CTNF 18/700,643 CTNF 82948 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Claim(s) 1-4, 7-14, 18, 21, 25, 27, 32, 33, 42, 53 are before the Examiner. Claim Rejections - 35 USC § 103 07-20-aia AIA The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. 07-21-aia AIA Claim (s) 1-4, 7-14, 18, 21, 25, 27, 32, 33, 42, 53 are rejected under 35 U.S.C. 103 as being unpatentable over Zheng WO2020163823, Li, Nucleic Acids Res. 2020 Jul 25;48(15):8255–8268 and Kanda, World J Gastroenterol. 2018 Jul 7;24(25):2661–2672; Teng, Biology 2020, 9, 157, 1-18 . . Zheng teaches the active ingredient in the claimed methods, at compound entry No. 17 at pages 95, 135; and compound entry No. 43 at pages 98, 174 and compound entry No. 44 at pages 98, 175. Zheng also teaches the inherent biochemical property of the ingredient, namely the inhibition of the anti-apoptotic Bcl-2 family proteins such as Bcl-2, Bcl- xL. Inter alia , under section Background, Zheng teaches why these proteins are attractive targets for development of therapies. These teachings of Zheng, include the limitations of claims 1-4, 7, 13, 14, 18, 27, 33 and 53. Applicant is encouraged to check for the limitations of the claims, in Zheng using word search technique: To quickly search for a specific word press Ctrl + F (Windows) or Cmd + F (Mac) to open the search bar, type your word, and press Enter. By using this technique, Zheng teaching with respect to, ‘liver’ (at page 49 line 2) ‘hepatocellular’ ‘cancer’ ‘administering’ ‘effective amount’ and so on. Zheng is silent with respect to the disease states of the method of claims relevant to claims 8-12, 21 and 25. The teachings of Li, Kanda, and Teng are invoked for the deficiency of Zheng. Li titled Upregulation of BCL-2 by acridone derivative (A22) through gene promoter i-motif for alleviating liver damage of NAFLD/NASH, at page 8255 column A, teaches that up-regulation of BCL-2 has been found to be closely related with anti-apoptosis. Likewise, Kanda at bottom of column A page 2663 onto column B, section under Bcl-2 family members and mitochondria in the progression of NASH, concludes that apoptosis resulting from mitochondrial injury is associated with the progression of NAFLD and NASH. Similarly, Teng concludes at page 14 of 18, that Venetoclax, a BCL2 inhibitor, approved by FDA for chronic lymphocytic leukemia, inhibited stellate cell proliferation and activation in vitro and impeded liver fibrosis. Likewise, Li at column B, page 8261; column A, page 8262; column B, page 8262; column A, page 8267; and Kanda section under Glucose metabolism and Apoptosis at column A, page 2666. Examination guidelines as to the position taken is predicated on the following: The new use for an old compound (of Zheng) must be novel as to the use directed and unobvious. The new use (if any) must account for the possibility that the underlying mechanism (inherent BcL-2 modulation) for the new therapy (NASH, NAFLD, insulin resistance, diabetes) is the same mechanism that allows for a prior art treatment using the same compound (or its obvious version, see Venetoclax above). As MPEP 2112 Requirements of Rejection Based on Inherency; Burden of Proof [R-10.2019], "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Accordingly, the claims do not recite an unobvious distinction over the prior art. Further, a reference is relevant not only for what it expressly teaches, but also for what it would have conveyed to one of ordinary skill in the art. See In re Opprecht , 12 USPQ2d 1235, 1236 (Fed. Cir. 1989); In re Bode , 193 USPQ 12 (CCPA 1976). In light of the foregoing discussion, the Examiner finds that the claimed subject matter as a whole would have been obvious to one of ordinary skill in the art at the time the invention was made, in view of the cited references and the knowledge generally available in the art. Accordingly, the claims are rejected under 35 U.S.C. § 103. Note: Applicant is encouraged is check file-wrapper of US Application No. 18006494 . Claim Rejections - 35 USC § 112 07-30-01 AIA 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, 7-14, 18, 21, 25, 27, 32, 33, 42, 53 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the enablement requirement. The specification does not reasonably provide enablement for making hydrates/solvates or prodrug of the pictured active ingredient. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. The specification does not reasonably provide enablement for making hydrates of the claimed compounds. The determination that "undue experimentation" would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the relevant factual considerations. Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). These include: (1) breadth of the claims; (2) nature of the invention; (3) state of the prior art; (4) amount of direction provided by the inventor; (5) the level of predictability in the art; (6) the existence of working examples; (7) quantity of experimentation needed to make or use the invention based on the content of the disclosure; and (8) relative skill in the art. All of the factors have been considered with regard to the claims, with the most relevant factors discussed below: The pictured active ingredient in the claimed is known in the prior art of Zheng WO2020163823. Neither the specification nor Zheng teach how to make solvates (hydrates) or prodrugs. The specification does not reasonably provide enablement for making hydrates (solvates) of the claimed compounds. The specification does not enable any person skilled in the art of synthetic organic chemistry to make the invention commensurate in scope with these claims. The factors to be considered in making an enablement rejection have been summarized above. In the present case the important factors leading to a conclusion of undue experimentation are the absence of any working example of a formed hydrate, the lack of predictability in the art, and the broad scope of the claims. There is no working example of any solvate or hydrate formed. None of the compounds made (based on data provided) form hydrates. These cannot be simply willed into existence. As was stated in Morton International Inc. v. Cardinal Chemical Co., 28 USPQ2d 1190 "The specification purports to teach, with over fifty examples, the preparation of the claimed compounds with the required connectivity. However ... there is no evidence that such compounds exist.., the examples of the '881 patent do not produce the postulated compounds.., there is ... no evidence that such compounds even exist." The same circumstance appears to be true here. There is no evidence that hydrates of these compounds actually exist; if they did, they would have formed. Hence, applicants must show that hydrates can be made, or limit the claims accordingly. g) The state of the art is that is not predictable whether hydrates will form or what their composition will be. In the language of the physical chemist, a hydrate of organic molecule is an interstitial solid solution. This phrase is defined in the second paragraph on page 358 of West (West, Solid State Chemistry and Its Applications, john Wiley & Sons, 1984). The solvent molecule is a species introduced into the crystal and no part of the organic host molecule is left out or replaced. Note in this case solvent is water (H2O). In the first paragraph on page 365, West (Solid-State Chemistry) says, "it is not usually possible to predict whether solid solutions will form, or if they do form what is their compositional extent".. Excipients can interact with the active pharmaceutical ingredient, and thus have an influence on its stability. The picture becomes even more complex when the hydrate can exist as two or more different polymorphic forms. Therefore, the predictable formation and use of hydrates of the claimed compounds finds no support in the specification. Thus, in the absence of experimentation one cannot predict if a particular solvent will hydrate any particular crystal. One cannot predict the stoichiometry of the formed hydrate, i.e. if one, two, or a half a molecule of solvent added per molecule of host. In the same paragraph on page 365 West (Solid State Chemistry) explains that it impossible to make meta-stable non-equilibrium hydrates, further clouding what Applicants mean by the word hydrate. Compared with polymorphs, there is an additional degree of freedom to hydrates, which means a different solvent or even the moisture of the air that might change the stabile region of the hydrate. h) The breadth of the claims includes all of the hundreds of thousands of compounds of formula (I) as well as the presently unknown list of solvents embraced by the term "hydrate". Thus, the scope is broad. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use any prodrug of compound A. PNG media_image1.png 260 419 media_image1.png Greyscale Finding a prodrug is an empirical exercise. Predicting, for example, if a certain ester of a claimed alcohol, for example, is in fact a prodrug that produces the active compound metabolically, in man, at a therapeutic concentration and at a useful rate is filled with experimental uncertainty. Although attempts have been made to predict drug metabolism de novo, this is still an experimental science. For a compound to be a prodrug, it must meet three tests. It must itself be biologically inactive. It must be metabolized to a second substance in a human at a rate and to an extent to produce that second substance at a physiologically meaningful concentration. Thirdly, that second substance must be biologically active. Determining whether a particular compound meets these three criteria in a clinical trial setting requires a large degree of experimentation. b) The direction concerning the prodrugs is limited to disclosure of generic concepts known to one of skill in the art at bottom of page 9. c) There is no working example of a prodrug of the compound of formula A. The derivatization of the only functional group available for any derivatization in the compound A is the carboxylic acid (to make a prodrug) finds no support in the specification with working examples for making and using, (especially in the context of the dose limitations in the claims). d) The nature of the invention is clinical use of compounds and the pharmacokinetic behavior of substances in the human body. e) The state of the prodrug art, is summarized by Wolff, Burger's medicinal Chemistry and Drug Discovery, Vol.1, Principles and Practice, John Wiley & sons, New York, 1997. The table on the left side of page 976 outlines the research program to be undertaken to find a prodrug. The second paragraph in section 10 and the paragraph spanning pages 976-977 indicate the low expectation of success. In that paragraph the difficulties of extrapolating between species are further developed. Since, the prodrug concept is a pharmacokinetic issue, the lack of any standard pharmacokinetic protocol discussed in the last sentence of this paragraph is particularly relevant. f). Wolff (Medicinal Chemistry) in the last paragraph on page 975 describes the artisans making Applicants' prodrugs as a collaborative team of synthetic pharmaceutical chemists and metabolism experts. All would have a Ph.D. degree and several years of industrial experience. It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved", and physiological activity is generally considered to be an unpredictable factor. Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIZAL S CHANDRAKUMAR whose telephone number is (571)272-6202. The examiner can normally be reached M-F 8-5 EST. 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. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at (571) 272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /NIZAL S CHANDRAKUMAR/Primary Examiner, Art Unit 1625 Application/Control Number: 18/700,643 Page 2 Art Unit: 1625 Application/Control Number: 18/700,643 Page 3 Art Unit: 1625 Application/Control Number: 18/700,643 Page 4 Art Unit: 1625 Application/Control Number: 18/700,643 Page 5 Art Unit: 1625
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