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. Election/Restrictions Claim Rejections - 35 USC § 103 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. Claim s 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Crew US 20180125821 ; Yang CN111606883 ; Buckley US 20190374657 ; Watkins WO2003082288 ; Khanam J Cell Biochem. 2019;120:1651-1666 ; Gurdal DrugRes. 2013;34:121 ‐ 128 ; Churcher, J. Med. Chem. 2018, 61, 444−452 ; Tinworth, Med.Chem.Comm 2016, 7, 2206−2216 ; and Wang, Acta Pharmaceutica Sinica B Volume 10, Issue 2, February 2020, Pages 207-238 . Claim 1 : of For definition of FragTAC, PBF-L-RBF and PROTAC se e specification [0006]-[0008]. Crew teaches a hetero bifun ctional (para (0015): PTM-L-ULM Note: See instant published application [0008], [0013] for definitions of acronyms, for example [0013] fragment-based PROTACs (FragTACs) FragTAC (any compound comprising a moiety binding an endogenous protein and a moiety binding a ligase of the polyubiquitin system is in herently a FragTAC compound) composition (abstract: compositions) comprising a compound of Formula I, PBF-L-RBF (Formula I) (para (0015): PTM-L-ULM) wherein PBF ( pro tein bin ding frag ment) is a protein binding fragment of a hetero-organic molecule (para (01061) which is capable of binding an endogenous protein (para (0014): recruit endogenous proteins, e.g., Tau; para [0022): PTM are mol ecules that bin d to Tau pro tein), L is an organic linker (para [0018), (04631) and RBF is a r ecr uiter binding fragment of a hetero-organic molecule (para (0383): t hal idomide) which is capable of binding a ligase of the polyubiquitin system (para (0022): ULM are molecules that bind to VHL E3 ubiquitin ligase and / or to CLM E3 ubiquitin ligase). Single small molecules, PROTACs , obtained by the union of three variables ( two d ifferent fun ctions lin ked together by a linker) for use as active ingredients in methods of treating diseases such as cancer (the same intended use of the instantly bifunctional molecules ) are w ell- k nown in the a rt as per Review articles of Churcher , titled Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones? ; Tinworth titled Small molecule mediated protein knockdown as a new approach to drug discovery ; Wang, titled Degradation of proteins by PROTACs and other strategies all of which exemplify many frag ments/ mol ecules corresponding to the terminologies highlighted above . See Churcher Abstract and Figs 1 and 2 at page 447; Tinworth Figs 2 to 4 at pages 2207, 2209 and 2210 and Wang, for extensive list of compounds overlapping with the structural features of the instant 82 compounds listed at page 95 Table 3 (more on this later). Claim s 2 , 3 and 5 : Compare highlighted (blue color) with pictured structural fragments in claims. Yang in Table page 101 includes compounds have the adamantly amine fragment 2 at instant claim 2 numbered page 3, second structure and instant claim 3 fragment of tha lidomide lined by alkylene and PEG linkers (see claim 5 ) Claims 4: Crew, Crew, Churcher and Tinworth while explicitly teach the thalidomide and thiazole containing moieties (see Tinworth bottom of page 2210 and 2211) of claim 4, do not exemplify the N- benzhydryl limitation of claim 4, in bifunctional molecules. Khanam , Watkins and Gurdal teach that this moiety has The teachings of , Khanam , Watkins and Gurdal in view of Buckley are invoked to cure the deficiency. According to Khanam page 1652, column A Watkins teach inhibitors of histone deacetylase and antiproliferative agents for the treatment of cancer and psoriasis at page 61 Table entry 3 and 6 Also see Gurdal Cytotoxic activities of some novel benzhydrylpiperazine derivatives. benzhydrylpiperazine derivatives and binding activity as against hepatocellular (HUH-7), breast (MCF-7) and colorectal (HCT-116) cancer cell lines . That N- b enzhydryl can be used to make bifu nctional mol ecules is further suggested by the teachings of Buckley which discloses compounds which bind ubiquitin ligase and a targeting moiety (para (0011), [05401 }; thalidomide and thiazole moieties (see page 114 for generic structures , (see page 127-128) , lin ked (Figures 24-27) to s tructurally d iverse, l arge number and v ariety of anticancer compounds (Figures 28A-28G) to make bif unctional molecules ( Figures 29A-31). Also see Buckley for the underlying d esign s trategy (Figures 1-3) for making bif unctional molecules and Figures 32- 33W. Combined with the teachings of Khanam, Watkins and Gurdal , Buckley compounds and strategy provide motivation to substitute N-benzhydryl for moieties having similar function in Buckley ’s bifunctional compounds. Note that the language of the claims FragTAC, PBF, RBF, Cereblon FragTAC, VHL FragTAC are not found in the teachings of the cited references would not be persuasiv e, be cause instantly exemplified 82 compounds in the Table-3 page 95-107 have all the structural elements and functions found in the prior art bifunctional compounds of Crew, Yang, Buckley and Churcher and Tinworth and thus claimed formula I encompasses selective combination of prior art elements. Therefore nothing unobvious is seen in the claims. Claim Rejections - 35 USC § 112 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 1-5 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for making few compounds (see pages 23-24) , does not reasonably provide enablement for plethora of conceivable compounds 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 make and use the invention commensurate in scope with these claims. 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: Base claim 1 is drawn to compounds of Formula I (hereinafter formula) The definition of the fragments making up the formula is found in the specification Defined as above the scope of PBF binding protein small molecule is large because the PBF relates complex large number of possibilites. See Underbakke , J Mol Biol. 2011 June 17; 409(4): 483–495 Abstract ; further according to Drinjakovic , https://temertymedicine.utoronto.ca/news/cell-holds-42-million-protein-molecules-scientists-reveal A c ell h olds 42 m illion p rotein m olecules . In addition, given many small organic molecules can conceivably bind to any of part of these proteins to modulate the activity of the protein they bind to, the scope of the fragments of PBF is large that bids little support in the specification. Some examples of these are found in the specification at page 4. These 7 examples have unique structures , for example differently in patent data bases, that is consistent with the possibilities implied by the above-mentioned 42 million protein molecules. Likewise, the RBF moiety can be any compound that recruits one or more endogenous degradation enzymes, and the L moiety can be any organic group that optimally links the two moieties with no or minimum impact on their biological functions. With these definitions for same reasons discussed for the fragment PBF, the number of possible structural moieties for RBF and L, render the scope of the formula large that finds little support in the specification. One of skill in the art would not anticipate such wide possibilities would provide for predictable properties, because biological properties are unpredictable and are ultimately tide to the chemical structure. See “Role of the Development Scientist in Compound Lead Selection and Optimization” by Venkatesh, J. Pharm. Sci. 89, 145-154 (2000) (p. 146, left column). Likewise, J. G. Cannon, Chapter Nineteen in Burger's Medicinal Chemistry and Drug Discovery, Fifth Edition, Volume I: Principles and Practice, Wiley-Interscience 1995, pp. 783-802, 784, teaches many caveats in analog design such as That productive small-molecule-protein interaction requires specific structural requirement for binding partners is one of commonsense. This fundamental medicinal chemistry principle is taught for related PROTACS. For example, see throughout, Tinworth , Med. Chem. Commun., 2016, 7, 2206 and Collins, Biochemical Journal (2017) 474 1127–1147. See page 2208, Fig. 1: see arrows in the partial cartoon shown below Also see Collins page 1141 Figure 3, page 1133 Figure 4 and page 1138 Figure 6. More specifically In this context, revealing teachings are found in Troup, Current strategies for the design of PROTAC linkers: a critical review, Explor Target Antitumor Ther. 2020;1:273-312 , at page 273: It has become increasingly clear that the length and composition of the linker play critical roles on the physicochemical properties and bioactivity of PROTACs. While linker design has historically received limited attention, the PROTAC field is evolving rapidly and currently undergoing an important shift from synthetically tractable alkyl and polyethylene glycol to more sophisticated functional linkers. Note that in University of Rochester v. G.D. Searle & Co. , 68 USPQ2d 1424 at 1438, the screening for over 600 compounds was deemed to be undue. Applicant’s scope far exceeds this number. The specification must teach how to make and use the invention, not teach how to figure out for oneself how to make and use the invention. In re Gardner , 166 USPQ 138 (CCPA 1970). Therefore, one skilled in the art could not make or use the claimed invention without undue experimentation. There is no structural guidance in the specification to guide one of skill in the art to choose from the plethora possibilities recited for the variables for L1. As such there is a substantial gap between what is taught in the specification and what is being claimed. For these reasons, one skilled in the art would be faced with undue amount of research. The specification lacks disclosure sufficient to make and use the invention, in predictable manner , commensurate with the scope of the claims. MPEP 2164.01(a) states, “A conclusion of Iack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. ln re Wright , 999 F.2d 1557,1562, 27 USPQ 2d 1510, 1513 (Fed. Cir. 1993).'' That conclusion is clearly justified here. Thus, undue experimentation would be required to make and use Applicants' invention. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT NIZAL S CHANDRAKUMAR whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-6202 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT 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, FILLIN "SPE Name?" \* MERGEFORMAT Andrew Kosar can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT (571) 272-0913 . 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