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 .
Election/Restriction
Applicant elected. without traverse, Group I, and species crystalline Form I, 2- {4- [(3 S)-piperidin-3 -yl]phenyl}- 2H-indazole-7-carboxamide tosylate monohydrate substantially free of Form Ill of 2- {4- [(3 S)-piperidin-3 -yl]phenyl} -2H-indazole- 7-carboxamide tosylate anhydrate, prepared from a solvent of water: dimethyl sulfoxide, on 09/15/2025.
Response to Amendment
Acknowledgment is made of the receipt and entry of the amendment filed on 01/21/2026.
Claim Status
Claims 1, 2, 6, 9-11, 13, 15, 17, 41, 48, 49, 52-53, and 55-61 are pending.
Claim 41 and 53 remain withdrawn.
Claims 1, 2, 6, 9-11, 13, 15, 17, 48, 49, 52, and 55-61 are currently under examination in this office action.
Priority
This instant application 18/310,238, filed on 05/01/2023, is a continuation of U.S. Patent Application Serial No. 17/339,896, filed June 4, 2021 (now U.S. Patent No. 11673877), which is a continuation of U.S. Patent Application Serial No. 16/584,401(now U.S. Patent No. 11,091,459), filed September 26, 2019, which is a continuation of International Application No. PCT/US2018/024603, filed March 27, 2018, which claims the benefit of U.S. Provisional Application No. 62/477,411, filed March 27, 2017.
Claim Interpretation
As disclosed by instant specification (See [0002], [0041]), instant claimed different crystalline Forms of 2-{4- [(3S)- piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate monohydrate is niraparib, an orally active ADP inhibitor.
Action Summary
Applicant's remarks filed 01/21/2026 have been fully considered. Any objection and rejection found in the previous Office Action and not repeated herein has been withdrawn in view of amendment and Applicant’s remarks .The text of those sections of Title 35 USC Code not included in this action can be found in a prior Office action.
Applicant filed Terminal Disclaimer over parent application US11091459 and US11673877 on 01/21/2026 which are approved on 02/11/2026. Thus, the rejections on the ground of double patenting over US No. 11091459 and US11673877 are withdrawn.
Rejections of claims 48-49, 52 and 55-61 under 35 U.S.C. 112(a), Claims 1, 2, 6, 9-11, 13, 15, 17, 48, 49, 52, and 55-58 rejected over Foley et al. (US 8436185B2) under 35 U.S.C. 102/103 are newly applied in this office action.
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.
Claims 48-49, 52 and 55-61 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the full scope of pharmaceutical compositions and article of manufacturing comprising the crystalline composition as recited in claim 1.
Claims 48-49 and 52 are drawn to composition consisting of crystalline form I prepared from different solvent mixture at broad range of water: organic solvent from 10:1 to 400:1. Instant specification only disclose one working process wherein crystalline form I was prepared from a solvent mixture of water: dimethyl sulfoxide at 200:1. In absence of sufficient working example comprising different solvent mixture, a POSA would not know if instantly claimed crystalline form I substantially free of Form III could be prepared from other solvent mixture.
Instant claims 55-61 are drawn to pharmaceutical composition and article comprising crystalline composition of claim 1, wherein pharmaceutical composition is construed under BRI as variety of dosage forms including liquid dosage form and solid dosage form comprising liquid excipient. Instant specification disclosed variety of pharmaceutical composition not limited to granules, tablet, liquid filled capsules, etc.(See [0027]). Instant spec also discloses some liquid excipient, e.g. glycerol, polyethylene glycol, etc. (See [0033]). However, incorporation of a crystalline solid into a liquid excipient results in dissolution of the crystalline form thereby eliminating its crystal lattice. In other words, the ordered, repeating lattice structure that defines a crystal is broken down, instantly claimed crystalline form as recited with specific XRPD peaks would not exist in the pharmaceutical composition comprising liquid excipient. The crystalline form might also be destructed during the manufacturing of some solid dosage form. For example, the grinding, compression, tableting and other mechanical force would destroy or alter the crystalline structure and solid-state properties.
Further, instant claimed crystalline form is tosylate monohydrate wherein external water molecules (moisture)/excipient exhibits various impact on the pharmaceutical hydrates and their behavior. The presence of water/moisture molecules influences crystalline solubility, thermodynamic rate and stability. Salameh (2005) teaches stability of crystal hydrates and their anhydrates in the presence of various excipients(e.g. micro crystalline cellulose (MCC), mannitol, polyvinylpyrrolidone PVP (See whole article). Salameh teaches phase transformation of an anhydrate to a hydrate or vice versa is of pharmaceutical significance because such transformations can alter the physical and chemical properties of the API leading to changes in the free energy and the thermodynamic activity of the API which can translate into altered API dissolution and bioavailability (See page 447, left column). Salameh teaches the effect of excipients on the dehydration and hydration of crystalline is complex. For example, mannitol enhanced dehydration of tested crystal hydrate, but had little effect on hydration. PVP (particular K12), when stored at high RH, was able to result in the partial dissolution of the active pharmaceutical ingredient and hence changed the hydration process from a solid state to a solution-mediated transformation(See abstract). The change from monohydrate to anhydrous crystalline form occurs through dehydration. In instant case, the ratio of anhydrate Form III would be increased during dehydration in process of manufacturing pharmaceutical composition. As such, instant claimed pharmaceutical composition might not comprise instant claimed crystalline composition consisting of crystalline form I substantially free of Form III defined by XRPD as recited in claim 1.
Instant specification discloses ZejulaTM capsule contains 100 mg of niraparib (as tosylate monohydrate)(See [0053]). Instant spec does not disclose ZejulaTM capsule or any other working example of pharmaceutical composition wherein instant claimed crystalline composition is retained with the defined ratio of crystalline Form I and III charactered by XRPD peaks. Instant specification does not adequately describe the conditions necessary to retain/preserve the claimed crystalline. Absent a clear description of pharmaceutical compositions and article of manufacturing that retain the crystallinity defined by XRPD as recited in claim 1, a POSA would not know if the final product comprises crystalline composition of claim 1 consisting of crystalline Form I substantially free of Form III.
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.
Claims 1, 2, 6, 9-11, 13, 15, 17, 48, 49, 52, and 55-61 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Independent claim 1 recites “A composition consisting of crystalline Form I of 2-{4- [(3S)- piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate monohydrate substantially free of Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate anhydrate, wherein the crystalline Form I is characterized by an X-ray powder diffraction (XRPD) comprising diffraction angles at 2θ values of 9.5±0.2, 24.9±0.2, and 26.0±0.2 degrees, and is further characterized by at least two diffraction angles selected from a group consisting of 2θ values of 12.4±0.2, 13.2±0.2, 17.4±0.2, 18.4±0.2, 21.0±0.2, 25.6±0.2,and 26.9±0.2 degrees…and Form III of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate anhydrate is characterized by an X-ray powder diffraction (XRPD) comprising diffraction angles at 2θ values of 17.8±0.2, 19.0±0.2, and 22.8±0.2 degrees”.
The difference between monohydrate crystalline Form I and anhydrate crystalline form III is monohydrate vs anhydrate which is slight different form. It is well recognized in the art that X-ray diffraction patterns may have different appearance due to artifacts/solvents, thus the small differences in X-ray diffraction must be carefully evaluated for true new crystal/ polymorphs. The further limitation “at least two diffraction angles” are directed to different combination of diffraction angles wherein 17.4±0.2 and 18.4±0.2 in Form I are very close to XRPD peaks of Form III characterized by only three diffraction (XRPD) at 17.8±0.2 and 19.0±0.2 degrees. It’s not clear how to differentiate crystalline form III characterized with only three XRPD peaks including 17.8±0.2 and 19.0±0.2 in absence of other characteristic peaks from crystalline Form I which might also comprise 17.4±0.2 and 18.4±0.2. A person of ordinary skilled in the art would not be appraised of the scope of crystalline form I in claim 1 and the limitations of claim 1 do not clearly set forth the metes and bounds of the patent protection desired. Claims 2, 6, 9-11, 13, 15, 17, 48, 49, 52, and 55-61 are also rejected due to their dependency on claim 1.
Applicant argues that the peak at 22.8 ±0.2 is the diagnostic peak of Form III anhydrate which can be used to quantify the relative proportions of Form III within a sample (Remarks, 8 and 9).
Response: Applicant argument is fully considered, but NOT persuasive. Although 22.8 ±0.2 might be one significant XRPD peak of crystalline Form III, in absence of sufficient description of XRPD patter of Form III, an ordinary skilled in the art would not determine if the 22.8 ±0.2 is from crystalline form III or other partial hydrate form, e.g. instantly disclosed crystal Form II.
Claim Rejections - 35 USC § 102/103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 55-61 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over ZEJULATM (niraparib) prescribing label 2017( retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208447lbl.pdf).
ZejulaTM (niraparib) is an oral capsule formulation comprising 2-{4-[(3S)-piperidin-3-yl]phenyl}-2Hindazole 7-carboxamide 4-methylbenzenesulfonate hydrate. Zejula label teaches niraparib tosylate monohydrate is a white to off-white, non-hygroscopic crystalline solid (See Description). ZejulaTM is an article of manufacture comprising multiple dose unit and written instruction for use and unit dose form packaged in bottle. The Office is not equipped to conduct experimentation in order to determine whether Applicant’s claimed pharmaceutical composition comprising crystalline form I is different and, if so, to what extent, from that of Zejula. Therefore, with the showing of the reference, the burden of establishing non-obviousness by objective evidence is shifted to the Applicants.
Claims 1, 2, 6, 9-11, 13, 15, 17, 48, 49, 52, and 55-58 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Foley et al. (US 8436185B2).
Foley discloses pharmaceutically acceptable crystal salts of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (i.e. niraparib), solvate, or a stereoisomer, tautomer thereof, and pharmaceutical composition comprising aforementioned salt as poly(ADP-ribose)polymerase (PARP) inhibitors for treating tumors with specific defects in DNA-repair pathways and as enhancers of certain DNA-damaging agents such as anticancer agents and radiotherapy (See abstract, Col. 1, lines 14-27; Examples 1-5).
Foley explicitly discloses preparation of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate monohydrate (See Example 1 and 2), wherein the solid was crystallized from THF /water or ethanol, and characterized by 1HNMR, X-ray powder diffraction, DSC and TGA. Forley teaches the amount of water is 5% compared to THF as solvent which is a ratio of 1:20 (water to organic solvent)(See Example 1, Col. 32, line 57-60).
Foley teaches pharmaceutical composition comprising the salt of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide and excipient/carriers for oral use, e.g. tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs, etc. (See Col. 7, lines 23, 43; Col. 12, lines 8-12, 33-67; Col. 13, lines 1-67). Foley teaches the pharmaceutical compositions may be in the form of a sterile injectable aqueous solutions in water or sodium chloride solution, or oil-in-water microemulsion (See Col. 13, lines 62-67). Foley also teaches dispersible powders and granules for preparation of an aqueous suspension by the addition of water (See Col. 13, lines 36-38) and the active ingredient is mixed with water soluble carrier such as polyethyleneglycol(See Col. 13, lines 1-3).
Foley does not disclose the XRPD peaks of the crystal tosylate salt. Please note XRPD peaks are considered as the property of crystal tosylate salt. It is well recognized in the art that X-ray diffraction patterns may have different appearance due to artifacts and small differences in X-ray diffraction may be due to other solvent. The Office is not equipped to conduct experimentation in order to determine whether Applicant’s claimed crystalline form is different and, if so, to what extent, from that of prior art.
It's well understood that pharmaceutic excipient and manufacturing process of pharmaceutical composition may cause crystalline structure to dissolution, convert to an amorphous form or otherwise lose its crystallinity, as elaborated in preceding 35 USC 112 section. Instant claimed monohydrate crystalline Form I as characterized by XRPD peaks would no longer retain the defined crystal structure with the defined XPPD pattern in pharmaceutical composition comprising liquid excipient. As such, Foley’ composition comprising the same niraparib tosylate monohydrate is considered as read on instant claimed pharmaceutical composition comprising niraparib tosylate monohydrate and at least one excipient.
In the alternative, even if instant claimed crystalline form is not identical to the crystalline form taught by Foley regarding specific XRPD peaks, the differences between what is disclosed and what is claimed are considered to be slight that pharmaceutical composition comprising 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide tosylate monohydrate taught by Foley is likely to possess similar characteristics of the instantly claimed pharmaceutical composition. It is well known for the skilled artisan in the pharmaceutical industry to explore different conditions for crystalline salt forms of compounds for purpose of solubility, stability, and bioavailability etc. Thus, instantly claimed crystalline form and pharmaceutical composition comprising the crystalline form would have been obvious to those of ordinary skill in the art within the meaning of USC 103. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05.
Accordingly, the claimed invention as a whole was at least prima facie obvious, if not anticipated by the cited reference, especially in the absence of sufficient, clear, and convincing evidence to the contrary. With the showing of the reference, the burden of establishing non-obviousness by objective evidence is shifted to the Applicants.
Conclusion
No claim is allowed.
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/L.M./Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628
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