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 .
Amended claims 1, 3-15 are pending.
Claims 12-15 are new and Claims 6-11 were previously withdrawn.
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.
Previously presented rejection of claims 1, 3-5, 12-15 are rejected under 35 U.S.C. 103 as being unpatentable over Crew US20180125821; Yang CN111606883; Buckley US20190374657; 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 and Cravatt US 11535597 is maintained.
US11535597 is added to augment the rationale for the rejection, in view of amendments to claims.
Amendments to claims and applicants arguments are not persuasive.
Amendments narrow the scope of the claim with respect to protein finding fragment part of the claimed compound.
Applicants argues focus that the exact structures (as amended) in part of the claimed formula is not found in the cited references. For example, at page 8 of 10 argues that N-benzhydryl piperazine in the heterobifuctional formula is not taught in the cited references. See instant claim 4 and 12. This is not persuasive. This moiety was specifically discussed in the previous action page 5, as being suggested for conjugation/linking to make heterobifunctional molecules.
Further US11535597 (issued for the same assignee) at front page and at Fig.1B
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teaches the same fragment groups as in the instant case, reading on the instant formula. Thus in the claimed
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, the above Fragment corresponds to PBF, L and RBF (not specified in the base claim) and with ‘why and how’ taught in the previously cited art references, one of skill in the art would have reasonable expectation of success.
On top of this, the as amended the claims are not limited to the this PBF portion.
Applicant’s response overlooks Yang CN111606883 compounds pictured at page 4 of previous action:
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Yang CN111606883 is equivalent to US 12582641 wherein the above pictured compounds and other adamantly compounds linked to thalidomide are shown in column 49 to column 54.
These compounds correspond to
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Further there is no motivation discussed in the office action, just overlooks multiple state of the art Reviews cited in the previous action.
Obviousness can be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art.
Again, the invention is a selective combination of the inventions by the prior arts done in a manner obvious to one of ordinary skill in the art. Patent for the combination of known elements wherein their functions remain the same withdraws “what is already known into field of its monopoly and diminishes resources available to skilled men”. Sakraida v. Ag Pro, Inc.189 USPQ 449, 425 US 273, (1976).
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.
Following is from previous action:
Claim 1:
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of
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For definition of FragTAC,
PBF-L-RBF
and PROTAC see specification [0006]-[0008].
Crew teaches a heterobifunctional (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 inherently a FragTAC compound) composition (abstract: compositions) comprising a compound of Formula I, PBF-L-RBF (Formula I) (para (0015):
PTM-L-ULM) wherein PBF (protein binding fragment) 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 molecules that bind to Tau protein), L is an organic linker (para [0018), (04631) and RBF is a recruiter binding fragment of a hetero-organic molecule (para (0383): thalidomide) 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 different functions linked 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 well-known in the art 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 fragments/molecules 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).
Claims 3 and 5:
Compare highlighted (blue color) with pictured structural fragments in claims.
Yang in Table page 101 includes compounds
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have the adamantly amine fragment 2 at instant claim 2 numbered page 3, second structure and instant claim 3 fragment of thalidomide 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
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limitation of claim 4, in bifunctional molecules.
The teachings of, Khanam, Watkins and Gurdal in view of Buckley are invoked to cure the deficiency.
According to Khanam page 1652, column A
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Watkins teach inhibitors of histone deacetylase and antiproliferative agents for the treatment of cancer and psoriasis at page 61 Table entry 3 and 6
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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-benzhydryl can be used to make bifunctional molecules 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), linked (Figures 24-27) to structurally diverse, large number and variety of anticancer compounds (Figures 28A-28G) to make
bifunctional molecules ( Figures 29A-31). Also see Buckley for the underlying design strategy (Figures 1-3) for making bifunctional 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 persuasive,
because
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.
Previously presented rejection of claims 1, 3, 5, 13-15 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 is maintained.
Applicant points out various disclosures in the specification. While Table 3 does have many possibilities of structures, made by standard methods using known select RBF moeities (see rejection under 103), Table 3 does not reasonably teach, for any and all linkers for example. Also the data in Figure 9, shows gradation of activities with regards to activity. What combination of the three possible moieties is capable of binding to any and all endogenous protein with predictable activity is not evidenced in the Fig.9.
Following is from previous action:
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)
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The definition of the fragments making up the formula is found in the specification
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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 cell holds 42 million protein molecules. 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
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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
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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.
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 5 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.
Claim language ‘the linker is a dimer, trimer, tetramer, or oligomer of [[an]] a multi-ether, multi-PEG, multi-amide, or alkyl moiety’ with respect to L of the claimed formula is confusing, since for example, multi-ether and multi-PEG are same chemical moiety (diethylene ether). If CH2-O-CH2-O-CH2- linkage are implied here, Applicant is encouraged to point out these in the specification. Also see extensive literature on linkers cited in the rejection under 112-1.
Also the term ‘alkyl’ refers to a monovalent function. As such it cannot link to things.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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.
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/NIZAL S CHANDRAKUMAR/Primary Examiner, Art Unit 1625
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