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 .
Priority
This application is the U.S. National Stage (371) application of PCT/CN2021/073899 filed on 01/27/2021 which claims priority to Foreign Application No. CN202110069353.7 filed on 01/19/2021.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/07/2024 has been received. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner and all references are considered except where they were lined through.
Drawings
The drawings are objected to because of missing labels as follows:
Figures 1 and 19 have a second arrow indicating a sequential step that is not labeled for “introducing Biotin agarose”.
Figures 11 and 14 have two arrows for two sequential steps and the second arrow is mislabeled as “PafA7KR” instead of “introducing Biotin agarose”.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: abbreviations for PafA and pup are discussed without an explanation for what the abbreviations are for. Appropriate correction is required.
Claim Objections
Claims 1, 3, 7, and 9 are objected to because of the following informalities: PafA and pup are discussed without an explanation for what the abbreviations are for. Appropriate correction is required.
Claim Interpretation
The examiner has interpreted the abbreviation PafA as “proteasomal accessory factor A” and pup as “prokaryotic ubiquitin-like protein”.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1-10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for using a peptide of 12-100 amino acids and for the interacting proteins of specification examples or embodiments (i.e., CheAs), does not reasonably provide enablement for any short peptide nor for any interacting protein. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
In re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991), the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was appropriate given the relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. Such is the case where there is a relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. In the instant case, the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. Specifically, the method of using any short peptide tetramer to detect any interacting protein with any biotin-modified molecule is overly broad and is not well supported by the specification.
The current disclosure does not satisfy the enablement requirement for detecting any interacting protein with any short peptide tetramer and with any biotin-modified molecule and whether any necessary experimentation is "undue as discussed In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Regarding claim 1, the claim recites a system for detecting interaction between known molecules and proteins based on covalent linkages that comprise a streptavidin-short peptide tetramer, a PafA enzyme and a biotin-modified known molecules. And regarding claims 7 and 9, the claims recite a method for identifying or verifying an interaction between known molecules and proteins using the system of claim 1. The specification does not provide enough support for an artisan to perform the assay without undue additional experimentation as described in in re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1998) as appropriate. See also MPEP § 2164.01(a) and § 2164.04.
The breadth of the claims:
Claim 1 is broadly drawn to a system for detecting interactions between known molecules and proteins that comprise any short peptide tetramer on streptavidin with PafA enzyme and with any biotin-modified molecule. Also, claim 1 does not specify the type of known molecule used in the detection of interaction nor the detected proteins (i.e., membrane proteins, secreted proteins or intracellular proteins). Thus, the claim 1 is broad and so are claims 7 and 9 that uses the system of claim 1.
The nature of the invention:
The invention is about a system for detecting interactions between known molecules and proteins based on covalent linkages that comprise a streptavidin-short peptide tetramer, a PafA enzyme and biotin-modified known molecules. The invention is also about a method for identifying or verifying an interaction between known molecules and proteins using the system of streptavidin-short peptide tetramer, PafA enzyme and biotin-modified known molecules.
The state of the prior art:
Although there has been reports about the use of proximity-tagging system to identify membrane protein-protein interactions as noted by Liu 1 et al. (Nature Methods, Volume 15, September 2018, 715–722, Abstract), use of proximity-tagging system to detect nucleic acid-protein interactions by Liu 2 et al. (US 2022/0411771 A1; Abstract; [0008]), and use of proximity-tagging system to detect molecule-molecule interactions as noted by Zhuang et al. (US 11,467,166 B2; Abstract; column 2, lines 8-35), there is no prior art that describes using proximity-tagging system to identify interacting proteins with any biotin-tagged molecule (i.e., protein, DNA, RNA, and small molecule) and by using short peptide tetramers. Protein-protein interactions remain difficult to detect as noted by Liu 1 (Abstract) and to extend to DNA, RNA and small molecules is even more difficult especially if the molecule-molecule interactions are weak as noted by Zhuang (Column 10, lines 36-44). It is understood from the prior art that while there have been dramatic improvements in the field of protein-protein interactions, it remains a challenge for a skilled artisan on how to tackle each type of interaction and how to offer the best approach in each case of interaction (i.e., strong, moderate or weak interaction).
Furthermore, in re Vaeck, 947 F.2d 488,495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991), the Court ruled that a rejection under 35 U.S.C. 112, first paragraph for lack of enablement was appropriate given the relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims. Such is the case here where there is a relatively incomplete understanding in the biotechnological field involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims of the instant application.
The level of one of ordinary skill:
Based on the complexity and unpredictability of protein-protein interactions, protein-nucleic acid interactions and molecule-molecule interactions as noted by Liu 1, Liu 2 and Zhuang, the level of a person having ordinary skill in the art is not high enough to detect all types of interactions with any biotinylated molecule using streptavidin short peptide tetramers. Liu 1 noted that although many methods for the detection of protein-protein interactions exist, membrane protein-protein interactions remain difficult to detect (Abstract). Liu 2 noted that mass spectrometry-based techniques capture RNA-protein interactions under natural conditions, but it is still difficult to design DNA fragments that are suitable for mass spectrometry techniques [0006]. Zhuang noted that weak molecule-molecule interactions are difficult to detect by existing methods because of their nature (i.e., hydrophobic) (Column 10, lines 36-44).
Thus, a person having ordinary skill in the art would not have been able to detect every type of protein-protein interaction, protein-nucleic acid interaction or molecule-molecule interaction with any biotinylated molecule using any short peptide tetramer of streptavidin.
The level of predictability in the art:
There is a high level of unpredictability in protein-protein interactions, protein-nucleic acid interactions and molecule-molecule interactions as noted by Liu 1, Liu 2 and Zhuang. Liu 1 noted that it is difficult to detect membrane protein-protein interactions although many methods for the detection of protein-protein interactions exist (Abstract). And Liu 2 noted that it is still difficult to design DNA fragments that are suitable for mass spectrometry techniques for capturing RNA-protein interactions under natural conditions [0006]. Furthermore, Zhuang noted that the nature of weak molecule-molecule interactions makes it difficult to detect with existing methods (i.e., hydrophobic) (Column 10, lines 36-44).
The amount of direction provided by the inventor:
As discussed above, the art acknowledges the complexity and unpredictability of protein-protein interactions, protein-nucleic acid interactions and molecule-molecule interactions. And thus, the inventor needs to show how the method of the instant application will enable a skilled artisan to detect every type of protein-protein interaction, protein-nucleic acid interaction or molecule-molecule interaction with any biotinylated molecule using any short peptide tetramer with streptavidin.
The specification of the instant application provides fourteen embodiments that cover protein-protein interactions, protein-nucleic acid interactions and molecule-molecule interactions (Embodiments 4-17, pages 80-101). Embodiment 4 teaches verifying the interaction between CheAs protein and CheZ protein (pages 80-82). Embodiment 5 teaches the detection of interacting proteins of CobB (Pages 82-85). Embodiment 6 teaches the detection of cell surface receptor of PD-1 protein (Pages 85-86). Embodiment 7 teaches the detection of interacting proteins of SARS-Co V-2 proteins (Pages 86-88). Embodiment 8 teaches the identification of interacting proteins of biotinylated m6A RNA (Pages 88-89). Embodiment 9 teaches verifying the interaction between biotinylated m6A RNA and YTDHF1, YTDHF2, YTDHF3 proteins (Page 89-90).
Embodiment 10 teaches the Identification of Interacting Proteins of Biotinylated DNA (Pages 90-92). Embodiment 11 teaches the Verification of Interaction between Biotinylated DNA and
EthR Protein (Pages 92-94). Embodiment 12 teaches the verification of specificity of DNA-RutR interaction (Pages 94-95). Embodiment 13 teaches the verification of Interaction between Biotinylated DNA and GCN4 (Pages 95-97). Embodiment 14 teaches the Identification of interacting proteins of lenalidomide small molecule (Page 97-98). Embodiment 15 teaches the verification of the interaction between c-di-GMP small molecule and ETHR protein (Pages 98-99). Embodiment 16 teaches the verification of interaction between c-di-GMP small molecule and CSP series short peptides (Pages 99-100). Embodiment 17 teaches the verification of interaction between Rapamycin small molecule and FKBP12 protein (Page 100-101).
Embodiments 4-17 do not provide a plan on how to approach each type of interaction based on its strength and nature (i.e., strong, moderate or weak) and only shows detection of different interacting proteins. Thus, the specification of the instant application fails to address a method for detecting any interacting protein with any biotinylated molecule using any short peptide tetramer with streptavidin and with a PafA enzyme.
The existence of working examples:
There are fourteen embodiments that cover protein-protein interactions, protein-nucleic acid interactions and molecule-molecule interactions and they are examples of the invention system put in use (Embodiments 4-17, pages 80-101). Embodiment 4 teaches verifying the interaction between CheAs protein and CheZ protein (pages 80-82). Embodiment 5 teaches the detection of interacting proteins of CobB (Pages 82-85). Embodiment 6 teaches the detection of cell surface receptor of PD-1 protein (Pages 85-86). Embodiment 7 teaches the detection of interacting proteins of SARS-Co V-2 proteins (Pages 86-88). Embodiment 8 teaches the identification of interacting proteins of biotinylated m6A RNA (Pages 88-89). Embodiment 9 teaches verifying the interaction between biotinylated m6A RNA and YTDHF1, YTDHF2, YTDHF3 proteins (Page 89-90). Embodiment 10 teaches the Identification of Interacting Proteins of Biotinylated DNA (Pages 90-92). Embodiment 11 teaches the Verification of Interaction between Biotinylated DNA and EthR Protein (Pages 92-94). Embodiment 12 teaches the verification of specificity of DNA-RutR interaction (Pages 94-95). Embodiment 13 teaches the verification of Interaction between Biotinylated DNA and GCN4 (Pages 95-97). Embodiment 14 teaches the Identification of interacting proteins of lenalidomide small molecule (Page 97-98). Embodiment 15 teaches the verification of the interaction between c-di-GMP small molecule and ETHR protein (Pages 98-99). Embodiment 16 teaches the verification of interaction between c-di-GMP small molecule and CSP series short peptides (Pages 99-100). Embodiment 17 teaches the verification of interaction between Rapamycin small molecule and FKBP12 protein (Page 100-101).
The embodiments are directed to detecting protein-protein interactions, protein-nucleic acid interactions and molecule-molecule interactions. They do not provide a plan on how to approach each type of interaction based on its strength and nature (i.e., strong, moderate or weak) and only shows detection of different interacting proteins.
Furthermore, there is no indication from the embodiments of the specification of the instant application that the broadly claimed method would work in detecting any interacting protein with any biotinylated molecule using any short peptide tetramer with streptavidin and with PafA enzyme. Thus, the specification does not provide guidance with respect to detecting any type of interacting protein and it cannot be assumed that the claimed method would work in detecting any interacting protein with any biotinylated molecule using any short peptide tetramer with streptavidin and with a PafA enzyme.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
With the lack of teaching in prior art in regards to detecting any interacting protein, the PHOSITA is expected to face an unreasonable amount of experimentation. Furthermore, the complexity of protein-protein interaction, protein-nucleic acid interaction and molecule-molecule interaction; and the possible occurrence in different parts of the living species add another challenge to a PHOSITA.
Thus, the specification of the instant application does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with the claims of the instant application. Consequently, claims 1-10 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for using a peptide of 12-100 amino acids and for detecting interacting proteins of specification examples (i.e., CheAs), does not reasonably provide enablement for any short peptide nor for any interacting protein.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 7 and 9 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.
The term “short peptide” in claims 1, 7 and 9 is a relative term which renders the claim indefinite. The term “short” 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 of the instant application does not define how short a peptide is and a skilled artisan would not have been able to ascertain the boundaries of the claims from the use of ambiguous term “short” which renders claims 1, 7 and 9 as indefinite.
Conclusion
While no claims are allowed, they are free of the prior art.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Liu 1 et al. teaches the use of proximity-tagging system to identify membrane protein-protein interactions (Nature Methods, Volume 15, September 2018, 715–722). Liu 1 et al. teaches using a PafA enzyme in PUP-IT system to detect prey proteins (Figure 1, a, “PUP-IT design”). Liu 1 et al. teaches using biotin-fused DE28 peptide (Page 716, right column, first paragraph). Liu 1 does not teach or suggest using a streptavidin-short peptide tetramer.
Liu 2 et al. teaches the use of proximity-tagging system to detect nucleic acid-protein interactions (US 2022/0411771 A1, priority to 02/25/2020; Abstract; [0008]). Liu 2 et al. teaches using a PafA enzyme and PUP-IT system for studying nucleic acid-protein interactions (Abstract; [0043]; [0062]). Liu 2 does not teach or suggest using a streptavidin-short peptide tetramer.
Zhuang et al. teaches using proximity-tagging system to detect molecule-molecule interactions (US 11,467,166 B2, priority to 10/23/2017; Abstract; column 2, lines 8-35). Liu 1 et al. teaches using a PafA enzyme in PUP-IT system to detect prey proteins (Figure 1a; “PUP-IT design”). Liu 1 et al. teaches using biotin-fused DE28 peptide (Column 4, lines 54-62). Zhuang does not teach or suggest using a streptavidin-short peptide tetramer.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OMAR RAMADAN whose telephone number is (571)270-0754. The examiner can normally be reached Monday-Friday 8:30 am - 5:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at (571) 272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/OMAR RAMADAN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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