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
1. Applicant's election with traverse and arguments filed 7/28/26 that Claims 1 and 9 are generic claims directed to the inventive method and kit, respectively, and encompass all of the identified species. The elected species is merely one preferred embodiment of the generic invention, as reflected in dependent Claims 6-8 and 17-19. Applicants further argue identified species are not patentably distinct inventions requiring separate searches. Rather, each species employs the same inventive RNA-tagging platform, including the same engineered ascorbate peroxidase, biotin-aniline probe, and epigenetic reader module for tagging RNA molecules associated with epigenetically modified chromatin. The identified species differ only in the particular epigenetic reader protein or fusion construct employed, while the underlying method, kit structure, mode of operation, and issues of patentability remain substantially the same; and request that the restriction requirement mailed 6/26/26 be withdrawn.
Applicants’ arguments are considered and the restriction requirement mailed 6/26/26 is withdrawn.
2. Rejoinder
Because all claims previously withdrawn from consideration under 37 CFR 1.142 have been rejoined, the restriction requirement as set forth in the Office action mailed on 6/26/26 is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a continuation or divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
3. Claims 1-19 filed 4/30/24 are present and under consideration in this Office Action.
4. Drawings filed 4/30/24 are acknowledged.
5. IDS filed 4/30/24 are considered. A signed copy of the IDS is provided with this Office Action.
6. Specification
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
7. Claim Rejections: 35 USC § 112(a)
The following is a quotation 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.
Written Description
I. Claims 1-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, as containing 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(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-19 of the instant application as interpreted are directed to any method or kit for tagging RNA molecules involved in an epigenetically modified chromatin in real-time in living cells, comprising: introducing an epigenetic reader module protein, an engineered ascorbate peroxidase and biotin-aniline probe into a living cell; oxidizing the biotin-aniline probe by the engineered ascorbate peroxidase and forming a covalent bond between the biotin-aniline probe and an RNA molecule of an epigenetically modified chromatin to obtain a biotin-tagged RNA molecule; and purifying the biotin-tagged RNA molecule for further sequencing, having any structure (claim 1 or 9), the claimed genus. Claims 2-8 & 10-19 do not describe the key structures viz. epigenetic reader module protein, an engineered ascorbate peroxidase and biotin-aniline probe employed in the method or kit.
Claims 1-19 are as follows.
1. A method of tagging RNA molecules involved in an epigenetically modified chromatin in real-time in living cells, comprising: introducing an epigenetic reader module protein, an engineered ascorbate peroxidase and biotin-aniline probe into a living cell; oxidizing the biotin-aniline probe by the engineered ascorbate peroxidase and forming a covalent bond between the biotin-aniline probe and an RNA molecule of an epigenetically modified chromatin to obtain a biotin-tagged RNA molecule; and purifying the biotin-tagged RNA molecule for further sequencing.
2. The method of claim 1, wherein the epigenetic reader module protein locates a location of the epigenetically modified chromatin and drags the engineered ascorbate peroxidase to the location.
3. The method of claim 1, wherein the oxidation of the biotin-aniline probe occurs when the engineered ascorbate peroxidase is exposed to H.sub.2O.sub.2.
4. The method of claim 1, wherein the epigenetic reader module protein is an evolutionarily conserved protein derived from natural proteins.
5. The method of claim 4, wherein the epigenetic reader module protein comprises chromodomain from CBX7 or Drosophila Polycomb (dPC) for H3K27me3 (trimethyl-histone H3 lysine 27), chromodomain from CBX1 for H3K9me3 (trimethyl-histone H3 lysine 9), and PHD domain from TAF3 for H3K4me3.
6. The method of claim 4, wherein the epigenetic reader module is further fused with a plurality of a repetitive peptide epitope and the engineered ascorbate peroxidase is fused with a single-chain variable fragment (scFv).
7. The method of claim 6, wherein the repetitive peptide epitope is recognizable by the scFV for recruiting the engineered ascorbate peroxidase.
8. The method of claim 7, wherein the repetitive peptide epitope has an amino acid sequence of SEQ ID NO:01 and the scFV has an amino acid sequence of SEQ ID NO:02.
9. A kit for tagging RNA molecules involved in an epigenetically modified chromatin in real-time in living cells, comprising: an epigenetic reader module protein; an engineered ascorbate peroxidase; and a biotin-aniline probe.
10. The kit of claim 9, wherein the components of the kit are directly delivered into a living cell.
11. The kit of claim 9, wherein the engineered ascorbate peroxidase oxidizes the biotin-aniline probe when the engineered ascorbate peroxidase is exposed to H.sub.2O.sub.2.
12. The kit of claim 11, wherein the oxidized biotin-aniline probe forms a covalent bond to an RNA molecule of an epigenetically modified chromatin to generate a biotin-tagged RNA molecule.
13. The kit of claim 12, wherein the biotin-tagged RNA molecule is further purified and enriched.
14. The kit of claim 9, wherein the epigenetic reader module protein locates a location of the epigenetically modified chromatin and drags the engineered ascorbate peroxidase to the location.
15. The kit of claim 9, wherein the epigenetic reader module protein is an evolutionarily conserved protein derived from natural proteins.
16. The kit of claim 9, wherein the epigenetic reader module protein comprises chromodomain from CBX7 or dPC for H3K27me3, chromodomain from CBX1 for H3K9me3, and PHD domain from TAF3 for H3K4me3.
17. The kit of claim 9, wherein the epigenetic reader modules is further fused with a plurality of a repetitive peptide epitope and the engineered ascorbate peroxidase is fused with a scFv.
18. The kit of claim 17, wherein the repetitive peptide epitope is recognizable by the scFV for recruiting the engineered ascorbate peroxidase.
19. The kit of claim 18, wherein the repetitive peptide epitope has an amino acid sequence of SEQ ID NO:01 and the scFV has an amino acid sequence of SEQ ID NO:02.
The purpose of the written description requirement is to ensure that the inventor had possession, at the time the invention was made, of the specific subject matter claimed. For a broad generic claim, the specification must provide adequate written description to identify the genus of the claim.
“A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus.”). Regents of the University of California v. Eli Lilly & Co., 119, F.3d 1559, 1568, 43 USPQ2d 1398, 1405 (Fed. Cir. 1997).
MPEP § 2163 further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the biomolecule, it is "not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed biomolecule.”
“The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice …, reduction to drawings …, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.” MPEP 2163.
Furthermore, a “‘representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure ‘indicates that the patentee has invented species sufficient to constitute the gen[us].’ See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (‘[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.’). ‘A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.’ In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).” MPEP 2163.
In University of California v. Eli Lilly & Co., 43 USPQ2d 1938, the Court of Appeals for the Federal Circuit has held that “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials”. As indicated in MPEP § 2163, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show that Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that a representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The factors considered in the Written Description requirement are (1) level of skill and knowledge in the art, (2) partial structure, (3) physical and/or chemical properties, (4) functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the (5) method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient." MPEP § 2163.
In the instant case, there is no structure associated with function with regard to the members of genus of epigenetic reader module protein, an engineered ascorbate peroxidase and biotin-aniline probe employed in the method or kit.
No information, beyond the characterization of: A method/kit of tagging RNA molecules involved in an epigenetically modified chromatin in real-time in living cells, comprising: introducing an epigenetic reader module protein, an engineered ascorbate peroxidase and biotin-aniline probe into a living cell; oxidizing the biotin-aniline probe by the engineered ascorbate peroxidase and forming a covalent bond between the biotin-aniline probe and an RNA molecule of an epigenetically modified chromatin to obtain a biotin-tagged RNA molecule; and purifying the biotin-tagged RNA molecule for further sequencing, wherein the epigenetic reader module protein comprises chromodomain from CBX7 or Drosophila Polycomb (dPC) for H3K27me3 (trimethyl-histone H3 lysine 27), chromodomain from CBX1 for H3K9me3 (trimethyl-histone H3 lysine 9), and PHD domain from TAF3 for H3K4me3, wherein the oxidation of the biotin-aniline probe occurs when the engineered ascorbate peroxidase is exposed to H.sub.2O.sub.2, and wherein the epigenetic reader module is further fused with a plurality of a repetitive peptide epitope and the engineered ascorbate peroxidase is fused with a single-chain variable fragment (scFv), and wherein the repetitive peptide epitope has an amino acid sequence of SEQ ID NO:01 and the scFV has an amino acid sequence of SEQ ID NO:02.
The genus of epigenetic reader module protein, an engineered ascorbate peroxidase and biotin-aniline probe employed in the method or kit required in the claimed invention is an extremely large structurally and functionally variable genus. While the argument can be made that the recited genus of epigenetic reader module protein, an engineered ascorbate peroxidase and biotin-aniline probe employed in the method or kit, with specific structures having the associated function/activity as borrowed from the instant specification. However, the incomplete claim limitations cannot be read into the claims based on the description in the instant specification.
The art clearly teaches the “Practical Limits of Function Prediction”:
(a) Devos et al., (Proteins: Structure, Function and Genetics, 2000, Vol. 41: 98-107), teach that the results obtained by analyzing a significant number of true sequence similarities, derived directly from structural alignments, point to the complexity of function prediction. Different aspects of protein function, including (i) enzymatic function classification, (ii) functional annotations in the form of key words, (iii) classes of cellular function, and (iv) conservation of binding sites can only be reliably transferred between similar sequences to a modest degree. The reason for this difficulty is a combination of the unavoidable database inaccuracies and plasticity of proteins (Abstract, page 98) and the analysis poses interesting questions about the reliability of current function prediction exercises and the intrinsic limitation of protein function prediction (Column 1, paragraph 3, page 99) and conclude that “Despite widespread use of database searching techniques followed by function inference as standard procedures in Bioinformatics, the results presented here illustrate that transfer of function between similar sequences involves more difficulties than commonly believed. Our data show that even true pair-wise sequence relations, identified by their structural similarity, correspond in many cases to different functions (column 2, paragraph 2, page 105). Our data show that even true pair-wise sequence relations, identified by their structural similarity, correspond in many cases to different functions (column 2, paragraph 2, page 105). Applicants’ are respectfully directed to the problems associated EC Classification in the section “Transferring the EC Classification enzyme to Non-Enzyme Comparisons”; pages 101-102 and Fig. 2a)-b), highlighting the structural and functional heterogeneity based on EC Classification numbers; as the stereo-specificity, substrate-specificity and catalytic properties vary widely.
(b) Whisstock et al., (Quarterly Reviews of Biophysics 2003, Vol. 36 (3): 307-340) also highlight the difficulties associated with “Prediction of protein function from protein sequence and structure”; “To reason from sequence and structure to function is to step onto much shakier ground”, closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function, in such cases, assignment of function on the basis of homology, in the absence of direct experimental evidence, will give the wrong answer (page 309, paragraph 4), it is difficult to state criteria for successful prediction of function, since function is in principle a fuzzy concept. Given three sequences, it is possible to decide which of the three possible pairs is most closely related. Given three structures, methods are also available to measure and compare similarity of the pairs. However, in many cases, given three protein functions, it would be more difficult to choose the pair with most similar function, although it is possible to define metrics for quantitative comparisons of different protein sequences and structures, this is more difficult for proteins of different functions (page 312, paragraph 5), in families of closely related proteins, mutations usually conserve function but modulate specificity i.e., mutations tend to leave the backbone conformation of the pocket unchanged but to affect the shape and charge of its lining, altering specificity (page 313, paragraph 4), although the hope is that highly similar proteins will share similar functions, substitutions of a single, critically placed amino acid in an active-site residue may be sufficient to alter a protein’s role fundamentally (page 323, paragraph 1).
(c) This finding is reinforced in the following scientific teachings for specific proteins in the art that suggest, even highly structurally homologous polynucleotides and encoded polypeptides do not necessarily share the same function. For example, Witkowski et al., (Biochemistry 38:11643-11650, 1999), teaches that one conservative amino acid substitution transforms a b-ketoacyl synthase into a malonyl decarboxylase and completely eliminates b-ketoacyl synthase activity.
As stated above, No information, beyond the characterization of: A method/kit of tagging RNA molecules involved in an epigenetically modified chromatin in real-time in living cells, comprising: introducing an epigenetic reader module protein, an engineered ascorbate peroxidase and biotin-aniline probe into a living cell; oxidizing the biotin-aniline probe by the engineered ascorbate peroxidase and forming a covalent bond between the biotin-aniline probe and an RNA molecule of an epigenetically modified chromatin to obtain a biotin-tagged RNA molecule; and purifying the biotin-tagged RNA molecule for further sequencing, wherein the epigenetic reader module protein comprises chromodomain from CBX7 or Drosophila Polycomb (dPC) for H3K27me3 (trimethyl-histone H3 lysine 27), chromodomain from CBX1 for H3K9me3 (trimethyl-histone H3 lysine 9), and PHD domain from TAF3 for H3K4me3, wherein the oxidation of the biotin-aniline probe occurs when the engineered ascorbate peroxidase is exposed to H.sub.2O.sub.2, and wherein the epigenetic reader module is further fused with a plurality of a repetitive peptide epitope and the engineered ascorbate peroxidase is fused with a single-chain variable fragment (scFv), and wherein the repetitive peptide epitope has an amino acid sequence of SEQ ID NO:01 and the scFV has an amino acid sequence of SEQ ID NO:02.
Furthermore, “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features” (See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895).
Therefore, one skilled in the art cannot reasonably conclude that applicant had possession of the claimed invention at the time the instant application was filed. Applicants are referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov.
8. No claim is allowed.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to TEKCHAND SAIDHA whose telephone number is (571)272-0940. The examiner can normally be reached on M-F 8.00-5.30. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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/TEKCHAND SAIDHA/
Primary Examiner, Art Unit 1652
Recombinant Enzymes, Hoteling
Telephone: (571) 272-0940
Fax: (571) 273-0940
Prosecution Insights