatment, optimizing the antibiotic strategy (pg. 1524, col 1, para 3). Cardinale teaches that an A-G transition at position 2,063 of the 23S rRNA gene of M. pneumoniae can be detected during adequate treatment with clarithromycin and seems to be associated with treatment failure (pg. 1524, col 1, para 3).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize method of ‘498 as a means of detecting the A-G transition at position 2,063 of the 23S rRNA gene indicative of macrolide resistance and to further choose an effective treatment, as taught by Cardinale, motivated by the desire to overcome the treatment failure, as taught by Cardinale, motivated by the desire to overcome the treatment failure and provide an effective (or “efficient amount of an”) antibiotic, as taught by Cardinale. There would be a strong expectation of success as both ‘498 and Cardinale are directed to molecular tests of animals, of which humans are a species, and bacteria, wherein such improvements represent the application of known techniques to known methods.
Claims 15-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-11, and 13-14 of copending Application No. 18/009,498 in view of in view of Koliou (Koliou MG, et al. Mycoplasma pneumoniae as a cause of vulvar ulcers in a non-sexually active girl: a case report. J Med Case Rep. 2017 Jul 9;11(1):187) and further in view of Cai (CN 107630097 A; published 01/26/2018).
This rejection is made only as necessitated by applicant’s amendment introducing claims 15-20. No inference should be drawn that claims 1-14 are not also rejectable under ‘809 in view of Koliou in view of Cai.
Both sets of claims are directed to a method of determining a presence of a pre-determined nucleic acid sequence in a sample comprising the steps of adding an RNA/DNA-dependent DNA polymerase with strand-displacement activity and at least five primers, incubating at a fixed sample, and determining whether an elongated DNA sequence is present in the sample, wherein the elongated DNA sequence is indicative of the pre-determined sequence in the sample and wherein no F3 primer is used.
‘498 claim 1 requires that the sample is obtained from an animal. The detection limitation of instant claim 15 is taught by ‘498 claim 10.
The treatment after the animal is identified as infected is recited claims 11, 13, and 14 of ‘489.
‘498 fails to teach:
that the primers target M. pneumoniae or HSV-1;
specific primer sequences thereof; and
administering an “efficient amount” of an anti-infective composition to the human subject that was sampled when an infection has been determined.
As cited and discussed in the 103 rejections above, Koliou teaches:
detecting nucleic acids from M. pneumoniae and HSV;
that HSV-1 and HSV-2 are species of HSV; and
administering an anti-infective to a human subject from whom samples had been taken and from which samples it had been determined said subject was infected with a Mycoplasma species.
Koliou teaches that, when [urogenital] ulcers develop in an adolescent, the differential diagnosis should include infections that may or may not be sexually transmitted such as an HSV and M. pneumoniae (pg. 3, col 1, para 3). Koliou teaches that direct detection of M. pneumoniae nucleotide sequences from clinical specimens has been proven to be a very sensitive and specific approach, which offers a rapid diagnosis of infection and the utilization of a combined approach with serology may surpass the limitations of either technique when used alone (pg. 3, col 1, para 1).
Koliou teaches administration of local antimicrobial treatment such as azithromycin significantly improved the skin lesions of the patient (pg. 3, col 2, lines 2-5).
As cited and discussed in the 103 rejections above, Cai teaches:
the primer sequences SEQ ID NO: 7-11 for the detection of HSV-1 in urogenital samples.
Cai teaches use of the primers for detection of pathogens including HSV-1 for urogenital tract infections that a method of using them is simple, accurate, and sensitive (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have utilized the method of ‘498 to detect at least M. pneumoniae and HSV of the differential diagnostic pathogens of Koliou, wherein HSV-1 is an obvious species of the genus of “an HSV” taught by Koliou, either with or without serology, motivated by the desire to perform a rapid diagnosis of infection of urogenital ulcers in adolescents, as taught by Koliou, where the combination would be obvious as a combination of equivalents for the same purpose of diagnostic assays for urogenital infections. It further would have been obvious to the POSITA before the EFD of the claimed invention to have treated the human subject diagnosed as positive with at least M. pneumoniae with an anti-infective, motivated by the teachings of Koliou that such local antimicrobial treatments significantly improved the skin lesions of such a patient. Additionally, it would have been obvious to the POSITA before the EFD of the claimed invention to select the a subset of the primers of Cai, which would be understood by the artisan as binding to the HSV-1 genome, to perform such an assay, motivated by the teachings of Cai their use in a method of detection enables simple, accurate, and sensitive detection, wherein omitting F3 is obvious, as discussed in MPEP 2144.04(II)(A) if not desired as in the method of ‘498.
There would have been as strong expectation for success as each is directed to the nucleic acid amplification of pathogens, and such represents the application of known methods/products to a known method.
Response to Arguments
Applicant's arguments filed 03/06/2026 have been fully considered but they are not persuasive.
Regarding the 102 as being anticipated by Piepenburg, on pg. 8, Applicant disagrees, but amends to expedite prosecution and alleges that Piepenburg does not disclose the use of at least five primers, wherein two or more are loop primers. Regarding the 103 over the same, on pg. 9, Applicant further argues that Piepenburg discloses an RPA system which is a completely different amplification technology from the presently claimed or classical LAMP and as such the POSITA would not be motivated to substitute loop primer into the RPA system of Piepenburg to arrive at the instant claims.
In contrast to the arguments of the Applicant, Piepenburg does disclose that the apoB set of primers participates in hybridization with a region that participates in hairpin-mediated product duplication (pg. 1120, Fig S2). Therefore, the method of Piepenburg is interpreted to fall within the broadest reasonable interpretation of a method of adding five primers comprising two “loop primers” as defined within the specification if the apoB region of Piepenburg is interpreted to be the pre-determined nucleic acid sequence.
Regarding the 103 over Georgiou as evidence by Tanner, on pg. 10-12, Applicant argues that Georgiou teaches a method based on six sbLAMP primers and two blocking primers and that, unlike Georgiou, the instant method is not directed to detection of specific SNPs. Applicant argues that the Office has not provided a motivation for why the artisan would have removed the blocking primers of Georgiou or an adequate evidentiary basis for the finding that includes a rational connection with the evidence presented as to why the artisan would modify Georgiou as evidenced by Tanner to remove blocking primers to arrive at the instant claims. Applicant argues that the removal of the blocking primers would lead to inoperability of Georgiou’s method. Applicant further argues that Georgiou fails to provide experimental evidence showing that omission of F3 is possible for a five primer system or that such a five-primer system without F3 would allow efficient amplification.
Applicant additionally argues that the inventors have surprisingly found that a reaction in the presence of B3 but absence of F3, detection is as fast and sensitive as a reaction with F3 primer, citing para [0049]. Applicant further notes that detection of a Mycoplasma strain was observed within 10 minutes of addition of primers and that shorter target sequences can be detected, citing para [0049].
In response to the arguments about the teachings of Georgiou regarding six SNP-based primers and two blocking primers, Georgiou teaches multiple embodiments. As cited, Georgiou teaches embodiments that exclude F3 (see pg. 22, lines 22-23; pg. 22, lines 36-37 and pg. 22, lines 22-23). Further, the claims as written recite “adding at least five DNA primers” and “comprising the steps of”. Accordingly, the claims encompass adding the blocking primers of Georgiou and there is no further need to provide a motivation or factual finding for their removal or that of F3. It is noted that a motivation has been provided to add LF [instant LPF] and LB [instant LPB] and/or B3 to increase efficiency of the reaction, as taught by Georgiou and that the total number of primers is further subject to routine optimization, as taught by Georgiou. The clerical error referring to “B3” as “L3” in the paragraph discussing routine optimization has been corrected. As there is no need for a motivation for the removal of the blocking primers in the combined method, the arguments directed to the inoperability are moot.
It is noted that the features upon which applicant relies (i.e., no blocking primers and exactly 5 primers) are not recited in each of the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Additional art has been applied where the claims have been directed to adding five primers.
Likewise, regarding the arguments directed at the inoperability of Georgiou in embodiments absent F3 and the efficiency of such a method, MPEP 2121(I) recites: “When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability”. Georgiou expressly discusses that detectable amplification of the nucleic acid can occur in the absence of F3 and/or B3 and discusses possible mechanisms in pg. 22, para 7, spanning pg. 23. Where the applicant makes arguments directed to a level of efficiency, it is noted that the features upon which applicant relies (i.e., “efficiency relative to an amplification including F3”) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Regarding the allegations of unexpected results, as discussed in MPEP 716.02: the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." The inventors present two sets of data in Fig. 1 and 2 directed to human pathogens (pg. 7, para 1), wherein Fig. 2 is a LAMP targeting human herpes virus [HSV-1; see pg. 22, para 2]. Fig. 1 is recited to be a “comparison of the five and six primer system for detecting a pre-determined 16S rRNA sequence in a bacterium of the Mollicutes class” (pg. 22, para 1). The inventors have also filed applications directed to related methods including application 18/008,809. The sum of the evidence is not commensurate in scope with the claims which the evidence is offered to support.
First, in Fig. 2 where clear divergence of “5 primer” and “6 primer” occurs at about 10 min, the “6 primer” appears to be more efficient with a higher relative fluoresce in a shorter amount of time. Second, application 18/008,809, submitted by the same inventors and published as US 2023/0212697 A1, discloses a method for determining the presence of a pre-determined nucleic acid sequence of a bacterium of the Mollicutes class wherein no F3 primer is used (pg. 1, para 1; see also Tables 1 and 2). Fig. 1 of ‘809 teaches the positive detection of a pre-determined sequence of a Mycoplasma strain using five primers (pg. 9, lines 2-4). Similarly, in Fig. 1 of ‘809, where clear divergence of “5 primer” and “6 primer” occurs at about 15 min, the “6 primer” appears to be more efficient with a higher relative fluoresce in a shorter amount of time. Therefore, absent supporting data (e.g., statistical replicates) and given the current broad scope of the claims, the evidence of unexpected results is not persuasive.
The context of the data presented being a single replicate in a system recited to be applicable to “a low number of … sequence in a sample” (pg. 9, line 1) is also noted. The art teaches that LAMP has increased variation at low numbers of template molecules. Namely, Hardinge (Hardinge P, Murray JAH. Full Dynamic Range Quantification using Loop-mediated Amplification (LAMP) by Combining Analysis of Amplification Timing and Variance between Replicates at Low Copy Number. Sci Rep. 2020 Jan 22;10(1):916) teaches that real-time monitoring of LAMP reactions by at least fluorescence dye binding shows increasing variation between replicates at low copy number due to the LAMP amplification mechanism, and that this effect increases with decreasing copy number and is associated with the amplification frequency (Abstract). Hardinge teaches that the increasing variation is not linked to the use of displacement primers (Abstract).
Regarding the arguments about the intended use of the SNP detection of Georgiou, it is noted that the features upon which applicant relies (i.e., determining the presence of a pathogen) are not recited in each of the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). The claims require determining whether a double-stranded elongated DNA sequence indicative of the presence of a pre-determined sequence of in a human sample. Only a subset specifically recites detection of a pathogen (i.e., claim 5 and dependents, claim 11 and dependents, and claims 17-20).
Further, as cited, Georgiou teaches that method for pathogen microorganisms including for bacteria (see pg. 48, para 2-3 and pg. 1, para 2). The claims, as drafted, do not require any particular target pre-determined nucleic acid sequence target that would exclude the targeting of a SNP. Indeed, single nucleotides polymorphisms within, for example, the 16S gene are widely used genetic markers, especially for species and subspecies identification, including for Mollicutes (see instant pg. 22, para 4). See, for example, Chakravorty (Chakravorty S, et al. A detailed analysis of 16S ribosomal RNA gene segments for the diagnosis of pathogenic bacteria. J Microbiol Methods. 2007 May;69(2):330-9. Epub 2007 Feb 22): “A separate analysis of three … regions … within V2 … contained the maximum SNP variations between Mycobacterium and Haemophilus species and the region spanning 205–242 contained most of the SNP variation between the Staphylococcal, Streptococcal, Haemophilus, Fusobacterium, Clostridium and Neisseria species as well as other bacterial genus analyzed” (3.3. Region V2 (nucleotides 137–242)). See also Cardinale, as cited in the double patenting rejections, which detection of strains and identification of mutations relevant to treatment resistance and teaches monitoring/detecting those mutations/SNPs indicative of resistant strains.
Regarding the double patenting rejections, Applicant requests that the provisional rejections be held in abeyance.
As recited in MPEP 804(I)(B)(1): “As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance”. Accordingly, the rejections are maintained and modified in view of amendments.
Conclusion
No claims are allowed.
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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/EMMA R HOPPE/Examiner, Art Unit 1683
/NANCY J LEITH/Primary Examiner, Art Unit 1636
