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 § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 11, 12, 15 and 17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cowley WO2023156386 (2023-08-24).
Cowley teach at bottom of page 137 and at near top of page 144
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corresponding to compounds of formula of base claim 11 (all the R variables being hydrogens and X=Y=CH2s) and compounds of dependent claims 12, 15, 17.
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) 11, 12, 15, 17 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Cowley WO2023156386 (2023-08-24) and Mishra, Biomedicine & Pharmacotherapy (2008), 62(2), 94-98.
Cowley teach at bottom of page 137 and at near top of page 144
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corresponding to compounds of formula of base claim 11 (all the R variables being hydrogens and X=Y=CH2s) and compounds of dependent claims 12, 15, 17.
The above pictured compounds fall under the scope of the claims 11, 12, 15 and 17. Claims 13 and 14 are drawn to (alkyl H vs methyl) homologs of the above pictured compounds. Further Cowley at pointed out pages teach how to make, using reductive amination methods to make N-substituted compounds. As per MPEP 2144.09 [R-01.2024], the compounds are obvious variants.
As to the limitation of claim 19:
The new use (if any) of an old compound must account for the possibility that the underlying mechanism for the new therapy is the same mechanism that allows for a prior art treatment using the same compound (or its obvious version).
As per 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."
High-throughput assays to find new use for old compounds are routine in the art of drug discovery. See Mishra, Biomedicine & Pharmacotherapy (2008), 62(2), 94-98. Also se Debnath, Expert Rev Anti Infect Ther. 2021 September ; 19(9): 1099–1106 for motivation.
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.
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.
Claims 1-20 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for making some possibilities of the claimed formulae I and II (herein after formula) , does not reasonably provide enablement for plethora of conceivable compounds of these formulae. For example, it is not seen where in the specification enabling disclosure is found compounds wherein for any of R3a, R3b, R4a or R4b being anything other than H. 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:
Compounds of claimed formula have many substituents layered on substituents encompassing wide variety and number of structures. These substituents and hence the compounds of the formula are drawn to species that vary widely in physical and chemical properties such as size, molecular weight, stereochemistry, logP, acidity, basicity, etc. These factors are known in the art (see multiple references cited below) to greatly influence biological properties, for example, binding interaction between target protein and small molecule and art recognized concepts relating to productive small molecule-macromolecule interaction.
Enablement is a two prong (make and use) requirement.
The formula is drawn to variables such as ‘alkyl’ vaguely defined (with umbrella terms) substituted or unsubstituted that find little support in the specification. For example, these substituents as in claim 2 are drawn to generically recited groups such as aryl that encompass large number of possibilities. Such claims are, in plain language, ‘reach through claims’, reaching through the all conceivable possibilities (clearly for future work). Further the substituents such as alkenyl directly connected to N, for example for R1, are uncommon in the medicinal chemistry art as these relate, to nucleophilic enamine functions. Note that nucleophilic enamine intermediates cause significant biological damage by making nearby carbon atoms nucleophilic, which triggers unwanted covalent modifications of crucial cellular targets. Also note that if a substituent is impossible, the claim can properly be rejected under 35 USC 112 paragraph 1 or 2. ... A compound with an impossible substituent clearly cannot be made, and hence a paragraph 1 rejection is proper. Further genetically defined functions such as oxo or amine as possible substituents would be incompatible, for example, with the Mannich-Type Condensation disclosed for assembling the core structure of the formula. One of skill in the art would anticipate that reactive functionalities (carbonyl and amine) if present as substituents would compete with the imine-formation necessary in the formation of N containing ring(s) of the recited formula. Organic chemistry is unpredictable and capricious as taught by Dorwald F. A. Side Reactions in Organic Synthesis, 2005, Wiley: VCH, Weinheim pg. IX of Preface pg. 1-15 which teaches that ” …as will be shown throughout this book, the outcome of organic reactions is highly dependent on all structural features of a given starting material, and unexpected products may readily be formed. [8]……...” . Consistent with this teaching, none of the compounds made have any reactive functionalities such as aldehyde, ketone, ester OH, SH, NH2 functionalities. The specification does not teach how to introduce such groups subsequent to assembling the invariable core structural template(s) of the recited formula.
With regards to how to use:
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, teaches many caveats in analog design such as the following at page 799 column B:
Alteration of distances between portions of the pharmacophore of a molecule (or even' between other portions). may produce profound qualitative and/or quantitative changes in pharmacological actions.
Structurally similar compounds show a wide gradation of activity consistent with the unpredictability in the art as per the teachings of Venkatesh and Cannon. Dealing with pharmacophore definition, post provisional filing date teaching Lish, Adv. Synth. Catal. 2023, 365, 4567 – 4575; Lish, J.Med.Chem.2024,67,18265−18289 are revealing in that most compounds made and tested show gradation of biological activity, even with most of these having aromatic R groups in the formula being hydrogen. Further, for example according to Lish, the compounds of formula with Z=N are inactive. Also see Table 4 page 4572; and Lish column B in page 18274. As such what combination of the variables would provide for predictive property is not taught in the specification, rendering making and using as per 112-1 (scope) requirement not satisfied.
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 such as pharmacophore (see above Lish citations) definition disclosed in the specification to guide one of skill in the art to choose from the plethora possibilities recited for the variables. What combination of substituents would provide for predictable results is not obvious from the disclosure. Again, pharmacological activity in general is a unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved”. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, states “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return.
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.
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.
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/NIZAL S CHANDRAKUMAR/Primary Examiner, Art Unit 1625
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