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 .
Claims 1-6, 35-40, 42, 43, 45, 48, 51, 52 and 53, 54 are before the Examiner.
Claim Rejections - 35 USC § 112, first paragraph
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 1-6, 35-40, 42, 43, 45, 48, 51, 52 and 53, 54 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for making few compounds of formulae I and IV does not reasonably provide enablement for the large number and variety of possibilities of the formulae. Similarly, it is not seen where in the specification enabling disclosure is found for methods of treating any and all cancer as per claims 52 and 53. 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:
Formulae of independent claims 1 and 35 contain large number of R 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 defy art recognized concepts relating to productive small molecule-macromolecule interaction, for example, as needed for the claimed method of claims 52 and 53. There is no guidance on what to choose from these large number of structural possibilities. Enablement is a two prong (make and use) requirement.
General method of making the compounds of formula I is disclosed at bottom of page 60. Consider the indicated bond in the instant formula I (partial structure shown).
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This bond is made by reductive amination reaction (step 4). The starting material needed to make the ketone for this step is made in step 1 which in turn was made by a Pd catalyzed reaction. More on this Pd reaction later.
The product of step 1 limits what can be present for R2 and R3 of formula I. None of the recited groups for R2 and R3, except for presence of H for either R2 or R3 is possible. Since R2 = H possibility is not claimed, because of the mandatory reductive amination needed for making the red arrow bond, R3 has to be H (or D). As such that
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is not possible as per the pointed out chemistry scheme.
Similarly, there is no disclosure for how to make any of the possibilities recited for R2, except for R2 being an alkyl. See compounds at page 62, [00178].
As noted above the Pd catalyzed step 1 also precludes having halogen (other than F, that is R1 cannot be, for example Br) on the starting material because of the anticipated oxidative addition of Pd (insertion) into C-halogen bond (mandatory in Pd catalyzed reactions).
Consistent with the above chemistry discussion, the only working examples present in the disclosure are all limited to R2 = C1 alkyl and R3 = H. See [078] Table at page 62.
Similarly, there is no enabling disclosure for making compounds wherein R6 is other than H. The only Examples present all have R5-H or F and R6 = H. The specification does not teach how to make intermediate 4 in Scheme 60, with substituents on the pyridine except R5 = H or F and R6 = H, such that the laundry list recited for R5 and R6 does not find support. Specification also does not teach where to procure such starting materials. Similarly, there is no enabling disclosure with respect to making compounds wherein R4 is other than H. Further, consider for example, the first possibility recited for R2. This makes no sense, since, any halogen on C adjacent to the basic N (of the piperazine moiety) is anticipated to be displaced by the said nitrogen. 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, "it is essential that there be no question that, at the time an application for patent is filed, (emphasis in original) the invention claimed therein is fully capable of being reduced to practice (i.e., that no technological problems, the resolution of which would require more than ordinary skill and reasonable time, remain in order to obtain an operative, useful embodiment)." Applicant is encouraged to point out enabling disclosure with respect to making any of compounds of formula IV of claim 35. 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. Dorwald 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]……...Even the most experienced chemist will not be able to foresee all potential pitfalls of a synthesis, especially so if multifunctional, structurally complex intermediates must be prepared.…..”
As to ‘use’ prong’ of the 112-1 requirement:
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.
Disclosure at pages 63-68 are not supportive of method for treating any and all cancer.
The term cancer is interpreted to include any and all forms of cancer. In light of this, it can be asserted that in spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer because it is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way.
According to disclosure at page 2 [0002], PARP inhibitors have demonstrated efficacy. This is questionable with respect to claimed method in view of the teachings in a post filing, state of the art Review: Bhamidipati, PARP inhibitors: enhancing efficacy through rational combinations. See Bhamidipati , Br J Cancer 129, 904–916 (2023). According to Bhamidipati , “despite initial responsiveness to PARPi, tumors eventually develop resistance through a variety of mechanisms. Rational combination strategies involving PARPi have been explored and are in various stages of clinical development. PARPi resistance is a key challenge that has prompted investigation into numerous rational combinations at various stages of clinical investigation. So far, there are promising clinical responses which have validated preclinical findings for PARPi combination partners across a variety of drug classes. Further work is needed to optimize the therapeutic window of PARPi combinations and identify confirmed predictive biomarkers of response to therapies to refine patient selection and maximize PARPi benefit. Also for suggestion of PARPi in combination therapy for cancer in Lloyd "Combined PARP and ATR Inhibition Potentiates Genome Instability and Cell Death in ATM-deficient Cancer Cells", Oncogene, 39(25):4869-4883. Consistent with this, there is not seen in the disclosure, sufficient evidence to support Applicant’s claims of treating cancer,
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.
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 of the pictured formula 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 definition disclosed in the specification to guide one of skill in the art to choose from the plethora possibilities recited for the variables.
The specification does not reasonably provide enablement for making 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 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. None of the compounds made (based on data provided) form solvates. The compounds of the claims are made as per prior art teaching acknowledged at page 11, lines 23-34. Thus, the compounds are not Applicants invention. The claims are drawn to solvates, yet the numerous examples presented all failed to produce a solvate. 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 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. g) 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 (West, Solid State Chemistry and Its Applications, john Wiley & Sons, 1984, Chapter 10). 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) 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 list of solvents embraced by the term "solvate". Thus, the scope is broad.
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.
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 1-6, 35-40, 42, 43, 45, 48, 51, 52 and 53, 54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 27, 28, 31, 32, 37, 38, 45-48,, 50 of copending Application No. 18833362 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the conflicting claims contain overlapping subject matter.
More specifically, the claimed formulae of 18833362 encompass the formulae of instant independent claims in genus-species relationship.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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 51 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.
According to MPEP 2173.05(s) [R-10.2019], where possible, claims are to be complete in themselves.
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) 1-6 and 51 is/are rejected under 35 U.S.C. 103 as being unpatentable over Johannes, US 11795158.
The instantly claimed compounds has substituents at the C of formula I (partial structure),
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while the claimed compound of 11795158 at column 115
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Compare instantly claimed formula I compounds 22 and 23 pictured at bottom of page 62, [00178], R2 = methyl and R3 = H in formula I.
This only modification is instant compound of claim 1-3 and 6. Claims 4-5 are not enabled (see section under 112-1). No comparative data is present for secondary consideration.
Johannes teaches H for methyl in an otherwise identical compound.
H and methyl are suggestive of one another: It has been established in In re Wood, In re Wood, 582 F.2d 638 (CCPA 1978), that the substitution of methyl for hydrogen on a known compound is not a patentable modification absent unexpected or unobvious results and further discusses that hydrogen and methyl are deemed obvious variants.
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
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