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
Claims 1-11 are pending. Claims 1-4 and 9-11 are the subject of this NON-FINAL Office Action.
Election/Restrictions
Applicants’ election without traverse of Group I (claims 1-7 and 9-11), and species of claim 1 in the reply filed on 06/22/2026 is acknowledged.
Claims 5-8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse.
Claim Rejections - 35 USC § 112- Indefiniteness
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.
Claim 1-4 and 9-11 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 pre-AIA the applicant regards as the invention.
The metes and bounds of the claims are so unclear and confusing that the Office cannot determine if the instant claims are patentable because it would require the Office to speculate as to the metes and bounds of the instant claims. See MPEP § 2173.06 (“Second, where there is a great deal of confusion and uncertainty as to the proper interpretation of the limitations of a claim, it would not be proper to reject such a claim on the basis of prior art. As stated in In re Steele, 305 F.2d 859, 134 USPQ 292 (CCPA 1962), a rejection under 35 U.S.C. 103 should not be based on considerable speculation about the meaning of terms employed in a claim or assumptions that must be made as to the scope of the claims.”).
Specifically, the meaning of both “high-speed photo-cross-linking shared linker” and “high-speed photo-cross-linking site” are unclear because the metes and bounds of “high-speed photo-cross-linking” are never defined with any clarity whatsoever. The specification merely passes over this phrase multiple times without ever defining it. Applicants seem to have invented a phrase, but failed to clearly define it. Although the “linker” and the “site” are described as having certain generic physical features (e.g. para. 0037), yet what makes the “linker” and the “site” specific to “high-speed photo-cross-linking” is never clearly and specifically defined. For example, what is “high” speed? This is subjective term of degree is never addressed. Moreover, the specific structures of the “linker” and the “site” that yield “high-speed photo-cross-linking” are never clearly linked. Instead, the claims broadly describe generic “high-speed photo-cross-linking shared linker for in vitro selection” comprises generic “molecular backbone and a side chain.” The “molecular backbone comprising, a solid phase binding site having a predetermined nucleotide sequence and located at 5′ end thereof for forming a bond to bind to said solid phase; a solid phase cleavage site for cleaving said solid phase including said solid phase binding site; [and] a side chain ligation site for ligating said side chain to said molecular backbone.” These are all generic structures. It is entirely unclear what specific structures encompassed by this generic language yield “high-speed photo-cross-linking,” much less what is “high-speed” versus low or medium.
Applicants are encouraged to claim the specific distinguishing features that are tied to “high-speed photo-cross-linking” compared to the prior art (see e.g. Figs. 1-3, comparing linkers here to “prior art” linkers).
In claim 1, the following is confusing: “said side chain comprising a fluorescent label, a protein fusing site locating at a free end thereof.” It is unclear what “thereof” refers to because there are multiple subjects in the clause: side chain, fluorescent label and protein fusing site. Thus, it is unclear at which “free end” the “protein fusing site” is “locating.”
As to claims 4 and 10, the “sequence for recognizing a carbohydrate antigen” is never defined, leaving the skilled artisan to guess what this encompasses. Instead, the specification discloses a single example: “Fixation of the biotinized GlcNAc onto the magnetic beads is confirmed by using the desirable carbohydrate recognition peptide, for example, a DNA fragment, PDO which is constructed by using POU domain of Oct1 protein. As shown in FIG. 5 , PDO comprises the sequences such as T7, 5′ cap, Ω, Kozak, GGGS (SEQ ID NO: 25), His-Tag, GGS and Y-tag, it is the peptide having the nucleotide sequence shown in below (SEQ ID NO: 10 in the sequence listing)” (para. 0161). From this single example, it is unclear what other “sequences” are encompassed. For example, can nucleic acids be used? Or must it be a peptide, as in the example? What core sequence is required? Are there essential tertiary or even quaternary structures required? Can an mRNA be used? If so, what sequence and structure is required? None of this is answered in the specification. Thus, it is entirely unclear the metes and bounds of “sequence for recognizing a carbohydrate antigen.”
For prior art purposes, this is any sequence, of any length, of any chemical composition (e.g. nucleic acid, peptide, carbohydrate, fat, etc.).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-4 and 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over Ichiki et al (WO 2014/142020 A1, cited as reference 3 on the IDS filed 9/29/2017), as evidenced by the English language equivalent of US Patent Application Publication No. 2016/0076022 A1 (see the entire reference, cited as reference 1 on the IDS filed 9/29/2017; all numbering refers to this English language equivalent), in view of Nemoto et al (US Patent Application Publication No. 2008/0312103 A1, cited in a prior action; see the entire reference) and Liu et al (Methods in Enzymology, Vol. 318, pages 268-293, 2000; see the entire reference). This rejection was made in the Office action mailed 10/6/2022.
Regarding claims 1, 4 and 10, Ichiki et al teach a linker comprising a backbone and an arm (side chain), where the backbone comprises (i) a spacer portion (51c) at the 5’ terminus that contains a solid phase binding site, and a nucleic acid sequence to keep a predetermined distance from the solid phase to suppress inhibition of the synthesis of the protein or peptide due to contact with the surface; (ii) a side chain ligation site at which the arm is ligated to the backbone; (iii) a photoreactive base derivative (2b) that is capable of photo crosslinking (photo-cross-linking site) for ligating mRNA having a complementary sequence with that of the molecular backbone that is located between the side chain ligation site and the solid phase binding site; and (iv) a reverse transcription starting region adjacent to the side chain ligation site, where the reverse transcription starting region is at the 3’ end of the backbone; and wherein the arm comprises (i) a connection portion (2a) for a protein (protein binding site) at the 3’ end of the arm; (ii) a fluorescent label, and (iii) a ligation formation site ligated to the ligation site of the backbone (e.g., paragraphs [0068], [0077]-[0078], [0082]-[0086]). Ichiki et al teach that the solid phase binding sites uses avidin-biotin binding to attach the linker to a bead (e.g., paragraphs [0078], [0107] and [0108]). The linker is capable of forming an mRNA-puromycin-protein conjugate (e.g., paragraphs [0007], [0070]-[0074] and [0082]-[0086]). Ichiki et al teach that the spacer portion (51c) has a plurality of bases, such as an oligonucleotide with about 50 or more bases, so that the mRNA-nucleic acid linker-protein complex can be efficiently produced on a solid phase (e.g., paragraphs [0076], [0101] and [0107]-[0109]).
Ichiki further teaches photo-cross-linking by using irradiation of light having 300 to 500 nm wavelength for 0.01 to 5 minutes to both of said molecular backbone and mRNA which are mutually bound through a complementary bond (“In a case of using CNVK as the photoreactive base derivative 2 b, it is possible to perform a crosslinking reaction by irradiating a complex of the nucleic acid linker 2 and the mRNA 23 with light in a first wavelength band for photo-coupling and with light in a second wavelength band for photo cleavage. The light in the first wavelength band is light of greater than or equal to 340 nm. For example, a crosslinking structure is formed by an atom which constitutes CNVK and an atom which constitutes a pyrimidine base in the mRNA 23 which forms a base pair with a purine base adjacent to CNVK on the 5′ side, through irradiation with light in a wavelength band of 340 nm to 380 nm. The second wavelength band is light of less than 350 nm. For example, the crosslinking is released through irradiation with light in a wavelength band of 280 nm to 345 nm. In the first wavelength band and the second wavelength band, parts of the first and the second wavelength bands may overlap each other”; “The light in the first wavelength band is light of greater than or equal to 340 nm. For example, irradiation with light in a wavelength band of 340 nm to 380 nm is performed. The irradiation time may be short in view of suppressing damage to the nucleic acid due to irradiation, and is preferably 5 seconds to 60 seconds. In addition, the irradiation time is more preferably 10 seconds to 50 seconds, and particularly preferably 20 seconds to 40 seconds. For example, 60% or more of an mRNA 23-nucleic acid linker 2 complex formation rate with respect to the total number of moles of the mRNA 23 and the nucleic acid linker 2 is obtained through irradiation with light of 365 nm for 30 seconds”).
Regarding claim 2, Ichiki teaches solid phase is composed of a magnetic bead coated by either streptavidin or avidin (“Examples of the beads carrier include magnetic beads, gold nanoparticles, agarose beads, and plastic beads, and magnetic beads are preferable due to easy handling using magnetism. It is possible to constitute a nucleic acid linker-immobilized array by sequencing the nucleic acid-immobilized beads in a reaction tank in a substrate for a beads device in which a plurality of reaction tanks are provided. Examples of the method of immobilizing a nucleic acid linker include, in addition to the above-described method of using avidin-biotin bonding, a method of modifying a nucleic acid linker with a functional group such as an amino group, a formyl group, and an SH group and using a beads carrier which is subjected to surface treatment using a silane coupling agent which has an amino group, a formyl group, and an epoxy group. Particularly, the method of using avidin-biotin bonding is preferable.”)
Ichiki et al do not teach the linker comprising a solid phase cleavage site, such as ribo-G, for cleaving the solid phase binding site and solid phase from the linker; and cleavage of the conjugate is conducted by using any one of the enzyme selected from the group consisting of endonuclease V, Rnase Tl, and RNase A.
Nemoto et al teach a linker for constructing an mRNA-puromycin-protein conjugate, where the linker comprises cleavage sites surrounding a solid phase binding site (e.g., paragraphs [0031]-[0033]). Nemoto et al teach the cleavage site is ribo-G (e.g., paragraph [0035]). Nemoto et al teach that the linker is bound to the solid phase by biotin, such as by using a solid phase binding site including a nucleotide bound with biotin, such as biotin-deoxythimine (biotin-dT) (e.g., paragraph [0034]). Nemoto et al teach that the cleavage sites allow the removal of mRNA-puromycin-protein conjugate from the solid support as necessary to allow for the analysis of protein function (e.g., paragraphs [0035] and [0054]). The cleavage is by y RNase T1, RNase A or RNase I (paras. 0010 & 0035, for example). Nemoto et al teach that the linker with the cleavage sites has improved efficiency when removing the mRNA-puromycin-protein conjugate bound to a solid phase from the solid phase (e.g., paragraph [0024]). Nemoto et al teach that the ability to remove the mRNA/cDNA-PM-PRT conjugate from the streptavidin bead allows one to use the conjugate in various analytical experiments (e.g., paragraph [0054]).
Liu et al teach mRNA templates containing puromycin at their 3’ end for the production of mRNA-protein fusions for in vitro protein selection (e.g., paragraph bridging pages 269-270). Liu et al teach that the standard linker for this application includes dA27 (e.g., Fig. 4). Liu et al teach that the linker length and sequence can be optimized, where the number of adenine nucleotides is varied (e.g., page 285-287, Optimizing Linker Length and Sequence).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the linker of Ichiki et al to include the cleavage site, such as ribo-G, as taught by Nemoto et al, outside solid phase binding site/spacer of Ichiki et al, because both Ichiki et al and Nemoto et al teach linkers capable of forming a mRNA-puromycin-protein conjugate. Both linkers are of similar structure and function, and one would have a reasonable expectation of success in incorporating the feature taught by Nemoto et al into the linker of Ichiki et al. One would have made such a modification in order to obtain the predictable result of providing a linker capable of being cleaved from the solid support while maintaining the connection between the linker, mRNA and protein. Further, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the linker of Ichiki et al to use adenine as the base for the spacer portion of about 50 or more bases, because Ichiki et al do not particularly limit the type of base that is used, and Liu et al teach that the standard linker makes use of adenine as a spacer. One would have had a reasonable expectation of success in that Ichiki et al teach that the nucleotide sequence is used to link the linker to a surface at a distance that allows efficient mRNA-nucleic acid linker-protein complex formation, and adenine is a nucleotide that has been used in the context of this type of linker. The use of adenine would have provided the same function to provide distance from the ribosome to the surface. One would have made such a substitution in order to achieve the expected result of providing a spacer region comprising 50 or more bases to provide the proper spacing, where the base is adenine.
One would have been motivated to make such a modification in order to receive the expected benefit of providing a linker that can be cleaved with improved efficiency to allow for the analysis of a protein that is part of a linker complex as taught by Nemoto et al.
Nemoto et al teach a linker for constructing an mRNA-puromycin-protein conjugate, where the linker comprises cleavage sites surrounding a solid phase binding site (e.g., paragraphs [0031]-[0033]). Thus, the linker of Nemoto et al, which contains a cleavage site, also relates to a linker-protein or peptide complex on a solid phase. Thus, one would have been able to select enzymes having the desired function. Nemoto et al teach that the cleavage sites allow the removal of mRNA-puromycin-protein conjugate from the solid support as necessary to allow for the analysis of protein function (e.g., paragraphs [0035] and [0054]). Thus, the addition of the cleavage site would allow for an assay to be carried out on the solid support, while further providing the benefit of allowing release of the complex from the solid support for further analysis of protein function. The modification allows for the prior art linker to function as it was intended while providing additional functionality.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Aaron Priest whose telephone number is (571)270-1095. The examiner can normally be reached 8am-6pm.
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/AARON A PRIEST/Primary Examiner, Art Unit 1681
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