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
Amendments to claims render the restriction requirement moot.
Pending claims 1-5, 10, 16, 18, 19, 22, 24, 27 and 93-95 are examined together.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5, 10, 16, 18, 19, 22, 24, 27 and 93-95 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11364234. Although the claims at issue are not identical, they are not patentably distinct from each other as explained below:
Independent case claims 1 and 6 of 11364234:
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While the claimed method of treatment is the same, there is also extensive overlap between the active ingredients of the instant claims (of formula VI) and those of the conflicting claims. The difference if any is in the language for the variables: the L possibility of direct bond of instant claim is the L possibility of 0 of ‘234. Similarly the instant proviso is, for one of the R1. The compound at the top right of instant numbered page 6 of dependent claim 16, falls under the scope of the claims of ‘234 (in anticipatory manner).
With regards to nematode infection: Dependent claim 9 of ‘234 with respect to Cooperia corresponds to one of the plethora of possibilities in instant claims 93, 94.
With regards to the subject treated: Dependent claim 18 of ‘234 with respect to human corresponds to one of the subjects of instant claim 95.
Likewise (Likewise means for the same chemistry and biological reasonings as above),
claims 1-5, 10, 16, 18, 19, 22, 24, 27 and 93-95 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 11517568. Although the claims at issue are not identical, they are not patentably distinct from each other as explained further below:
The compound at the top right of instant numbered page 6 of dependent claim 16, is positional isomer of the column 49 (second from top) of dependent claim 7 of 11517568. According to MPEP, 2144.09 Homologs, Analogues, Isomers [R-01.2024] are obvious variants of each other.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Feldman, Understanding ‘Evergreening’ : Making Minor Modifications Of Existing Medications To Extend Protections, Health Affairs June 2022 41:6, 801-804
Dwivedi, Evergreening: A deceptive device in patent rights, Technology in Society 32 (2010) 324–330.
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, 10, 16, 18, 19, 22, 24, 27 and 93-95 are is/are rejected under 35 U.S.C. 103 as being unpatentable over Harrington, 2nd Annual Donnelly Centre Retreat, May 10, 2018, pages 1-38 in view of and Bohm, ChemBioChem 2004, 5, 637- 643 and Shah Journal of Enzyme Inhibition and Medicinal Chemistry, October 2007; 22(5): 527–540; Goldfarb, US 8642660 and Guzman WO2005030188; and Commercial (On Sale) Chemical Library compounds from vendor Enamine.
Harrington titled “Characterizing Novel Inhibitors of Neuromuscular function that may arrest worm infections”, teaches at page 16, wact-45 (see instant page 17, [0080]. Compound wact-45 corresponds to the fourth compound of instant dependent claim 16 top of page 6, without the F on the ring, instantly excluded (as per base claim 1); wact-45 is effective to induce locomotory defects in nematodes Haemonchus contortus and Cooperia oncophora (compare the limitations of instant dependent claims 93, 94 with regards to disorders treated). That substituting fluorine (F) for hydrogen (H) in medicinal chemistry as a common strategy to enhance drug potency, metabolic stability, and membrane permeability, is well-known in the art, for example, as taught by Bohm titled ‘Fluorine in Medicinal Chemistry’ and Shah titled ‘The role of fluorine in medicinal chemistry’.
Harrington teaching does not include the large number of compounds of instant claims. The teachings of Goldfarb, Guzman and commercially available compounds falling under the scope of the instantly recited active ingredients are invoked the deficiency.
Goldfarb teaches method using lifespan-altering compounds for altering the lifespan of eukaryotic organisms, and screening for such compounds, wherein the compounds include the dependent claim 16 numbered page 6, third compound from the top RN 1423505-81-0 and dependent claim 16 numbered page 7, third compound from the top RN 1423750-10-0. Note that nematodes (roundworms) are multicellular eukaryotic organisms belonging to the kingdom Animalia; RN means Chemical Abstract Registry Numbers identifying compounds akin to Social Security numbers.
Guzman at page Example 7 Table at page 45-92 large number of phenylpiperazine derivatives as modulators of muscarinic receptors. Note that muscarinic receptor modulators regulate cell death primarily through anti-apoptotic mechanisms.
The above noted Guzman Table include compounds
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falling under the scope of base claim 1 (and dependent claim 16 compound see claim numbered page 6, second listed compound with the above second pictured Guzman compound).
Further large number of pictured compounds of dependent claim 16 are commercial “on-sale” from Chemical Library Supplier Enamine, and thus within the purview of one of skill in the art for high-throughput screening, for example, such as taught in above cited Goldfarb. These are listed below
RN 1423750-10-0
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RN 1423505-81-0
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RN 1260807-18-8
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RN 1260767-12-1
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RN 864414-92-6
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RN 849502-36-9
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RN 835598-26-0
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RN 467240-91-1
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RN 428827-52-5
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RN 428822-59-7
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RN 424819-33-0
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RN 423746-42-3
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RN 416867-05-5
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RN 416864-71-6
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RN 415972-05-3
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RN 415956-55-7
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RN 415952-64-6
USPATFULL
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RN 415947-56-7
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RN 415946-90-6
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RN 415924-99-1
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RN 354551-27-2
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RN 296264-98-7
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Taken together, one of skill in the art would have reasonable expectation of success in arriving at instant claim limitations. The compounds are known (in related art Goldfarb, Guzman and commercially available from Enamine); Harrington detailed instructions for how to assess (HTS of Artal-Sanz discussed below and Goldfarb), nematode specific activity (C.elegans, H. contortus & C. oncophora) of compound. Applicant needs to point out comparative data for secondary considerations.
Therefore nothing unobvious is seen in the claims.
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.
Claims 1-5, 10, 16, 18, 19, 22, 24, 27 and 93-95 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for few compounds of the pictured formulae (herein after formula or compound) for specific nematodes, does not reasonably provide enabling disclosure for the plethora of possible active ingredients and large number of nematode infections. 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:
The active ingredients of the claims are drawn to compounds of formula with variables of large number of groups layered with substituents layered on substituents encompassing wide variety and number of conceivable structures that find little support in the specification. These substituents and hence the compounds of given 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 (see specification penultimate page Table 2, and more discussion below).
There is no data showing that compound formula II is effective against any nematode or is effective to treat any nematode infection, or is effective to treat any disease arising from such a nematode infection.
Enablement is acknowledged for nematode C. elegans as per Table 1 at page 57, further in view of teachings of Harrington (2018). Further, Artal-Sanz (Biotechnol. J. 2006, 1, 1405-1418) teach that the nematode worm Caenorhabditis elegans has emerged as a convenient and versatile tool that can be used as a platform for devising and streamlining efficient drug discovery and drug target identification methodologies (Abstract). Artal-Sanz teaches that, while among animal models, C.elegans is certainly the most cost effective choice for a target validation scheme (page 1416, left column, fourth paragraph, lines 7-9), there are a number of pitfalls of the C. elegans model system, such as the fact that a particular C. elegans disease model might not completely recapitulate the pathophysiology of the human disease (page 1416, left column, second paragraph). Importantly, Artal-Sanz teaches (page 1416, left column, third paragraph) that hits identified in worms may need considerable optimization before being used in humans. Artal-Sanz teaches (page 1415, left column, second paragraph) that invertebrate and nonmammalian models can only be useful at the early stages of research to provide quick answers and suggest putative new therapeutics, towards the identification of putative novel targets and drug leads. Artal-Sanz teaches that any discovery will need to be further tested and validated in mammalian systems in order to increase confidence to predict drug action and safety in humans. Artal-Sanz teaches (page 1415, right column, second paragraph) that even though various assays have been validated, no drug exists yet that was identified explicitly in a worm-based assay.
With regards to how to make compounds included in claim 1:. While large number of the compounds of formula included in the claims are previously known in the art (see citations presented under section 103), there is no disclosure on how to make functionalized R13, R11, R18:
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Specification is silent as to how to procure starting materials needed to make such compounds by using the guidance in the exemplified chemistry method (singular). Consider for example Br substituted on the cycloalkyl in
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. This would be incompatible in the only reaction method taught in the specification for installing the piperazine, as this requires displacement of halogen. See top of numbered page 56. Thus, the specification is silent as how to procure starting materials need and further does not show how to use them. According to the U.S. Court of Customs and Patent Appeals in In re Argoudelis , De Boer, Eble, and Herr 168 USPQ 99 at 101, "[o]rdinarily no problem in this regard arises since the method of preparing almost all starting materials can be set forth in writing if the materials are not already known and available to the workers in the art, and when this is done the specification is enabling to the public". In re Argoudelis , De Boer, Eble, and Herr 168 USPQ 99 at 104.
Further 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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Similarly, the specification does not reasonably provide enablement for making solvate of the claimed compounds in predictable manner. In the present case the important factors leading to a conclusion of undue experimentation are the absence of any working example of a formed solvate, the lack of predictability in the art, and the broad scope of the claims. There is no working example of any solvate or solvate formed. Solvates/hydrates 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 solvates of these compounds actually exist; if they did, they would have formed. Hence, applicants must show that solvates can be made, or limit the claims accordingly. The state of the art is that is not predictable whether solvates will form or what their composition will be. In the language of the physical chemist, a solvate of organic molecule is an interstitial solid solution. This phrase is defined in the second paragraph on page 358 of West (Solid State Chemistry). The solvent molecule is a species introduced into the crystal and no part of the organic host molecule is left out or replaced. In the first paragraph on page 365, West (Solid-State Chemistry and Its Applications, 1984, John Wiley & Sons) says, "it is not usually possible to predict whether solid solutions will form, or if they do form what is their compositional extent". Thus, in the absence of experimentation one cannot predict if a particular solvent will solvate any particular crystal. One cannot predict the stoichiometry of the formed solvate, 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 solvates, further clouding what Applicants mean by the word solvate. Compared with polymorphs, there is an additional degree of freedom to solvates, which means a different solvent or even the moisture of the air that might change the stabile region of the solvate. h) The breadth of the claims includes all of the hundreds of thousands of compounds of formula (I) as well as the presently unknown possibilities of solvates embraced by the term “solvate”.
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 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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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