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 .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Feb. 19, 2026. Claims 1 and 3-21 are pending. Claims 8-12, 14-21 are withdrawn. Claims 1, 3-7 and 13 are currently examined.
Election/Restrictions
Applicant's election without traverse of Group I (1, 3-7 and 13), in the reply filed on Feb. 19, 2026, is acknowledged.
Accordingly, claims 8-12, 14-21 are withdrawn as being directed to a non-elected group. Also, it is noted that claim 13 depends from a withdrawn method claim.
Claim Objection
The base claim 6 is objected to because of the following informalities:
In claim 6, the phrase “…the fusion protein has a nucleic acid sequence …” should be “…the fusion protein is encoded by a nucleic acid sequence…”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 6 is 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.
Claim 6 is directed to the reporter mycobacteriophage of claim 1, wherein the fusion protein has a nucleic acid sequence which is at least 90% identical to SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO: 11, or SEQ ID NO: 13.
The written description rejection is made because the claims are interpreted as being drawn to a nucleic acid sequence recited as being “at least 90% identity” to the instant claimed SEQ ID NOs 3, 5, 7, 9 11 and 13. This means that up to 10% nucleic acid sequence can vary. The applicable standard for the written description requirement can be found in MPEP 2163; University of California v. Eli Lilly, 43 USPQ2d 1398 at 1407; PTO Written Description Guidelines; Enzo Biochem Inc. v. Gen-Probe Inc., 63 USPQ2d 1609; Vas- Cath Inc. v. Mahurkar, 19 USPQ2d 1111; and University of Rochester v. G.D. Searle & Co., 69 USPQ2d 1886 (CAFC 2004).
The instant application claims a reporter mycobacteriophage comprising a heterologous nucleic acid comprising a promoter-reporter construct encoding a promotor operably linked to a nucleotide sequence encoding a fusion protein of luciferase protein linked to a fluorescent protein. The instant specification discloses that the fusion protein has a nucleic acid sequence which is at least 90%, 95%, or 99% identical to the SEQ ID NOs:3, 5, 7, 9, 11 and 13 (See claims [0047] to [0050]). However, the specification does not indicate which portions of the claimed SEQ ID NOs are essential to retain the ability to be a fusion protein of luciferase protein and fluorescent protein or which portions of SEQ ID NOs can be modified or altered up to 10% and still retain the ability for being a luciferase protein and fluorescent protein for constructing the reporter mycobacteriophage.
The court clearly states in Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.). As discussed above, the skilled artisan cannot envision the detailed sequence of the nucleic acid sequence that are "at least 90% identical” to the claimed SEQ ID NOs. Therefore, the full breadth of the claim 6 does not meet the written description provision of 35 U.S.C. 112, first paragraph.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 5, 7 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Jacobs et al. (US 6225066 B1, published on May 1, 2001, hereinafter “Jacobs”, submitted by IDS filed on 04/26/2023) in view of Bryan et al. (US 6436682 B1, patented on Aug. 20, 2002, hereinafter “Bryan”, submitted by IDS filed on 04/26/2023).
The base claim 1 is directed to reporter mycobacteriophage comprising a heterologous nucleic acid comprising a promoter-reporter construct encoding a promotor operably linked to a nucleotide sequence encoding a fusion protein, wherein the fusion protein comprises a luciferase protein linked to a fluorescent protein.
Jacobs et al. teaches their invention relates to broad host range and mycobacterial species-specific reporter mycobacteriophages, (reporter mycobacteriophages), methods of producing such reporter mycobacteriophages, and the use of such reporter mycobacteriophages to rapidly diagnose mycobacterial infection. In order to produce these reporter mycobacteriophages, reporter genes and transcriptional promoters are introduced into the genomes of mycobacterial species-specific mycobacteriophages. The promoter and reporter gene-containing mycobacteriophages (reporter mycobacteriophages) are then incubated with a clinical sample which may contain the mycobacteria of interest (See column 3, lines 5-30). Fig. 2 of Jacobs teaches the luciferase shuttle plasmid pYUB180 wherein reporter gene FFlux (Firefly luciferase lux) is fused to the BCG hsp60 promoter.
Accordingly, Jacobs teaches a reporter mycobacteriophage comprising a promoter-reporter construct with a promoter operably linked to a luciferase reporter gene. However, it is silent on a fusion protein comprising a luciferase protein linked to a fluorescent protein.
Bryan teaches a fusion nucleic acid, particularly DNA, encoding a fusion protein of Gaussia or Pleuromamma luciferase protein with DNA encoding a GFP or phycobiliprotein (See column 7, lines 1-25) and a method for constructing the fusion proteins of the luciferases and GFPs (See column 49, lines 64-66). Bryan also teaches that an expression vector refers to a recombinant DNA or RNA construct, Such as a plasmid, a phage, recombinant virus or other vector that, upon introduction into an appropriate host cell, results in expression of the cloned DNA. Appropriate expression vectors are well known to those of skill in the art (See column 22, lines 49-67). Furthermore, Bryan teaches the advantage to use the fusion protein of luciferase and fluorescent protein are: “A) In Vivo use-unlike chemistry-based luminescence or radioactivity-based assays, fusion proteins can be genetically incorporated into living cells or whole organisms. This greatly increases the range of possible applications; B) Flexible and precise modification-many different response modifying elements can be reproducibly and quantitatively incorporated into a given luciferase-GFP pair, C) Simple purification-only one reagent would need to be purified, and its purification could be monitored via the fluorescent protein moiety. Ligand-binding motifs can be incorporated to facilitate affinity purification methods” (See column 85, lines 48-59). Bryan also teaches that the fusion protein can be utilized as a reporter system based on Bioluminescence Resonance Energy Transfer (BRET) (See column 10, lines 16-44) and discloses that there are many advantages using the BRET system. For example, BRET sensors are self-rationing. The reporter and target are integrated into Single polypeptide. This ensures1.1:1 stoichiometry among luciferase, GFP and target (or a 1: N:1 stoichiometry if more than one, typically a homodimer, GFP can be bound to a luciferase). GFP fluorescence allows absolute quantitation of Sensor. The null State gives signal that verifies Sensor functionality. Quantifiable null state facilitates disruption-of-BRET sensors (DBRET). BRET sensors have better signal-to-noise ratio than GFP FRET sensors because there is no cellular autofluorescence, no excitation of the acceptor from the primary exciting light, the quantum yield of luciferase greatly enhanced by non-radiative energy transfer to GFP, and there is minimal Signal overlap between emission of the luciferase and emission of the GFP (See column 87, lines 30-49).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the fusion protein of Bryan into the invention of Jacobs to arrive at an invention as claimed. One of skill in the art would be motivated to do so to clone the fluorescent gene such GFP of Bryan into the reporter mycobacteriophages plasmid of Jacobs to construct a heterologous nucleic acid to encoding a fusion protein to express a luciferase protein linked to a fluorescent protein. There would be a reasonable expectation of success to develop such a reporter mycobacteriophage as claimed.
Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claim 5, it requires a first fluorescent protein is connected to the N-terminus of the luciferase protein and a second fluorescent protein is connected to the C-terminus of the luciferase protein. DNA cloning is a route technique in the art. Bryan teaches that the fusions of nucleic acid encoding the luciferases and GFPs provided herein with other luciferases and GFPs are provided. Of particular interest are fusions that encode pairs of luciferases and GFPS, such as a Renilla luciferase and a Renilla GFP (or a homodimer or other multiple of a Renilla GFP) (See column 15, lines 33-44) and the FIGS. 1 and 2 shows that a promoter element and a multiple cloning Site located upstream or downstream from DNA encoding Gaussia or Pleuromamma luciferase are also provided (See Column 7, lines 1-13; Fig. 1-2). Based on the teaching as described above, one of skilled in the art can use the multiple cloning site located upstream or downstream from DNA encoding Gaussia or Pleuromamma luciferase to clone a pair of the GFP by inerting them to the C-terminus of the luciferase protein and N-terminus of the luciferase protein as claimed. Furthermore, it would be obvious for one of ordinary skill in the art to apply the cloning set into Jacobs’s reporter mycobacteriophages construct, and the result would be predictable to make such a construct based on the teachings of Bryan.
Regarding claim 7, it requires that a composition comprising the reporter mycobacteriophage of claim 1. Although Jacobs does not explicitly use the term “composition”, Jacobs teaches that “The TM4::lacZ mycobacteriophage formed bright blue plaques when plated on media containing X-gal” (See column 55, lines 54-60) and Luciferase activity was determined following liquid infection of M. smegmatis mc2-155 with phGSl and phGSS. (See column 62, lines 37-53). Here these descriptions indicate a reporter mycobacteriophage being in a “composition” such as in a medium as claimed.
Regarding claim 13, it requires that a kit for detection of a mycobacterial cell in a sample, comprising a reporter mycobacteriophage capable of infecting the mycobacterial cell; a substrate for detecting the fusion protein; and instructions for performing the method of claim 8, wherein the reporter mycobacteriophage comprises a heterologous nucleic acid comprising a promoter-reporter construct encoding a promotor operably linked to a nucleotide sequence encoding a fusion protein, wherein the fusion protein comprises a luciferase protein linked to a fluorescent protein.
Jacobs teaches the reporter mycobacteriophage capable of infecting the mycobacterial cell by stating that the reporter mycobacteriophage DS6A has been shown to infect both M. tuberculosis and ECG. It has been demonstrated that DS6A can infect over 3,000 different types of M. tuberculosis strains (See column 50, lines 45-51), teaches the substrate for detecting the fusion protein by stating that the presence of luciferase reporter genes can be detected by the emission of photons in the presence of a substrate, such as luciferin or decanal (See column 51, lines 42-46), and teaches utilizing the reporter mycobacteriophage in detection of a viable target microbe in a sample (See Abstract). Furthermore, Jacobs teaches that the reporter mycobacteriophages are specific for the mycobacteria which is sought to be detected. The reporter mycobacteriophages efficiently introduce the recombinant nucleic acids which encode the expression of the reporter gene's gene product into the mycobacteria of interest, and the mycobacteria then express the gene product (See column 3, lines 19-30). Although Jacobs does not explicatively teach the term “kit”, however, the concept of packaging components into a kit is well known and routine in the art. It would have been obvious to one of ordinary skill in the art at the time the invention was made to package components into a kit. One would be motivated to do this for commercial exploitation of the invention by providing convenience for the end user. At the same time, Bryan teaches a kit containing appropriate reagents and an article of manufacture for generating bioluminescence in combination with the article (See column 15, lines 8-32; Column 75). It would also be obvious for one of ordinary skill in the art to introduce the kit of Bryan into Jacobs’ invention at the time the invention was made to develop a kit as claimed, and the result would be predictable based on the details teaching of the kit taught by Bryan.
In addition, according to MPEP § 2112.01(III), “Where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, ** > 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004) < (Claim at issue was a kit requiring instructions and a buffer agent. The Federal Circuit held that the claim was anticipated by a prior art reference that taught a kit that included instructions and a buffer agent, even though the content of the instructions differed.). See also In re Gulack, 703 F.2d 1381, 1385-86, 217 USPQ 401, 404 (Fed. Cir. 1983) (“Where the printed matter is not functionally related to the substrate, the printed matter will not distinguish the invention from the prior art in terms of patentability…. [T]he critical question is whether there exists any new and unobvious functional relationship between the printed matter and the substrate.”).”
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Jacobs in view of Bryan as applied to claims 1, 5, 7 and 13 above and further in view of Yeh et al. (ACS Chem Biol. 2019 May 17;14(5):959-965. Epub 2019 Apr 17., Hereinafter “Yeh”).
Claim 3 requires that the reporter mycobacteriophage of claim 1, wherein the luciferase protein comprises nLuc, teLuc, yeLuc, LumiLuc, an amino acid variant thereof, or a combination.
Jacobs and Bryan teach a reporter mycobacteriophage comprising a heterologous nucleic acid comprising a promoter-reporter construct, where the fusion protein can be firefly luciferase and GFP. However, it is silent on the luciferase proteins as claimed.
Yeh teaches engineered a LumiLuc luciferase with broad substrate specificity. In the presence of corresponding pyridyl substrates (i.e., pyCTZ, 6pyDTZ, or 8pyDTZ), LumiLuc generates highly bright blue, teal, or yellow bioluminescence. They compared the LumiLuc-8pyDTZ pair with several benchmark reporters in a tumor xenograft mouse model. Their new pair, which does not need organic cosolvents for in vivo administration, surpasses other reporters by detecting early tumors. They further fused LumiLuc to a red fluorescent protein, resulting in a LumiScarlet reporter with further red-shifted emission and enhanced tissue penetration (See Abstract).
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the LumiLuc of Yeh into Jacobs and Bryan’s teachings to arrive at an invention as claimed. One of skill in the art would be motivated to do so to clone the LumiLuc into the reporter mycobacteriophage construct to be benefited with the brighter LumiLuc, and there would be a reasonable expectation of success to develop such a reporter mycobacteriophage containing the LumiLuc luciferase as claimed.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Jacobs in view of Bryan as applied to claims 1, 5, 7 and 13 above and further in view of Tsang J. ( https://blog.addgene.org/bright-monomeric-fluorescent-proteins-mneongreen-mtfp1-and-mwasabi, April 25, 2019).
Claim 4 requires the fluorescent protein comprises mNeonGreen, moxNeonGreen, mTourquoise, mTourquoise2, cyan-excitable orange fluorescent protein (CyOFP), cyan-excitable red fluorescent protein (CyRFP), monomeric cyan-excitable red fluorescent protein (mCyRFPl), tdTomato, mCherry, mApple, mCardinal, mMaroon, mScarlett, mWassabi, an amino acid variant thereof, or a combination.
Jacobs and Bryan teach a reporter mycobacteriophage comprising a heterologous nucleic acid comprising a promoter-reporter construct, where the fusion protein can be firefly luciferase and GFP. However, it is silent on the fluorescent protein as claimed.
Tsang teaches that mNeonGreen is a yellow-green fluorescent protein that was derived from the tetrameric yellow fluorescent protein (LanYFP) from the marine invertebrate Branchiostoma lanceolatum in 2012. It was reported as the brightest monomeric green or yellow fluorescent protein that time. It is 1.5 to 3 times brighter than the most commonly used GFPs and YFPs. Its excitation maxima are at 506 nm and its emission maxima is at 517 nm. Because mNeonGreen wavelengths lie between the green and yellow fluorescent protein wavelengths, it can be imaged either with standard green fluorescent protein filters or yellow fluorescent protein filters, with no or minimal reduction in emission readout, respectively.
It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the mNeonGreen of Tsang into Jacobs and Bryan’s teachings to arrive at an invention as claimed. One of skill in the art would be motivated to do so to use the mNeonGreen as the fusion protein in the reporter mycobacteriophage system, and there would be a reasonable expectation of success to develop such a reporter mycobacteriophage containing the mNeonGreen as claimed.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Jacobs in view of Bryan as applied to claims 1, 5, 7 and 13 above and further in view of Suzuki et al. (Nat Commun. 2016 Dec 14; 7:13718. Hereinafter “Suzuki”) and LC128715 (https://www.ncbi.nlm.nih.gov/nuccore/LC128715.1?report=GenBank, Feb. 14, 2017).
Claim 6 requires a nucleic acid sequence which is at least 90% identical to SEQ ID NO:3, SEQ ID NO: 5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO: 11, or SEQ ID NO: 13.
Jacobs and Bryan teach a reporter mycobacteriophage comprising a heterologous nucleic acid comprising a promoter-reporter construct, where the fusion protein can be firefly luciferase and GFP. However, it is silent on the SEQ ID NOs as claimed.
Suzuki teaches they report five new spectral variants of the bright luminescent protein, enhanced Nano-lantern (eNL), made by concatenation of the brightest luciferase, NanoLuc, with various color hues of fluorescent proteins. eNLs allow five-color live-cell imaging, as well as detection of single protein complexes and even single molecules (See Abstract). Suzuki also release the sequences of the luminescent proteins in the GenBank. One of the sequences, LC128715, is identical to the SEQ ID NO: 3 as claimed (See Table A below).
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740
670
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It would have been prima facie obvious for one having ordinary skill in the art before the effective filing date of the claimed invention to introduce the GeNL sequence of LC128715.1 into Jacobs and Bryan’s teachings to arrive at an invention as claimed. One of skill in the art would be motivated to substitute one nucleic acid sequence for another (See MPEP 2144.06: Substituting equivalents known for the same purpose), and there would be a reasonable expectation of success to develop such a reporter mycobacteriophage containing the sequence as claimed.
Conclusion
No claims are allowed.
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/RUIXUE WANG/Examiner, Art Unit 1672