DETAILED ACTION
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 .
Status of the Claims
Claims 1-13 and 16 are pending in the present application.
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-13, drawn to a compound of formula (I), in the reply filed on June 18, 2026 is acknowledged. The traversal is on the ground(s) that search and examination of the alleged inventions would not place a serious burden on the Office. This is not found persuasive because the current application is examined under unity of invention analysis, which does not take search and examination burden into account. Furthermore, the inventions lack unity of invention because the technical feature of a compound of formula (I) is not a special technical feature, as explained in the restriction requirement.
The requirement is still deemed proper and is therefore made FINAL.
Applicant's election with traverse of Compound 33 in the reply filed on June 18, 2026 is acknowledged.
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Elected compound 33 is a compound of formula (I) wherein:
X is CH;
X1 is N;
X2 and X3 are both CRx with Rx being H;
X4 is O;
X5 is C;
Y is C;
R1 is alkyl (ethyl);
R2 and R3 are both H;
ring B is a 6-membered partially unsaturated monocyclic heterocycloalkane containing 1 nitrogen atom;
q is 0;
ring A is a 9-membered bicyclic heteroaromatic ring containing 3 nitrogen atoms;
and p is 1 with R5 being CF3.
Alternatively, compound 33 is a compound of formulas (I-1) and (I-2) wherein the variables are elected as described above and LA is a bond.
The traversal is on the ground(s) that search and examination of the alleged species together would not place a serious burden on the Office, and that cited Compound 57 of Angibaud (WO 2009/053373 A1) does not read on instant formula (I). This is not found persuasive because restriction and election. Furthermore, the special technical feature of instant Formula (I) is not a special technical feature because Angibaud teaches that compounds of their invention can include any isotopes of atoms present in the invention, for example deuterium (p. 15, lines 1-3). Thus, it would have been obvious to deuterate the piperazine ring of Compound 57 of Angibaud, thus resulting in a compound of instant formula (I), since Angibaud suggests deuterated versions of claimed compounds are alternatively useful. The below example suggested by Angibaud would read on a compound of formula (I) where ring B is piperazine, R4 is D, and q is 2.
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The requirement is still deemed proper and is therefore made FINAL.
Compound 33 has been found free of the prior art. Therefore, examination has been expanded to include the following species, herein referred to as Compound 57A:
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Compound 57A is a compound of instant formula (I) wherein:
X is CH;
X1, X2, and X3 are all each CRx with Rx being H;
X4 is O;
X5 is C;
Y is C;
R1 is alkyl (methyl);
R2 and R3 are both H;
ring B is piperazinyl, q is 1, and R4 is D; and
ring A is a 6-membered bicyclic heteroaromatic ring containing 1 nitrogen atom with p being 0.
Claim withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on June 18, 2026.
Claims 9-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on June 18, 2026.
Claims 1-8 and 11-13 are under examination as they relate to elected Group 1 and elected species of Compound 33 and expanded species of Compound 57A.
Priority
This application claims foreign priority to CN202111160607.2, filed Sept. 30, 2021; to CN202111472095.3, filed Dec. 03, 2021; to CN202210050069.X, filed Jan. 17, 2022; to CN202210217852.0, filed Mar. 07, 2022; to CN202210322736.5, filed Mar. 29, 2022; to CN202210506382.X, filed May 10, 2022; and to CN202210625556.4, filed June 02, 2022; and is a 371 of PCT/CN2022/123443, filed Sept. 30, 2022.
Drawings
The drawings have been entered and accepted by the Examiner.
Claim Rejections – Improper Markush
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Claims 1-8 and 11-13 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
The Markush grouping of compounds represented by the formula recited in Claim 1 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
The Markush grouping of claim 1 is directed to compounds of formulas (I), (I-1), and (I-2), or a pharmaceutically acceptable salt thereof:
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The variables X, X1, X2, X3, X4, X5, Y, rings A and B, R1, R2, R3, R4, and R5 encompass a myriad of substituents forming heterocycles so diverse, that they will confer the above structure complete different structural and biological properties. Moreover, these variables can be substituted with Ra, Rb, Ra1 and LA substituents which would confer the above structure with completely different structural and biological properties. For example, Ring A represents a substituted or unsubstituted, 5- to 10-membered heteroaromatic ring, and Ring B represents piperazinyl, piperidyl, 5-10 membered heterocycle, 6- to 8-membered bridged heterocycle, or 5- to 11-membered spiro heterocycle. With the myriad of compounds that arise from the various definitions and combinations of the variables present in this formula, the result is a group of compounds that include distinct ring systems and a variety of substitution patterns resulting in compounds with no single structural similarity that are not obvious variants of each other. To this end, a comparison of two compounds of the formula (I) presented in claim 11 of the instant specification demonstrates a lack of significant structural similarity and shows compounds of the formula recited in instant Claim 1 are not obvious variants of each other:
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As these compounds demonstrate, the compounds according to the formula (I) include compounds with no common core structure that are not obvious variants of each other. With no significant structural similarity, the Markush grouping is improper.
Although claims 2-8 and 11 narrow the scope of certain variables of formulas (I), (I-1), and (I-2), each of these claims still encompasses a wide range of compounds with no significant structural similarity.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections – 35 USC § 112
112(a) – Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(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 1-8 and 11-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a compound of formula (I) wherein:
X is selected from CH and v is 1;
X1 is from N;
X2 and X3 are CH;
X4 is O;
X5 is N;
LA is selected from a bond or C1-6 alkyl;
Ring B is selected from piperazine substituted with 1-2 D, halogen, cyano, amino, hydroxyl, or C1-6 alkyl, or alternatively is one of the rings depicted below:
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;
Ring A is
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,
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,
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,
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,
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, or is
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substituted with C1-4 alkyl or C1-4 haloalkyl;
R2 and R3 are each D, halogen, cyano, or methyl;
does not reasonably provide enablement for the full scope of variables of Ring A, Ring B, Ring C, Ring D, RA, RB, m, and n the instant claims. 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.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Nature of the invention:
The invention is drawn to compounds of the formula (I) or a pharmaceutically acceptable salt thereof.
Breadth of the invention:
The scope of the claimed invention is very broad, as it is drawn to compounds of the following formulas:
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allowing for myriad compounds as recited in the instant claims. These variables can be further substituted, further broadening the scope of recited compounds.
State of the prior art and predictability in the art:
The invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F. 2d 833, 839, 166, USPQ 18, 24 (CCPA 1970).
In terms of the law, MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F. 2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F. 2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F. 2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Tautermann (Quantum Mechanics in Drug Discover, Humana Press, 2020, Chapter 1, pp. 1-17), cited for evidentiary purposes, teaches drug discovery is a very challenging, cost-intensive, and in terms of investment risky endeavor; on average, it takes 10–15 years and an investment of more than 2.5 billion dollars to get a new drug to the Market; especially the clinical phases cause extremely high costs and late-stage failures, especially in phase II studies, are quite common (page 1, 1st paragraph). Tautermann teaches the largest attrition in clinical phases is observed in phase II studies; the main goal is the assessment of the efficacy of the compound yielding a clinical proof of concept; a recent analysis from four major pharma companies revealed that the cause for attrition in phase II is mainly caused by lack of efficacy followed by safety issues; efficacy for a certain indication is usually preclinically tested in animal models; however, the translatability from animal models to the human situation is not always given; there are several reasons for this; often the disease condition cannot adequately be induced in animals (page 3, last paragraph). Tautermann teaches small molecules have several advantages, such as being cell and brain permeable, the lower cost of goods in their production, and oral administration; however, they are not always the easiest path forward for challenging targets; especially in the case of difficult or so far undruggable targets, new design strategies are required to be successful (page 5, last paragraph). Thus, Tautermann further establishes that the state of the art of drug design is highly unpredictable.
Level of ordinary skill in the art:
An ordinary artisan in the area of drug development would have experience in synthesizing chemical compounds for particular activities. The synthesis of new drug candidates, while complex, is routine in the art. The process of finding new drugs that have in vitro activity against a particular biological target (i.e., receptor, enzyme, etc.) is well known. Additionally, while high throughput screening assays can be employed, developing a therapeutic method, as claimed, prior to synthesizing and testing compounds is generally not well-known or routine, given the complexity of certain biological systems.
The amount of direction provided and working examples:
The compound core depicted with specific substituents represents a narrow subgenus for which applicant has provided sufficient guidance to make and use; however, the disclosure is not sufficient to allow extrapolation of the limited examples to enable the scope of the compounds instantly claimed. Applicant has provided no working examples of any compounds, compositions, or pharmaceutically acceptable salts where Ring B is beyond the rings identified above.
Within the specification, “specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula.” See MPEP 608.01(p).
MPEP § 2164.01 (a) states, “A conclusion of lack 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. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here that Applicant is not enabled for making these compounds.
112(b)
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.
Claims 1-5 and 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.
In claim 1, the structures for formulas (I), (I-1), and (I-2) denote the limitation (R5)p. However, p is not defined anywhere in this claim. Thus, this limitation is indefinite. Claims 2-5 and 12-13, which depend on claim 1, fail to further define p and are also rejected.
For examination purposes, p will be construed as having a value of 0, 1, or 2, consistent with the definition of p in claim 6.
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) 1-8 and 11-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Angibaud (WO 2009/053373 A1).
Angibaud teaches the following compound as Compound 57 (p. 80, left col., row 2).
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Angibaud teaches that compounds of their invention can include any isotopes of atoms present in the invention, for example deuterium (p. 15, lines 1-3). Angibaud teaches these compounds are PARP inhibitors (p. 1, lines 5-8) useful in treating PARP-mediated disorders (claim 9). Angibaud also teaches pharmaceutical compositions of compounds of the invention (p. 41, lines 16-18), and teaches a preferred dose of 0.1 mg to 200 mg per unit dosage form (p. 51, lines 12-14).
Regarding claims 1-8 and 11, it would have been prima facie obvious to one of ordinary skill in the art prior to the filing of the instant invention to deuterate the piperazine ring of Compound 57 of Angibaud, since Angibaud suggests deuterated versions of claimed compounds are alternatively useful in their invention, thus resulting in a compound of instant formula (I) (compound 57A) with a reasonable expectation of success.
Regarding claim 12, it would have been obvious to make a pharmaceutical composition of compound 57A since Angibaud teaches pharmaceutical compositions of their compounds.
Regarding claim 13, it would have been prima facie obvious to one of ordinary skill in the art to utilize the amount of compounds of formula (I) taught by Angibaud as a starting point for optimizing the amount and treatment regimen of Compound 57A utilized to treat PARP-mediated disorders because Angibaud teaches compounds of their formula are useful in treating PARP-mediated diseases and because dosage and treatment regimen are result-effective variables, i.e. a variable that achieves a recognized result. Therefore, the determination of the optimum or workable dosages would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Taken all together, all this would result in the invention of instant claims 1-8 and 11-13 with a reasonable expectation of success.
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 1-3 and 12-13 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 8, 13, and 16 of copending Application No. 18/697,419 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims.
Reference claim 1 recites compounds of the following formula (I) or a stereoisomer, solvate, deuterated compound, or pharmaceutically acceptable salt thereof:
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Reference claim 3 recites sub-formulas of reference formula (I):
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Reference formula (I) read on instant formula (I) recited in claim 1, and also reads on instant formulas (I-1) and (I-2) when LA is a bond. Furthermore, the variable definitions of reference formula (I) are the same or more specific than those of instant formula (I). Thus, reference formula (I) is a species of generic instant formula (I), and anticipates instant claim 1.
Regarding instant claims 2-3, reference formulas (II) and (II-b) from reference claim 3 read on instant formulas (II), (II-a), (III), (IV), and (IV-b) because the variable definitions are the same or more specific than said instant formulas.
Regarding instant claim 12, reference claim 13 teaches a pharmaceutical composition comprising a compound of reference claim 1. Because the compounds of reference claim 1 read on instant claim 1, a pharmaceutical composition of compounds of reference claim 1 read on a pharmaceutical composition of compounds of instant claim 1. Thus, reference claim 13 reads on instant claim 12.
Regarding instant claim 13, a composition of reference claim 16 comprising 1-1440 mg of a compound of reference claim 1 reads on the corresponding dosage of 1-1500 mg recited in instant claim 13 of a compound of instant claim 1.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1-8 and 11-13 are rejected.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OLIVER D. HEES whose telephone number is (571)272-9840. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, AMY L. CLARK can be reached at (571) 272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/O.D.H./Examiner, Art Unit 1628
/Rayna Rodriguez/Primary Examiner, Art Unit 1628
Prosecution Insights