DETAILED ACTION Notice of Pre-AIA or AIA Status The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Claim Rejections - 35 USC § 112 The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. Claim s 1- 4, 8, 10, 12, 14-17, 19-21, 23-26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, because the specification, while being enabling for practice of the method using the carbene precursor of formula I , does not reasonably provide enablement for practice of the method without a carbene source other than the precursor of formula I . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands , 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404, “Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.” The nature of the invention The claims are drawn to enzymatic modification of 5-methylcytosine or 5-hydroxymethylcytosine using ten eleven translocation enzymes (Tet) via carbene insertion in the 5-methyl or 5-hydroxymethyl moiety . The invention is the class of invention which the CAFC has characterized as “the unpredictable arts such as chemistry and biology.” Mycogen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Fed. Cir. 2001). The breadth of the claims The claims are drawn to any carbene inserted . Quantity of Experimentation The quantity of experimentation required to practice the method to the full extent of the claimed scope would be large, owing primarily to the unpredictability of acceptable substrates for the enzymatic reaction. The unpredictability of the art and the state of the prior art Generally, the suitability of a given substrate for a given enzyme is unpredictable. The specification notes (paragraph [0183]): “Previous studies have shown that using a heme enzyme, replacing oxygen with a synthetic diazo-acetate reagent enable access to a synthetic iron-carbon intermediate (iron carbenoid) that is similar in structure to the wild type iron-oxo intermediate. Access to this intermediate allows the enzyme to insert a carbon center into the C-H bond creating a new carbon-carbon (C-C) bond…Additional studies also show that non-heme iron oxidases, homologous to TET, also carry out these chemistries…”. Therefore, while compatibility of diazo compounds with TET have been demonstrated in the prior art, compatibility with other carbene sources has not. Working Examples The working example in the specification is limited to diazo compounds as carbene precursors falling within the scope of formula I (shown in claims 5-7 and 9). Guidance in the Specification. There is no guidance in the specification regarding how to predict what carbene sources would work in the Tet-mediated modification of 5-methylcytosine/5-hydroxymethylcytosine, and which would not. Level of Skill in the Art The level of skill in the art is deemed to be high. Conclusion Given the unpredictability of substrate-enzyme compatibility, the narrow scope of the working examples, balanced only against the level of skill in the art, the claims are not enabled to the full extent of the claimed scope. Conclusion Claims 5-7 and 9 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT SAMUEL C WOOLWINE whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-1144 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT 9am-5:30pm . 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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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /SAMUEL C WOOLWINE/ Primary Examiner, Art Unit 1681