Office Action 1: Non-Final Rejection (2024-09-26)
Rejection types: 112 - Written Description/Enablement, Double Patenting

CLAIMS:
CLAIMS

We claim:

1\. A method for improving the generation of stable human Foxp3+ T cells, the method comprising contacting with, or delivering to, a human T cell an effective 5-methylcytosine to 5- hydroxymethylcytosine converting amount of at least one catalytically active TET family enzyme, functional TET family derivative, TET family catalytically active fragment thereof, or combination thereof.
2\. The method of claim 1, wherein the human T cell is a purified human CD4+ T cell.
3\. The method of claim 1, further comprising contacting with, or delivering to, the human T cell a composition comprising at least one cytokine, growth factor, activating reagent, or combination thereof.
4\. The method of claim 3, wherein said composition comprises TGF-3.
5\. A method for improving efficiency or rate with which an induced pluripotent stem (iPS) cell is produced from an adult somatic cell, the method comprising contacting with, or delivering to a somatic cell, an effective 5-methylcytosine to 5-hydroxymethylcytosine converting amount of at least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active thereof, or combination thereof.
6\. The method of claim 5, wherein the catalytically active TET family enzyme is TET1 or TET2.
7\. The method of claim 5, further comprising comprising contacting with, or delivering to, the somatic cell, an effective amount of a TET family inhibitor.
8\. The method of claim 7, wherein the TET family inhibitor is a TET3 inhibitor.
9\. The method of claim 5, further comprising contacting the somatic cell with or delivering to the somatic cell a combination of nucleic acid sequences encoding Oct-4, Sox2, c-MYC, and Klf4.

10\. The method of claim 5, wherein the combination of nucleic acid sequences encoding Oct-4, Sox2,c-MYC, and Klf4 are delivered in a viral vector.

11\. The method of claim 5, wherein the somatic cell is a fibroblast.

12\. A method for improving efficiency of cloning a mammal by nuclear transfer or nuclear transplantation, the method comprising contacting a nucleus extracted from a cell to be cloned with an effective 5-methylcytosine to 5-hydroxymethylcytosine converting amount of at least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active fragment thereof, or combination thereof, during a nuclear transfer protocol.

13\. The method of claim 12, wherein the catalytically active TET family enzyme is TET1 or TET2.

14\. The method of claim 12, further comprising contacting the nucleus from the cell to be cloned with a TET family inhibitor.

15\. The method of claim 14, wherein the TET family inhibitor is a TET3 inhibitor.

16\. A method for detecting a 5-hydroxymethylcytosine nucleotide in a biological sample, the method comprising contacting a biological sample with a detectably labeled antibody or a binding portion thereof, labeled intrabody, or labeled protein, that specifically binds to 5-hydroxymethylcytosine, and detecting the amount of bound label, wherein the presence of the bound label is indicative of the 5-methylcytosine being converted to 5-hydroxymethylcytosine.

17\. A kit for modulating gene transcription via hydroxylation of 5-methylcytosine to 5- hydroxymethylcytosine, the kit comprising the following separate components:(a) at least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active fragment thereof, or combination thereof, or nucleic acid molecule that comprises a sequence encodingat least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active fragment, or combination thereof in an appropriate buffer or solution; and
(b) packaging materials and instructions therein to use said kit to hydroxylate 5-methylcytosine to 5-hydroxymethylcytosine, for the purpose of modulating gene transcription.

18\. The kit of claim 17, further comprising a composition comprising at least one cytokine, growth factor, activating reagent, or combination thereof for the purposes of generating stable human Foxp3+ regulatory T cells.

19\. The kit of claim 18, wherein the composition comprises TGF-3.

20\. The kit of claim 17, further comprising at least one nucleic acid sequence selected from the group consisting of nucleic acid sequences encoding Oct-4, Sox2, c-MYC, and Klf4, or any combination thereof.

21\. The kit of claim 20, wherein the nucleic acid sequences encoding Oct-4, Sox2, c-MYC, and Klf4 are incorporated into a viral vector.

22\. The kit of claim 17, further comprising at least one reagent suitable for the detection of 5- hydroxymethylcytosine.

23\. The kit of claim 22, wherein the reagent suitable for the detection of 5-hydroxymethylcytosine is an antibody, an antigen-binding portion thereof, an intrabody, or a protein, that specifically binds to 5-hydroxymethylcytosine.

24\. The kit of claim 22, wherein the reagent suitable for the detection of 5-hydroxymethylcytosine is an antibody, an antigen-binding portion thereof, an intrabody, or a protein that is specific for cytosine-5-methylsulfonate.

25\. A method for improving stem cell therapies, the method comprising contacting with, or delivering to, a stem cell an effective 5-methylcytosine to 5-hydroxymethylcytosine converting amount of at least one catalytically active TET family enzyme, functional TET family derivative,TET catalytically active fragment thereof, or combination thereof, or at least one nucleic acid molecule that comprises a sequence encoding a catalytically active TET family enzyme, a functional TET family derivative, TET catalytically active fragment thereof, or combination thereof.

26\. A method for treating an individual affected with or at risk for cancer, the method comprising administering to an individual affected with, or at risk for, cancer, an effective amount of at least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active fragment, or a combination thereof, involved in transforming 5-methylcytosine into 5- hydroxymethylcytosine.

27\. The method of claim 26, wherein the agent that specifically modulates hydroxylase activity is an inhibitor.

28\. The method of claim 26, wherein the agent that specifically modulates hydroxylase activity is an activator.

29\. The method of claim 26, wherein the cancer is a leukemia.

30\. The method of claim 29, wherein the leukemia is an acute myeloid leukemia comprising the t(10:11)(q22:q23) Mixed Lineage Leukemia translocation of TET1.

31\. A method for screening for an agent with TET family enzyme modulating activity, the method comprising the steps of:(a) providing a cell comprising at least one TET family enzyme, functional TET family derivative, TET catalytically active fragment, recombinant TET family enzyme thereof, or combination thereof;
(b) contacting said cell with a test agent, thereby creating a test sample; and
(c) detecting the level of 5-hydroxymethylated cytosine in the cell in the test sample with the level expressed in a control sample; and
(d) determining whether or not the test agent increases or decreases the level of 5- hydroxymethylated cytosine, wherein a statistically significant decrease in the level of 5- hydroxymethylated cytosine indicates the test agent is an inhibitor, and a statistically significant increase in the level of 5-hydroxymethylated cytosine indicates the test agent is an activator.

32\. The method as in any one of claims 1, 5, 12, 17, 25, 26, and 31, in which the catalytically active TET family enzyme is selected from the group consisting of TET1, TET2, TET3, and CXXC4.

33\. The method as in any one of claims 1, 5, 12, 17, 25, 26, and 31, in which the functional TET family derivative comprises SEQ ID NO: 1.

34\. The method as in any one of claims 1, 5, 12, 17, 25, 26, and 31, in which the TET family catalytically active fragment comprises SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5.

35\. A method for covalent tagging of 5-hydroxymethylcytosine in a nucleic acid, the method comprising contacting a nucleic acid molecule with an enzyme that adds one or more glucose molecules to a 5-hydroxymethylcytosine residue to generate glucosylated-5- hydroxymethylcytosine or gentibiose-containing-5-hydroxymethylcytosine, wherein the enzyme is an alpha-glucosyltransferase, beta-glucosyltransferase, or a beta-glucosyl-alpha-glucosyl- transferase.

36\. The method of claim 35, wherein the 5-hydroxymethylcytosine is naturally occurring.

37\. The method of claim 35, further comprising the step of first contacting said nucleic acid with at least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active fragment thereof, or combination thereof, thereby converting 5- methylcytosine to hydroxymethylcytosine.

38\. The method of claim 35, wherein the nucleic acid is contacted in vitro, in a cell, or in vivo.

39\. A method for detecting 5-hydroxymethylcytosine in a nucleic acid, the method comprising contacting a nucleic acid with an enzyme that utilizes labeled glucose or glucose-derivative donor substrates to add one or more labeled glucose molecules or glucose-derivatives to a 5- hydroxymethylcytosine residue to generate glucosylated-5-hydroxymethylcytosine or gentibiose- containing-5-hydroxymethylcytosine, wherein the enzyme is an alpha-glucosyltransferase, a beta-glucosyltransferase, or a beta-glucosyl-alpha-glucosyl-transferase.

40\. The method of claim 39, wherein the glucose or glucose-derivative donor substrate is a uridine diphosphate glucose.

41\. The method of claim 39, wherein the labeled glucose or glucose-derivative donor substrates is radioactively labeled.

42\. The method of claim 39, wherein the 5-hydroxymethylcytosine is naturally occurring.

43\. The method of claim 39, further comprising the step of first contacting said nucleic acid with at least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active fragment thereof, or combination thereof, thereby converting 5- methylcytosine to 5-hydroxymethylcytosine.

44\. The method of claim 39, wherein the nucleic acid is contacted in vitro, in a cell, or in vivo.

45\. A method for detecting 5-hydroxymethylcytosine in a nucleic acid, the method comprising contacting the covalently tagged 5-hydroxymethylcytosine of claim 35 with a protein that recognizes a glucose molecule, glucose-derivative or gentibiosyl molecule.

46\. The method of claim 45, wherein the protein recognizes only the glucose molecule, glucose- derivative, or gentibiosyl.

47\. The method of claim 45, wherein the protein recognizes the glucose molecule, glucose-derivative,or gentibiosyl only in the context of 5-hydroxymethylcytosine.

48\. The method of claim 45, wherein the protein is a lectin.

49\. The method of claim 48, wherein the lectin is Musa acuminata lectin.

50\. The method of claim 45, wherein the protein is an antibody or antigen-binding fragment thereof.

51\. The method of claim 50, wherein the antibody or antibody fragment thereof is modified with a tag.

52\. The method of claim 51, wherein the tag is a biotin molecule a bead, a gold particle, or a fluorescent molecule.

53\. The method of claim 45, wherein the protein is an enzyme.

54\. The method of claim 53, wherein the enzyme is hexokinase or beta-glucosyl-alpha-glucosyl- transferase.

55\. A method for detecting 5-hydroxymethylcytosine in a nucleic acid, the method comprising contacting a nucleic acid with an enzyme and utilizing glucose or glucose-derivative donor substrates that trap covalent enzyme-DNA intermediates to detect 5-hydroxymethylcytosine residues, wherein the enzyme is an alpha-glucosyltransferase, a beta-glucosyltransferase, or a beta-glucosyl-alpha-glucosyl-transferase.

56\. The method of claim 55, wherein the glucose donor substrate is a uridine diphosphate glucose analog.

57\. The method of claim 56, wherein the uridine diphosphate glucose analog is uridine-2-deoxy-2- fluoro-glucose.

58\. The method of claim 55, wherein the 5-hydroxymethylcytosine is naturally occurring.

59\. The method of claim 55, further comprising the step of first contacting said nucleic acid with at least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active fragment thereof, or combination thereof, thereby converting 5- methylcytosine to 5-hydroxymethylcytosine.

60\. The method of claim 55, wherein the enzyme is tagged.

61\. The method as in any one of claims 35, 39, and 55, in which the alpha-glucosyltransferase is encoded by a bacteriophage selected from the group consisting of T2, T4, and T6 bacteriophages.

62\. The method as in any one of claims 35, 39, and 55, in which the beta-glucosyltransferase is encoded by a bacteriophage selected from T4 bacteriophages.

63\. The method as in any one of claims 35, 39, and 55, in which the beta-glucosyl-alpha-glucosyl- transferase is encoded by a bacteriophage selected from the group consisting of T2 and T6 bacteriophages.

64\. The method of claim 55, wherein the nucleic acid is contacted in vitro, in a cell, or in vivo.

65\. A method to detect 5-hydroxymethylcytosine in a nucleic acid, the assay comprising contacting a nucleic acid with sodium hydrogen sulfite to convert a 5-hydroxymethylcytosine in a nucleic acid to cytosine-5-methylsulfonate, and contacting the sodium hydrogen sulfite contacted nucleic acid with a protein specific for cytosine-5-methylsulfonate.

66\. The method of claim 65, wherein the protein is an antibody, an antigen binding fragment thereof,an enzyme, or an intrabody.

67\. The method of claim 66, wherein the antibody comprises an antiserum.

68\. The method of claim 66, wherein the antibody, antigen binding fragment thereof, enzyme, or intrabody is modified with a tag.

69\. The method of claim 68, wherein the tag is a biotin molecule, a bead, a gold particle, or a fluorescent molecule.

70\. The method of claim 65, further comprising isolating the 5-hydroxymethylcytosine containing nucleic acid with the protein specific for cytosine-5-methylsulfonate.

71\. The method of claim 65, wherein the nucleic acid is in vitro, a cell, or in vivo.

72\. A kit for the detection and purification of methylcytosine and 5-hydroxymethylcytosine for use in downstream applications, the kit comprising:(a) one or more catalytically active TET family enzymes, functional TET family derivatives, or TET catalytically active fragments thereof for the conversion of methylcytosine to 5- hydroxymethylcytosine;

(b) one or more enzymes encoded by bacteriophages of the "T even" family;
(c) one or more glucose or glucose-derivative donor substrates;
(d) one or more proteins to detect glucose or glucose-derivative modified nucleotides;
(e) standard DNA purification columns, buffers, and substrate solutions; and
(f) packaging materials and instructions therein to use said kits.

73\. The kit of claim 72, wherein the enzyme encoded by bacteriophages of the "T even" family is selected from the group consisting of alpha-glucosyltransferases, beta-glucosyltransferases, andbeta-glucosyl-alpha-glucosyl-transferases.

74\. The kit of claim 73, wherein the alpha-glucosyltransferase is encoded by a bacteriophage selected from the group consisting of T2, T4, and T6 bacteriophages.
75\. The kit of claim 73, wherein the beta-glucosyltransferase is encoded by a bacteriophage selected from T4 bacteriophages.

76\. The kit of claim 73, wherein the beta-glucosyl-alpha-glucosyl-transferase is encoded by a bacteriophage selected from the group consisting of T2 and T6 bacteriophages.

77\. The kit of claim 72, wherein the glucose or glucose-derivative donor substrate is uridine diphosphate glucose (UDPG).

78\. The kit of claim 72, wherein the glucose or glucose-derivative donor substrate is radiolabeled.

79\. The kit of claim 77, wherein the uridine diphosphate glucose is radiolabeled with 14C or 3H.

80\. The kit of claim 72, wherein the protein to detect glucose or glucose-derivative modified nucleotides is a lectin, an antibody or an antigen binding fragment thereof, or an enzyme.

81\. The kit of claim 80, wherein the protein recognizes only the glucose or glucose-derivative.

82\. The kit of claim 80, wherein the protein recognizes the glucose or glucose-derivative only in the context of 5-hydroxymethylcytosine.
83\. The kit of claim 80, wherein the antibody or antigen binding fragment thereof is modified with at least one tag.

84\. The kit of claim 83, wherein the tag is a biotin molecule, a bead, a gold particle, or a fluorescent molecule.

85\. The kit of claim 80, wherein the enzyme is a hexokinase or a beta-glucosyl-alpha-glucosyl- transferase.

86\. The kit of claim 80, wherein the lectin is Musa acuminata lectin (BanLec).

87\. The kit of claim 80, wherein the lectin is modified with a gold particle or a fluorescent tag.

88\. A method for diagnosing a myelodysplastic syndrome, a myeloproliferative disorder, acute myelogenous leukemia, systemic mastocytosis, or chronic myelomonocytic leukemia in an individual in need thereof, the method comprising the steps of (i) determining a level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, in a tissue or a cell sample from an individual in need thereof, and(ii) comparing the level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, in the tissue or cell sample from the individual with a level of 5-methylcytosine, 5- hydroxymethylcytosine, or a combination thereof, in a tissue or cell sample from a normal control,
wherein a difference in the level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, between the sample from the individual in need and the control sample is indicative of the individual having a myelodysplastic syndrome, a myeloproliferative disorder, acute myelogenous leukemia, systemic mastocytosis, or chronic myelomonocytic leukemia.
89\. The method of claim 88, further comprising a step of comparing the level of 5-methylcytosine, 5- hydroxymethylcytosine, or a combination thereof, in a tissue or cell sample of the individual to the level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, in at least one sample from a diseased tissue or a diseased cell, wherein if the level of 5-methylcytosine, 5- hydroxymethylcytosine, or a combination thereof, in the tissue or cell sample from the individual in need is similar to the level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, from at least one of the samples from the diseased tissue or cell then the individual is diagnosed with a myelodysplastic syndrome, a myeloproliferative disorder, acute myelogenous leukemia, systemic mastocytosis, or chronic myelomonocytic leukemia.

90\. A method for monitoring progression of or an effect of a therapy on a myelodysplastic syndrome,a myeloproliferative disorder, acute myelogenous leukemia, systemic mastocytosis, or chronic myelomonocytic leukemia, the method comprising the steps of (i) determining a level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof,
in a tissue or cell sample from an individual in need thereof to establish a baseline level of 5- methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, in the tissue or cell sample;
(ii) determining a level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, in a tissue or cell sample from the individual at least one time following the establishment of the baseline level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof in the tissue or cell sample thereby etsablishing at least one follow-up level of 5-methylcytosine, 5- hydroxymethylcytosine, or a combination thereof, wherein a difference in the follow-up level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, relative to the baseline level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, in the tissue or cell sample is indicative of the progression or effect of a therapy on a myelodysplastic syndrome,
a myeloproliferative disorder, acute myelogenous leukemia, systemic mastocytosis, or chronic myelomonocytic leukemia in the individual.
91\. The method of claim 88 or 90, in which the level of 5-methylcytosine, 5-hydroxymethylcytosine,
or a combination thereof, is assessed using an assay to convert 5-hydroxymethylcytosine to cytosine-5-methylsulfonate.

92\. A kit for the detection and purification of 5-hydroxymethylcytosine, the kit comprising:(a) at least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active fragment thereof, or combination thereof for the conversion of methylcytosine to 5-hydroxymethylcytosine;
(b) sodium bisulfite;
(c) one or more proteins to detect sodium bisulfite treated nucleotides;
(e) standard DNA purification columns, buffers, and substrate solutions; and
(f) packaging materials and instructions therein to use said kits.

93\. The kit of claim 92, wherein the protein is an antibody, an antigen binding fragment thereof, an intrabody, or an enzyme.

94\. The kit of claim 92, wherein the protein is specific for cytosine-5-methylsulfonate.

95\. The kit of claim 94, wherein the antibody, antigen binding fragment thereof, intrabody, or enzyme is modified with at least one tag.

96\. The kit of claim 95, wherein the tag is selected from the group consisting of a biotin molecule, a bead, a gold particle, or a fluorescent molecule.

OFFICE ACTION:
DETAILED ACTION
Notice of Pre-AIA  or AIA  Status
The present application is being examined under the pre-AIA  first to invent provisions.
Priority
This application is a continuation application (CON) of U.S. Application Serial Number 17/675,502, filed 2/18/2022; which is a CON of U.S. Application Serial Number 17/350,181, filed 6/17/2021; which is a CON of U.S. Application Serial Number 16/380,846, filed 4/10/2019; which is a CON of U.S. Application Serial Number 15/440,815, filed 2/23/2017; which is a CON of U.S. Application Serial Number 15/341,344, filed 11/02/2016; which is a CON of U.S. Application Serial Number 15/193,796, filed 6/27/2016; which is a CON of U.S. Application Serial Number 13/795,739, filed 3/12/2013; which is a CON of U.S. Application Serial Number 13/120,861, filed 6/07/2011.  13/120,861 is a 371 of PCT/US2009/058562, filed 9/28/2009.  This application claims benefit to U.S. Provisional Application Serial Numbers 61/121,844, filed 12/11/2008, 61/100,995, filed 9/29/2008 and 61/100,503, filed 9/26/2008.  Claims 97-123 are pending and have been examined on the merits.
Information Disclosure Statement
The information disclosure statements submitted on 7/19/2024 have been considered by the examiner.
Claim Rejections - 35 USC § 112
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.
Claim 111 is 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 “substantially identical” in claim 111 is a relative term which renders the claim indefinite. The term “substantially identical” 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. Appropriate correction is required.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA  35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA  35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 123 is rejected under 35 U.S.C. 112(d) or pre-AIA  35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 123 recites that the nucleic acid molecule is a eukaryotic nucleic acid molecule which fails to further limit the subject matter of the claim upon which it depends, claim 97 because claim 97 recites that the nucleic acid is an isolated eukaryotic nucleic acid molecule.  Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA  as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 97-100, 102-104, 108-113 and 117-123 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 31-38, 45-46, 48-54 and 57-58 of copending Application No. 18588930 (reference application; herein ‘930).
Although the claims at issue are not identical, they are not patentably distinct from each other because claim 31 of ‘930 recites a method for detecting a methylated cytosine residue in a nucleic acid, comprising: (a) contacting said nucleic acid with a polypeptide having at least 90% sequence identity with a TET1 polypeptide, a TET2 polypeptide, a TET3 polypeptide, a CXXC4 polypeptide, a catalytically active fragment thereof, a variant thereof, or any combination thereof to generate a product nucleic acid; and (b) performing a reaction on said product nucleic acid or a derivative thereof, to identify a presence of said methylated cytosine residue in said nucleic acid; claim 45 of ‘930 recites the method of claim 31, wherein said nucleic acid is a DNA molecule; claim 46 of ‘930 recites the method of claim 45, wherein said DNA molecule comprises isolated genomic DNA; claim 49 of ‘930 recites the method of claim 31, further comprising derivatizing said product nucleic acid; claim 50 of ‘930 recites wherein said derivatizing comprises, prior to (b), contacting said product nucleic acid with a glucose molecule or a glucose derivative donor substrate; claim 51 recites the method of claim 50, wherein said derivatizing comprises contacting said product nucleic acid with α-glucosyltransferase (AGT) or a conservatively substituted variant thereof; and claim 52 of ‘930 recites the method of claim 50, wherein said derivatizing comprises contacting said product nucleic acid with β-glucosyltransferase (BGT) or a conservatively substituted variant thereof; hence, a person of ordinary skill in the art at the time of filing would have found it obvious to practice a method of converting a methylated cytosine residue in an isolated eukaryotic nucleic acid molecule to a modified cytosine residue, the method comprising: (a) contacting said nucleic acid molecule with a polypeptide that converts said methylated cytosine residue to a modified cytosine residue, wherein said polypeptide comprises a TET1 polypeptide, a TET2 polypeptide, a TET3 polypeptide, or a CXXC4 polypeptide, or a catalytically active fragment thereof; and (b) contacting said isolated eukaryotic nucleic acid molecule with a glucosyltransferase polypeptide to derivatize said modified cytosine residue, wherein said glucosyltransferase polypeptide comprises β-glucosyltransferase (BGT) or α-glucosyltransferase (AGT) because it would be obvious for the isolated genomic DNA in the claims of ‘930 to be isolated eukaryotic DNA; therefore, instant claims 97, 102-104, 119 and 122-123 are prima facie obvious.
Instant claims 98-99, 108-113 and 117-118 are prima facie obvious over claims 31-38 of ‘930 because they disclose the subject matter of instant claims 98-99, 108-113 and 117-118; therefore, instant claims 98-99, 108-113 and 117-118 are prima facie obvious.
Instant claims 102-104 and 119-121 are prima facie obvious over claims 31 and 49-54 of ‘930 because they disclose the subject matter of instant claims 102-104 and 119-121; therefore, instant claims 102-104 and 119-121 are prima facie obvious.
Instant claim 100 is prima facie obvious over claims 31 and 49 of ‘930 because claims 31 and 49 of ‘930 disclose the subject matter of instant claim 100.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 97-99, 102-105, 108-113 and 117-123 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 31-34 and 36-50 of copending Application No. 18588987 (reference application; herein ‘987).
Although the claims at issue are not identical, they are not patentably distinct from each other because claim 31 of ‘987 recites a method comprising contacting a nucleic acid molecule with an isolated enzyme comprising a TET polypeptide, a catalytically active fragment thereof, a variant thereof, or any combination thereof in an amount effective to convert 5-methylcytosine of said nucleic acid molecule to an oxidized derivative thereof; claim 36 of ‘987 recites the method of claim 31, wherein said TET polypeptide comprises a TET1 polypeptide, TET2 polypeptide, or CXXC4 polypeptide, and comprises a polypeptide having at least 90% sequence identity to any one of SEQ ID NOs: 27, 28, or 29; claim 43 of ‘987 recites the method of claim 31, wherein said nucleic acid molecule comprises isolated eukaryotic genomic DNA; claim 45 of ‘987 recites the method of claim 31, further comprising adding a sugar residue to said oxidized derivative of said 5-methylcytosine in said nucleic acid molecule; claim 46 of ‘987 recites the method of claim 45, wherein adding said sugar residue to said oxidized derivative of said 5-methylcytosine in said nucleic acid molecule comprises adding a glucose molecule or a glucose-derivative donor substrate to said oxidized derivative of said 5-methylcytosine in said nucleic acid molecule; claim 47 of ‘987 recites the method of claim 46, wherein said adding a glucose molecule or a glucose-derivative donor substrate to said oxidized derivative of said 5-methylcytosine in said nucleic acid molecule comprises contacting said oxidized derivative of said 5-methylcytosine in said nucleic acid molecule with an α-glucosyltransferase (AGT) polypeptide or a variant thereof; and claim 48 of ‘987 recites the method of claim 46, wherein said adding said glucose molecule or said glucose-derivative donor substrate to said oxidized derivative of said 5-methylcytosine in said nucleic acid molecule comprises contacting said oxidized derivative of said 5-methylcytosine in said nucleic acid molecule with said β-glucosyltransferase (BGT) polypeptide or a conservatively-substituted variant of said BGT polypeptide; hence, a person of ordinary skill in the art at the time of filing would have found it obvious to practice a method of converting a methylated cytosine residue in an isolated eukaryotic nucleic acid molecule to a modified cytosine residue, the method comprising: (a) contacting said nucleic acid molecule with a polypeptide that converts said methylated cytosine residue to a modified cytosine residue, wherein said polypeptide comprises a TET1 polypeptide, a TET2 polypeptide, a TET3 polypeptide, or a CXXC4 polypeptide, or a catalytically active fragment thereof; and (b) contacting said isolated eukaryotic nucleic acid molecule with a glucosyltransferase polypeptide to derivatize said modified cytosine residue, wherein said glucosyltransferase polypeptide comprises β-glucosyltransferase (BGT) or α-glucosyltransferase (AGT); therefore, instant claims 97-99, 102-104, 108-113,  117-119 and 122-123 are prima facie obvious.
Regarding instant claim 105, claim 44 of ‘987 teaches that the isolated eukaryotic genomic DNA is from a somatic cell, e.g., a cell sample of a subject; therefore, instant claim 105 is prima facie obvious.
Instant claims 120-121 are prima facie obvious over claims 31, 45-46 and 48-50 of ‘987 because they disclose the subject matter of instant claims 120-121; therefore, instant claims 120-121 are prima facie obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 97-100, 102-103, 108-113 and 117-123 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 9816986 (herein “’986”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the method for detecting a methylated cytosine residue in a nucleic acid set forth in claims 1-8 of ‘986 comprises contacting a mammalian nucleic acid molecule, i.e., a eukaryotic nucleic acid molecule, with a TET enzyme, i.e., which is a dioxygenase which can a TET1, TET2, TET3 or CXXC4 polypeptide which can be identical to SEQ ID NOs: 27, 28 or 29, which comprises SEQ ID NO: 1 (see col. 14, l. 28 – col. 15, l. 6 of disclosure of ‘986) which converts 5-methylcytosine of said nucleic acid molecule to a modified cytosine residue, 5-hydroxymethylcytosine, and glycosylating the 5-hydroxymethylcytosine with UDPG and beta-glycosyltransferase (BGT) wherein the nucleic acid can be genomic DNA; hence, a person of ordinary skill in the art at the time of filing would have found it obvious to practice a method of converting a methylated cytosine residue in an isolated eukaryotic nucleic acid molecule to a modified cytosine residue, the method comprising: (a) contacting said nucleic acid molecule with a polypeptide that converts said methylated cytosine residue to a modified cytosine residue, wherein said polypeptide comprises a TET1 polypeptide, a TET2 polypeptide, a TET3 polypeptide, or a CXXC4 polypeptide, or a catalytically active fragment thereof; and (b) contacting said isolated eukaryotic nucleic acid molecule with a glucosyltransferase polypeptide to derivatize said modified cytosine residue, wherein said glucosyltransferase polypeptide comprises β-glucosyltransferase (BGT) because the method for detecting a methylated cytosine residue in a nucleic acid set forth in claims 1-8 of ‘986 comprises said conversion; therefore, instant claims 97-99, 102-103, 108-113, 117-119 and 122-123 are prima facie obvious over claims 1-8 of ‘986.
Regarding instant claims 120-121, claims 1-8 of ‘956 recite a method for detecting methylated cytosine residues in a mammalian nucleic acid comprising contacting the nucleic acid with at least one catalytically active TET family enzyme and further comprising adding a glucose molecule to the produced 5-hydroxymethylcytosine with beta-glucosyltransferases meeting the limitations of instant claims 120-121 as seen at col. 30, l. 59 – col. 31, l. 19 of the disclosure of ‘956; therefore, instant claims 120-121 are prima facie obvious over claims 1-8 of ‘956.
Regarding instant claim 100, the method made obvious by claims 1-8 of ‘956 comprises detecting a methylation status of said nucleic acid molecule based on a presence or an absence of said modified cytosine residue; therefore, instant claim 100 is prima facie obvious.
NOTE: It is proper to consult the disclosure for defining the claim (MPEP 1504.06).  Claim 1 of ‘986 recites a TET enzyme or a catalytically active fragment thereof comprising SEQ ID NO: 1.  Col. 14, l. 28 – col. 15, l. 6 of disclosure of ‘986 defines these TET enzymes.  Claim 1 recites a beta-glucosyltransferase and claim 3 of ‘986 discloses the beta-glucosyltransferase comprises an Asp-Ile-Arg-Leu sequence.  Col. 30, l. 59 – col. 31, l. 19 of the disclosure of ‘956 defines these glucosyltransferases.
Claims 97-100, 102-105, 108-113 and 117-123 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 10443091 (herein “’091”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the method for detecting a methylated cytosine residue in a nucleic acid set forth in claims 1-3, 5 and 7-13 of ‘091 comprises contacting a nucleic acid molecule with a TET enzyme, i.e., which is a dioxygenase, which can a TET1, TET2, TET3 or CXXC4 polypeptide which can be identical to SEQ ID NOs: 27, 28 or 29 which comprises SEQ ID NO: 1 (see col. 14, l. 25 – col. 15, l. 3 of disclosure of ‘091) which converts 5-methylcytosine of said nucleic acid molecule to a modified cytosine residue, 5-hydroxymethylcytosine, and glycosylating the 5-hydroxymethylcytosine with an alpha-glucosyltransferase or a beta-glucosyltransferase wherein the nucleic acid can be from a cell (claim 7 of ‘091), i.e., a eukaryotic nucleic acid molecule; therefore, instant claims 97-99, 102-104, 108-113, 117-119 and 122-123 are prima facie obvious over claims 1-3, 5 and 7-13 of ‘091.
Regarding instant claims 120-121, claims 1-3, 5 and 7-13 of ‘091 recite a method for detecting methylated cytosine residues in a mammalian nucleic acid comprising contacting the nucleic acid with at least one catalytically active TET family enzyme and further comprising adding a glucose molecule to the produced 5-hydroxymethylcytosine with beta-glucosyltransferases meeting the limitations of instant claims 120-121 as seen at col. 30, l. 59 – col. 31, l. 19 of the disclosure of ‘091; therefore, instant claims 120-121 are prima facie obvious over claims 1-3, 5 and 7-13 of ‘091.
Regarding instant claims 100 and 105, the method made obvious by claims 1-3, 5 and 7-13 of ‘091 comprises detecting a methylation status of said nucleic acid molecule based on a presence or an absence of said modified cytosine residue wherein the nucleic acid can be from a cell; therefore, instant claims 100 and 105 are prima facie obvious.
NOTE: It is proper to consult the disclosure for defining the claim (MPEP 1504.06).  Claim 5 of ‘091 recites a catalytically active TET family enzyme.  Col. 14, l. 25 – col. 15, l. 3 of the disclosure of ‘091 defines these TET enzymes.  Claim 1 recites alpha-glucosyltransferase and beta-glucosyltransferase.  Col. 30, l. 59 – col. 31, l. 19 of the disclosure of ‘091 defines these glucosyltransferases.
Claims 97-123 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1- 19 of U.S. Patent No. 10731204 (herein “’204”).
Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of ‘204 is drawn to a method of converting a methylated cytosine residue in an isolated nucleotide sequence to a modified base, the method comprising contacting said isolated nucleotide sequence with an enzyme or a catalytically active fragment thereof that converts said methylated cytosine residue in said isolated nucleotide sequence to said modified base, wherein said modified base comprises a hydroxymethylated cytosine residue, wherein said enzyme or said catalytically active fragment thereof comprises TET1, TET2, TET3, CXXC4, a catalytically active fragment of any of these, or any combination thereof; claim 3 of ‘204 recites the method of claim 1, further comprising detecting a methylation status of said isolated nucleotide sequence based on a presence or an absence of said modified base; claim 6 of ‘204 recites the method of claim 3, wherein said detecting comprises contacting said isolated nucleotide sequence with a glucosyltransferase protein that utilizes a labeled glucose or a labeled glucose-derivative donor substrate to add a labeled glucose molecule or a labeled glucose-derivative to said hydroxymethylated cytosine residue to generate a labeled glucosylated-hydroxymethylated cytosine residue, wherein said glucosyltransferase comprises beta-glucosyltransferase or alpha-glucosyltransferase; and claim 10 of ‘204 recites the method of claim 1, wherein said isolated nucleotide sequence is obtained from a cell sample or a tissue sample of a subject, i.e., the isolated nucleotide sequence is an isolated eukaryotic nucleic acid molecule; hence, a person of ordinary skill in the art at the time of filing would have found it obvious to practice a method of converting a methylated cytosine residue in an isolated eukaryotic nucleic acid molecule to a modified cytosine residue, the method comprising: (a) contacting said nucleic acid molecule with a polypeptide that converts said methylated cytosine residue to a modified cytosine residue, wherein said polypeptide comprises a TET1 polypeptide, a TET2 polypeptide, a TET3 polypeptide, or a CXXC4 polypeptide, or a catalytically active fragment thereof; and (b) contacting said isolated eukaryotic nucleic acid molecule with a glucosyltransferase polypeptide to derivatize said modified cytosine residue, wherein said glucosyltransferase polypeptide comprises β-glucosyltransferase (BGT) or α-glucosyltransferase (AGT); therefore, instant claims 97-100, 102-105, 108-113, 117-119 and 122-123 are prima facie obvious.
NOTE: col. 14, l. 48 – col. 15, l. 6 of the disclosure of ‘204 discloses that SEQ ID NOs: 27, 28 and 29 constitute TET1, TET2 and CXXC4, respectively and that all comprise SEQ ID NO: 1.
Regarding instant claim 101, claim 4 of ‘204 discloses that detecting comprises contacting said methylated cytosine residue or said modified base with bisulfite; therefore, instant claim 101 is prima facie obvious.
Regarding instant claim 106, claim 11 of ‘204 discloses that the isolated nucleotide sequence is obtained from an extracellular fluid sample; therefore, instant claim 106 is prima facie obvious.
Regarding instant claim 107, claim 12 of ‘204 discloses that the isolated nucleotide sequence is obtained from a subject having cancer or suspected of having cancer; therefore, instant claim 107 is prima facie obvious.
Regarding instant claims 114-116, claims 16-18 of ‘204 discloses that the modified cytosine residue is indirectly labeled with a fluorophore or a biotinyl group; therefore, instant claims 114-116 are prima facie obvious.
Regarding instant claims 120-121, col. 31, ll. 1-28 of the disclosure of ‘204 discloses that the beta-glucosyltransferase meets the limitations of instant claims 120-121; therefore, instant claims 120-121 are prima facie obvious.
NOTE: It is proper to consult the disclosure for defining the claim (MPEP 1504.06).  Claim 1 of ‘204 recites catalytically active TET family enzymes.  Col. 14, l. 48 – col. 15, l. 6 of the disclosure of ‘204 defines these TET enzymes.  Claim 6 of ‘204 recites alpha-glucosyltransferase and beta-glucosyltransferase.  Col. 31, ll. 1-28 of the disclosure of ‘204 defines these glucosyltransferases.
Claims 97-104, 106-113 and 117-123 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 10767216 (herein “’216”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the method set forth in claims 1-16 of ’216 comprises contacting a mammalian nucleic acid molecule, i.e., a eukaryotic nucleic acid molecule, with a TET1, TET2, TET3 or CXXC4 enzyme, i.e., which is a dioxygenase, which can a TET1, TET2 or CXXC4 polypeptide which can be identical to SEQ ID NOs: 27, 28 or 29 which comprises SEQ ID NO: 1 (see col. 14, l. 49 – col. 15, l. 7 of disclosure of ‘216) in an amount effective to convert 5-methylcytosine of the nucleic acid sequence to a modified base, i.e. 5-hydroxymethylcytosine, and glycosylating the modified base with an alpha-glucosyltransferase or a beta-glucosyltransferase; therefore, instant claims 97-99, 102-104, 108-113, 117-119 and 122-123 are prima facie obvious over claims 1-16 of ’216.
Regarding instant claim 100, the method set forth in claims 1-16 of ’216 comprises detecting a methylation status of said nucleic acid molecule based on a presence or an absence of said modified cytosine residue; therefore, instant claim 100 is prima facie obvious.
Regarding instant claim 101, claim 12 of ‘216 discloses that the method comprises contacting said methylated cytosine residue or said modified base with bisulfite; therefore, instant claim 101 is prima facie obvious.
Regarding instant claim 106, claim 4 of ‘216 discloses that the isolated nucleotide sequence is obtained from an extracellular fluid sample; therefore, instant claim 106 is prima facie obvious.
Regarding instant claim 107, claim 6 of ‘216 discloses that the isolated nucleotide sequence is obtained from a subject having cancer or suspected of having cancer; therefore, instant claim 107 is prima facie obvious.
Regarding instant claims 120-121, claims 1-16 of ’216 further recites utilizing a glucose donor substrate to glycosylate 5-hydroxymethylcytosine residues, wherein the enzyme can comprise an alpha-glucosyltransferase or a beta-glucosyltransferase which meets the limitations of instant claims 120-121 as seen at col. 31, ll. 3-30 of the disclosure of ‘216; therefore, instant claims 120-121 are prima facie obvious over claims 1-16 of ’216.
NOTE: It is proper to consult the disclosure for defining the claim (MPEP 1504.06).  Claim 11 of ‘216 recites a catalytically active TET1, TET2, TET3 and CXXC4 enzymes.  Col. 14, l. 49 – col. 15, l. 7 of the disclosure of ‘216 defines these TET enzymes.  Claim 16 of ‘216 recites alpha-glucosyltransferase and beta-glucosyltransferase.  Col. 31, ll. 3-30 of the disclosure of ‘216 defines these glucosyltransferases.
Claims 97-100, 103-104, 106, 108-113 and 117-123 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 12018320 (issues 6/25/2024 from application 17/675502; herein “’320”).
Although the claims at issue are not identical, they are not patentably distinct from each other because the method set forth in claims 1-13 of ’320 can comprise contacting a polynucleotide from an extracellular fluid, e.g., a eukaryotic nucleic acid molecule, with a TET1, TET2, TET3 or CXXC4 enzyme, i.e., which can be identical to SEQ ID NOs: 27, 28 or 29 which comprises SEQ ID NO: 1 (see col. 14, l. 59 – col. 15, l. 17 of disclosure of ‘320) in an amount effective to convert 5-methylcytosine of the nucleic acid sequence to a modified base, i.e. 5-hydroxymethylcytosine, and glycosylating the modified base with an alpha-glucosyltransferase or a beta-glucosyltransferase; therefore, instant claims 97-99, 103-104, 108-113, 117-119 and 122-123 are prima facie obvious over claims 1-13 of ’320.
Regarding instant claim 100, the method set forth in claims 1-13 of ’320 can comprise sequencing which would comprise detecting a methylation status of said nucleic acid molecule based on a presence or an absence of said modified cytosine residue; therefore, instant claim 100 is prima facie obvious.
Regarding instant claim 106, claim 2 of ‘320 discloses that the isolated nucleotide sequence is obtained from an extracellular fluid sample; therefore, instant claim 106 is prima facie obvious.
Regarding instant claims 120-121, claims 1-13 of ’320 make obvious a method comprising glycosylating the modified base, i.e., using a glucose donor substrate to glycosylate 5-hydroxymethylcytosine residues, wherein the enzyme can comprise an alpha-glucosyltransferase or a beta-glucosyltransferase which meets the limitations of instant claims 120-121 as seen at col. 31, ll. 4-31 of the disclosure of ‘320; therefore, instant claims 120-121 are prima facie obvious over claims 1-13 of ’320.
NOTE: It is proper to consult the disclosure for defining the claim (MPEP 1504.06).  Claims 6-10 of ‘320 recite a catalytically active TET1, TET2, TET3 and CXXC4 enzymes.  Col. 14, l. 59 – col. 15, l. 17 of the disclosure of ‘320 defines these TET enzymes.  Claim 13 of ‘320 recites alpha-glucosyltransferase and beta-glucosyltransferase.  Col. 31, ll. 4-31 of the disclosure of ‘216 defines these glucosyltransferases.
Conclusion
No claims are allowed.

APPLICANT REBUTTAL: REMARKS
Claims 97-123 were pending prior to entry of the abovementioned amendments. Claims 97, 99-101, 109, 110, 111, 115, 117, 119, and 122 have been amended for clarification and antecedent basis purposes. The amendments to the claims are fully supported by the application as originally filed, U.S. Patent App. No. 18/588,987, now U.S. Patent Pub. No. 2024/0318235 (the "Application"), and the original claims. Claim 123 has been cancelled. No new matter is added. Accordingly, upon entry, claims 97-122 will be pending.
Reconsideration is respectfully requested in light of the abovementioned amendments and following remarks.
35 U.S.C.
112(b)
Claim 111 stands rejected under 35 U.S.C. § 112(b) as indefinite.
Without conceding to the validity of the rejection, and solely to expedite prosecution, claim 111 has been amended. Applicant submits this amendment fully addresses the § 112(b) rejection and requests withdrawal of the rejection under § 112(b).
35 U.S.C.
112(d)
Claim 123 stands rejected under 35 U.S.C. as being of improper dependent form.
Without conceding to the validity of the rejection, and solely to expedite prosecution, claim 123 has been cancelled, rendering the rejection moot. Applicant respectfully requests withdrawal of the rejection under § 112(d).
DOUBLE PATENTING
Various claims stand rejected on the ground of double patenting as being unpatentable over one or more of claims 31-38, 45-46, 48-54 and 57-58 of copending Application No. 18/588,930 (reference application; herein "'930"), claims 31-34 and 36-50 of copending Application No. 18/588,987 (reference application; herein "'987"), claims 1-8 of U.S. Patent No. 9,816,986 (herein "'986"), claims 1-13 of U.S. Patent No. 10,443,091 (herein "'091"), claims 1- 19 of U.S. Patent No. 10731204 (herein "'204"), claims 1-16 of U.S. Patent No. 10,767,216
(herein "'216"), and claims 1-13 of U.S. Patent No. 12,018,320 (issues 6/25/2024 from application 17/675502; herein "'320").
Applicant respectfully disagrees, but solely for the purpose of advancing prosecution, Applicant submits herewith a terminal disclaimer over each of the above-cited patents. Applicant respectfully submits that the double patenting rejections are obviated in view of the terminal disclaimers.
Entry of the foregoing and prompt and favorable consideration of the subject application on the merits are respectfully requested. The Applicant has amended the claims to expedite prosecution of preferred embodiments. The Applicant reserves the right to prosecute any cancelled subject matter in continuation, divisional or continuation-in-part applications, claiming priority to this application.
In the event that there are any questions concerning this amendment or the application in general, the Examiner is respectfully urged to telephone the undersigned so that prosecution of this application may be expedited.
FEE AUTHORIZATION
The Director is hereby authorized to charge fee deficiencies or credit overpayments associated with the instant filing, in above-referenced matter to NIXON PEABODY LLP Deposit Account No. 50-4181, referencing Attorney Docket Number 701039-063007USX6. Any overpayments should also be credited to said Account.
November 26, 2024
Respectfully submitted,

NEXT OFFICE ACTION: Information Disclosure Statement
The information disclosure statement submitted on 10/3/2024 has been considered by the examiner.
EXAMINER'S AMENDMENT
An examiner’s amendment to the record appears below. Should the changes and/or additions be unacceptable to applicant, an amendment may be filed as provided by 37 CFR 1.312. To ensure consideration of such an amendment, it MUST be submitted no later than the payment of the issue fee.
The application has been amended as follows:
119.	The method of claim 97, wherein said glucosyltransferase polypeptide comprises said BGT or [[said]]a conservatively-substituted variant of BGT.
Reasons for Allowance
The following is an examiner’s statement of reasons for allowance: With the claim amendment received 11/26/2024, the rejections under 35 U.S.C. 112(b) and 112(d) are overcome.  With the terminal disclaimer received and approved 11/26/2024, the double patenting rejections over co-pending applications 18/588930 and 18/588987 and U.S. Patents 9816986, 10443091, 10731204, 10767216 and 12018320 are overcome.  Thorough searching has confirmed that, with the examiner’s amendment set forth above, the claims are in condition for allowance.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee.  Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
Claims 97-122 are allowed.

CITED REFERENCE SUMMARIES: Ref US2009058562: Claims:
1. A method for improving the generation of stable human Foxp3+ T cells, the method comprising contacting with, or delivering to, a human T cell an effective 5- methylcytosine to 5-hydroxymethylcytosine converting amount of at least one catalytically active TET family enzyme, functional TET family derivative, TET family catalytically active fragment thereof, or combination thereof.
2. The method of claim 1, wherein the human T cell is a purified human CD4+ T cell.
3. The method of claim 1, further comprising contacting with, or delivering to, the human T cell a composition comprising at least one cytokine, growth factor, activating reagent, or combination thereof.
4. The method of claim 3, wherein said composition comprises TGF-β.
5. A method for improving efficiency or rate with which an induced pluripotent stem (iPS) cell is produced from an adult somatic cell, the method comprising contacting with, or delivering to a somatic cell, an effective 5-methylcytosine to 5- hydroxymethylcytosine converting amount of at least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active thereof, or combination thereof.
6. The method of claim 5, wherein the catalytically active TET family enzyme is TETl or TET2.
7. The method of claim 5, further comprising comprising contacting with, or delivering to, the somatic cell, an effective amount of a TET family inhibitor.
8. The method of claim 7, wherein the TET family inhibitor is a TET3 inhibitor.
9. The method of claim 5, further comprising contacting the somatic cell with or delivering to the somatic cell a combination of nucleic acid sequences encoding Oct- 4, Sox2, c-MYC, and KIf 4.
10. The method of claim 5, wherein the combination of nucleic acid sequences encoding Oct-4, Sox2, c-MYC, and Klf4 are delivered in a viral vector.
11. The method of claim 5, wherein the somatic cell is a fibroblast.
12. A method for improving efficiency of cloning a mammal by nuclear transfer or nuclear transplantation, the method comprising contacting a nucleus extracted from a cell to be cloned with an effective 5-methylcytosine to 5-hydroxymethylcytosine converting amount of at least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active fragment thereof, or combination thereof, during a nuclear transfer protocol.
13. The method of claim 12, wherein the catalytically active TET family enzyme is TETl or TET2.
14. The method of claim 12, further comprising contacting the nucleus from the cell to be cloned with a TET family inhibitor.
15. The method of claim 14, wherein the TET family inhibitor is a TET3 inhibitor.
16. A method for detecting a 5-hydroxymethylcytosine nucleotide in a biological sample, the method comprising contacting a biological sample with a detectably labeled antibody or a binding portion thereof, labeled intrabody, or labeled protein, that specifically binds to 5-hydroxymethylcytosine, and detecting the amount of bound label, wherein the presence of the bound label is indicative of the 5-methylcytosine being converted to 5-hydroxymethylcytosine.
17. A kit for modulating gene transcription via hydroxylation of 5-methylcytosine to 5- hydroxymethylcytosine, the kit comprising the following separate components: (a) at least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active fragment thereof, or combination thereof, or nucleic acid molecule that comprises a sequence encodingat least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active fragment, or combination thereof in an appropriate buffer or solution; and (b) packaging materials and instructions therein to use said kit to hydroxylate 5- methylcytosine to 5-hydroxymethylcytosine, for the purpose of modulating gene transcription.
18. The kit of claim 17, further comprising a composition comprising at least one cytokine, growth factor, activating reagent, or combination thereof for the purposes of generating stable human Foxp3+ regulatory T cells.
19. The kit of claim 18, wherein the composition comprises TGF-β.
20. The kit of claim 17, further comprising at least one nucleic acid sequence selected from the group consisting of nucleic acid sequences encoding Oct-4, Sox2, c-MYC, and Klf4, or any combination thereof.
21. The kit of claim 20, wherein the nucleic acid sequences encoding Oct-4, Sox2, c- MYC, and KIf 4 are incorporated into a viral vector.
22. The kit of claim 17, further comprising at least one reagent suitable for the detection of 5-hydroxymethylcytosine.
23. The kit of claim 22, wherein the reagent suitable for the detection of 5- hydroxymethylcytosine is an antibody, an antigen-binding portion thereof, an intrabody, or a protein, that specifically binds to 5-hydroxymethylcytosine.
24. The kit of claim 22, wherein the reagent suitable for the detection of 5- hydroxymethylcytosine is an antibody, an antigen-binding portion thereof, an intrabody, or a protein that is specific for cytosine-5-methylsulfonate.
25. A method for improving stem cell therapies, the method comprising contacting with, or delivering to, a stem cell an effective 5-methylcytosine to 5- hydroxymethylcytosine converting amount of at least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active fragment thereof, or combination thereof, or at least one nucleic acid molecule that comprises a sequence encoding a catalytically active TET family enzyme, a functional TET family derivative, TET catalytically active fragment thereof, or combination thereof.
26. A method for treating an individual affected with or at risk for cancer, the method comprising administering to an individual affected with, or at risk for, cancer, an effective amount of at least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active fragment, or a combination thereof, involved in transforming 5-methylcytosine into 5-hydroxymethylcytosine.
27. The method of claim 26, wherein the agent that specifically modulates hydroxylase activity is an inhibitor.
28. The method of claim 26, wherein the agent that specifically modulates hydroxylase activity is an activator.
29. The method of claim 26, wherein the cancer is a leukemia.
30. The method of claim 29, wherein the leukemia is an acute myeloid leukemia comprising the t(10:ll)(q22:q23) Mixed Lineage Leukemia translocation of TETl.
31. A method for screening for an agent with TET family enzyme modulating activity, the method comprising the steps of: a) providing a cell comprising at least one TET family enzyme, functional TET family derivative, TET catalytically active fragment, recombinant TET family enzyme thereof, or combination thereof; b) contacting said cell with a test agent, thereby creating a test sample; and c) detecting the level of 5-hydroxymethylated cytosine in the cell in the test sample with the level expressed in a control sample; and (d) determining whether or not the test agent increases or decreases the level of 5- hydroxymethylated cytosine, wherein a statistically significant decrease in the level of 5-hydroxymethylated cytosine indicates the test agent is an inhibitor, and a statistically significant increase in the level of 5-hydroxymethylated cytosine indicates the test agent is an activator.
32. The method as in any one of claims 1, 5, 12, 17, 25, 26, and 31, in which the catalytically active TET family enzyme is selected from the group consisting of TETl, TET2, TET3, and CXXC4.
33. The method as in any one of claims 1, 5, 12, 17, 25, 26, and 31, in which the functional TET family derivative comprises SEQ ID NO: 1.
34. The method as in any one of claims 1, 5, 12, 17, 25, 26, and 31, in which the TET family catalytically active fragment comprises SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5.
35. A method for covalent tagging of 5-hydroxymethylcytosine in a nucleic acid, the method comprising contacting a nucleic acid molecule with an enzyme that adds one or more glucose molecules to a 5-hydroxymethylcytosine residue to generate gluco s ylated- 5 -hydroxymethylcyto sine or gentibio se-containing- 5 - hydroxymethylcytosine, wherein the enzyme is an alpha-glucosyltransferase, beta- glucosyltransferase, or a beta-glucosyl-alpha-glucosyl-transferase.
36. The method of claim 35, wherein the 5-hydroxymethylcytosine is naturally occurring.
37. The method of claim 35, further comprising the step of first contacting said nucleic acid with at least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active fragment thereof, or combination thereof, thereby converting 5-methylcytosine to hydroxymethylcytosine.
38. The method of claim 35, wherein the nucleic acid is contacted in vitro, in a cell, or in vivo.
39. A method for detecting 5-hydroxymethylcytosine in a nucleic acid, the method comprising contacting a nucleic acid with an enzyme that utilizes labeled glucose or glucose-derivative donor substrates to add one or more labeled glucose molecules or glucose-derivatives to a 5-hydroxymethylcytosine residue to generate glucosylated-5- hydroxymethylcytosine or gentibiose-containing-5-hydroxymethylcytosine, wherein the enzyme is an alpha-glucosyltransferase, a beta-glucosyltransferase, or a beta- glucosyl-alpha-glucosyl-transferase.
40. The method of claim 39, wherein the glucose or glucose-derivative donor substrate is a uridine diphosphate glucose.
41. The method of claim 39, wherein the labeled glucose or glucose-derivative donor substrates is radioactively labeled.
42. The method of claim 39, wherein the 5-hydroxymethylcytosine is naturally occurring.
43. The method of claim 39, further comprising the step of first contacting said nucleic acid with at least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active fragment thereof, or combination thereof, thereby converting 5-methylcytosine to 5-hydroxymethylcytosine.
44. The method of claim 39, wherein the nucleic acid is contacted in vitro, in a cell, or in vivo.
45. A method for detecting 5-hydroxymethylcytosine in a nucleic acid, the method comprising contacting the covalently tagged 5-hydroxymethylcytosine of claim 35 with a protein that recognizes a glucose molecule, glucose-derivative or gentibiosyl molecule.
46. The method of claim 45, wherein the protein recognizes only the glucose molecule, glucose-derivative, or gentibiosyl.
47. The method of claim 45, wherein the protein recognizes the glucose molecule, glucose-derivative, or gentibiosyl only in the context of 5-hydroxymethylcytosine.
48. The method of claim 45, wherein the protein is a lectin.
49. The method of claim 48, wherein the lectin is Musa acuminata lectin.
50. The method of claim 45, wherein the protein is an antibody or antigen-binding fragment thereof.
51. The method of claim 50, wherein the antibody or antibody fragment thereof is modified with a tag.
52. The method of claim 51, wherein the tag is a biotin molecule a bead, a gold particle, or a fluorescent molecule.
53. The method of claim 45, wherein the protein is an enzyme.
54. The method of claim 53, wherein the enzyme is hexokinase or beta-glucosyl-alpha- glucosyl-transferase.
55. A method for detecting 5-hydroxymethylcytosine in a nucleic acid, the method comprising contacting a nucleic acid with an enzyme and utilizing glucose or glucose-derivative donor substrates that trap covalent enzyme-DNA intermediates to detect 5-hydroxymethylcytosine residues, wherein the enzyme is an alpha- glucosyltransferase, a beta-glucosyltransferase, or a beta-glucosyl-alpha-glucosyl- transferase.
56. The method of claim 55, wherein the glucose donor substrate is a uridine diphosphate glucose analog.
57. The method of claim 56, wherein the uridine diphosphate glucose analog is uridine-2- deoxy-2-fluoro-glucose.
58. The method of claim 55, wherein the 5-hydroxymethylcytosine is naturally occurring.
59. The method of claim 55, further comprising the step of first contacting said nucleic acid with at least one catalytically active TET family enzyme, functional TET family derivative, TET catalytically active fragment thereof, or combination thereof, thereby converting 5-methylcytosine to 5-hydroxymethylcytosine.
60. The method of claim 55, wherein the enzyme is tagged.
61. The method as in any one of claims 35, 39, and 55, in which the alpha- glucosyltransferase is encoded by a bacteriophage selected from the group consisting of T2, T4, and T6 bacteriophages.
62. The method as in any one of claims 35, 39, and 55, in which the beta- glucosyltransferase is encoded by a bacteriophage selected from T4 bacteriophages.
63. The method as in any one of claims 35, 39, and 55, in which the beta-glucosyl-alpha- glucosyl-transferase is encoded by a bacteriophage selected from the group consisting of T2 and T6 bacteriophages.
64. The method of claim 55, wherein the nucleic acid is contacted in vitro, in a cell, or in vivo.
65. A method to detect 5-hydroxymethylcytosine in a nucleic acid, the assay comprising contacting a nucleic acid with sodium hydrogen sulfite to convert a 5- hydroxymethylcytosine in a nucleic acid to cytosine-5-methylsulfonate, and contacting the sodium hydrogen sulfite contacted nucleic acid with a protein specific for cytosine-5-methylsulfonate.
66. The method of claim 65, wherein the protein is an antibody, an antigen binding fragment thereof, an enzyme, or an intrabody.
67. The method of claim 66, wherein the antibody comprises an antiserum.
68. The method of claim 66, wherein the antibody, antigen binding fragment thereof, enzyme, or intrabody is modified with a tag.
69. The method of claim 68, wherein the tag is a biotin molecule, a bead, a gold particle, or a fluorescent molecule.
70. The method of claim 65, further comprising isolating the 5-hydroxymethylcytosine containing nucleic acid with the protein specific for cytosine-5-methylsulfonate.
71. The method of claim 65, wherein the nucleic acid is in vitro, a cell, or in vivo.
72. A kit for the detection and purification of methylcytosine and 5- hydroxymethylcytosine for use in downstream applications, the kit comprising: (a) one or more catalytically active TET family enzymes, functional TET family derivatives, or TET catalytically active fragments thereof for the conversion of methylcytosine to 5-hydroxymethylcytosine; (b) one or more enzymes encoded by bacteriophages of the "T even" family; (c) one or more glucose or glucose-derivative donor substrates; (d) one or more proteins to detect glucose or glucose-derivative modified nucleotides; (e) standard DNA purification columns, buffers, and substrate solutions; and (f) packaging materials and instructions therein to use said kits.
73. The kit of claim 72, wherein the enzyme encoded by bacteriophages of the "T even" family is selected from the group consisting of alpha-glucosyltransferases, beta- glucosyltransferases, and beta-glucosyl-alpha-glucosyl-transferases.
74. The kit of claim 73, wherein the alpha-glucosyltransferase is encoded by a bacteriophage selected from the group consisting of T2, T4, and T6 bacteriophages.
75. The kit of claim 73, wherein the beta-glucosyltransferase is encoded by a bacteriophage selected from T4 bacteriophages.
76. The kit of claim 73, wherein the beta-glucosyl-alpha-glucosyl-transferase is encoded by a bacteriophage selected from the group consisting of T2 and T6 bacteriophages.
77. The kit of claim 72, wherein the glucose or glucose-derivative donor substrate is uridine diphosphate glucose (UDPG).
78. The kit of claim 72, wherein the glucose or glucose-derivative donor substrate is radiolabeled.
79. The kit of claim 77, wherein the uridine diphosphate glucose is radiolabeled with 14C or 3H.
80. The kit of claim 72, wherein the protein to detect glucose or glucose-derivative modified nucleotides is a lectin, an antibody or an antigen binding fragment thereof, or an enzyme.
81. The kit of claim 80, wherein the protein recognizes only the glucose or glucose- derivative.
82. The kit of claim 80, wherein the protein recognizes the glucose or glucose-derivative only in the context of 5-hydroxymethylcytosine.
83. The kit of claim 80, wherein the antibody or antigen binding fragment thereof is modified with at least one tag.
84. The kit of claim 83, wherein the tag is a biotin molecule, a bead, a gold particle, or a fluorescent molecule.
85. The kit of claim 80, wherein the enzyme is a hexokinase or a beta-glucosyl-alpha- glucosyl-transferase.
86. The kit of claim 80, wherein the lectin is Musa acuminata lectin (BanLec).
87. The kit of claim 80, wherein the lectin is modified with a gold particle or a fluorescent tag.
88. A method for diagnosing a myelodysplastic syndrome, a myeloproliferative disorder, acute myelogenous leukemia, systemic mastocytosis, or chronic myelomonocytic leukemia in an individual in need thereof, the method comprising the steps of (i) determining a level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, in a tissue or a cell sample from an individual in need thereof, and (ii) comparing the level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, in the tissue or cell sample from the individual with a level of 5- methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, in a tissue or cell sample from a normal control, wherein a difference in the level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, between the sample from the individual in need and the control sample is indicative of the individual having a myelodysplastic syndrome, a myeloproliferative disorder, acute myelogenous leukemia, systemic mastocytosis, or chronic myelomonocytic leukemia.
89. The method of claim 88, further comprising a step of comparing the level of 5- methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, in a tissue or cell sample of the individual to the level of 5-methylcytosine, 5- hydroxymethylcytosine, or a combination thereof, in at least one sample from a diseased tissue or a diseased cell, wherein if the level of 5-methylcytosine, 5- hydroxymethylcytosine, or a combination thereof, in the tissue or cell sample from the individual in need is similar to the level of 5-methylcytosine, 5- hydroxymethylcytosine, or a combination thereof, from at least one of the samples from the diseased tissue or cell then the individual is diagnosed with a myelodysplastic syndrome, a myeloproliferative disorder, acute myelogenous leukemia, systemic mastocytosis, or chronic myelomonocytic leukemia.
90. A method for monitoring progression of or an effect of a therapy on a a myelodysplastic syndrome, a myeloproliferative disorder, acute myelogenous leukemia, systemic mastocytosis, or chronic myelomonocytic leukemia, the method comprising the steps of (i) determining a level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, in a tissue or cell sample from an individual in need thereof to establish a baseline level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, in the tissue or cell sample; (ii) determining a level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, in a tissue or cell sample from the individual at least one time following the establishment of the baseline level of 5-methylcytosine, 5- hydroxymethylcytosine, or a combination thereof in the tissue or cell sample thereby etsablishing at least one follow-up level of 5-methylcytosine, 5- hydroxymethylcytosine, or a combination thereof, wherein a difference in the follow- up level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, relative to the baseline level of 5-methylcytosine, 5-hydroxymethylcytosine, or a combination thereof, in the tissue or cell sample is indicative of the progressi
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