DETAILED ACTION
Status of Claims
The amendment submitted September 1, 2026 has been entered.
Claims 1-2, 4-8, 10, 12, 14, 16, 18, 20, 22, and 24-26 are pending and under consideration.
Claims 2, 4, 8, 10, 12, 14, 16, 18, 20, 22, 24, and 26 are withdrawn in the instant office action as explained below in the Election/Restriction section.
Claims 1, 5-7, and 25 are under consideration in the instant office action as explained below in the Election/Restriction section.
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
Applicant’s election without traverse of Group I, Claims 1, 2, 5-7, 10, 14, 18, 22 and 25 drawn to a crystalline form of a compound of Formula I and a pharmaceutical composition containing a crystalline form of a compound of Formula I in the reply filed on September 1, 2026 is acknowledged.
Applicant’s election without traverse crystalline form B as a species of Formula I in the reply filed on August 28, 2026 is likewise acknowledged.
Claims 1, 5-7 and 25 read on the elected species.
Claims 5-6, and 56-64 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 30, 2026
Claims 1, 5-7 and 25 are under consideration and the subject of this Office Action.
Priority
This application is a 371 National Phase Application of PCT/CN2023/073719 filed January 29, 2023. PCT/CN2023/073719 has PCTCN2022075258 filed January 30, 2022.
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119
(a)-(d), and the certified copy has been filed.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
One information disclosure statements (IDS) submitted on March 25, 2025 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
Abstract Objections
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because the abstract is less than 50 words. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Rejections - 35 USC § 112(b)
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.
Claims are 6-7 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.
At page 9, last line Claim 6 contains a reference to figures and page 10, lines 6, 22, and 27 of claim 7. As per MPEP 2173.05(s): “ Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).”
At page 9, last line, Claim 6, the term “an X-ray powder diffraction pattern substantially as shown in FIG. 8” in is a relative term which renders the claims indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The examiner invites Applicant to clarify what is required to determine and assess if the XRD is “substantially as shown.”
Similar phasing is recited in claim 7. By example only, on page 10, line 6 of claim 7 recites “a thermogravimetric analysis curve substantially as shown in FIG. 9.”
Consequently, the Examiner requests Applicant’s aide in correcting and/or clarifying similar language as used throughout claim 7.
Regarding claim 7, the phrase "for example" is repeated throughout the claim and renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
By example only, at page 10, line 3, claim 7 recites “for example, the crystalline form B of the compound of formula I has a thermogravimetric analysis curve showing a weight loss of 0.1817% during heating from 28.73 °C to 149.63 °C; for another example, the crystalline form B of the compound of formula I has a thermogravimetric analysis curve substantially as shown in FIG. 9.”
Consequently, the Examiner additionally requests Applicant’s aide in correcting any additional uses of “for example.”
Therefore, claims 6-7 are rejected for being indefinite.
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.
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 non-obviousness.
Claims 1, 5-7 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al (USPN 12,145,944 B2) in view of Papadakis et al (Papadakis, Emmanouil, Anjan K. Tula, and Rafiqul Gani. "Solvent selection methodology for pharmaceutical processes: Solvent swap." Chemical Engineering Research and Design 115 (2016): 443-461), Newman (Newman, A., 2013. Specialized solid form screening techniques. Organic Process Research & Development, 17(3), pp.457-471) and Thorson et al. (Thorson, M.R., Goyal, S., Schudel, B.R., Zukoski, C.F., Zhang, G.G., Gong, Y. and Kenis, P.J., 2011. A microfluidic platform for pharmaceutical salt screening. Lab on a Chip, 11(22), pp.3829-3837).
Regarding claims 1, 5-7 and 25, Wang teaches compound 59, which is identical to a compound of formula I as per instant invention as shown below (column 55, last compound).
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Wang also teaches at column 161, the preparation and use of salts of compounds of Formula I, and in particular highlighting compound 59 as per column 161, lines 14-17 and furthermore as per lines 22-59“The present disclosure encompasses the preparation and use of salts of Compounds of the Disclosure. As used herein, the pharmaceutical “pharmaceutically acceptable salt” refers to salts or zwitterionic forms of Compounds of the Disclosure. Salts of Compounds of the Disclosure can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with a suitable acid. The pharmaceutically acceptable salts of Compounds of the Disclosure can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Non-limiting examples of salts of compounds of the disclosure include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphsphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, paratoluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzene sulfonate, and p-toluenesulfonate salts. In addition, available amino groups present in the compounds of the disclosure can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. In light of the foregoing, any reference Compounds of the Disclosure appearing herein is intended to include compounds of Compounds of the Disclosure as well as pharmaceutically acceptable salts, hydrates, or solvates thereof.”
The present disclosure encompasses the preparation and use of solvates of Compounds of the Disclosure. Solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents. The term “solvate” as used herein is a combination, physical association and/or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Thus, “solvate” encompasses both solution-phase and isolatable solvates. Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, and ethanol, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure. One type of solvate is a hydrate. A “hydrate” relates to a particular subgroup of solvates where the solvent molecule is water. Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M. Caira et al, J. Pharmaceut. Sci., 93(3):601-611 (2004), which describes the preparation of solvates of fluconazole with ethyl acetate and with water. Similar preparation of solvates, hemisolvates, hydrates, and the like are described by E. C. van Tonder et al., AAPS Pharm. Sci. Tech., 5(1):Article 12 (2004), and A. L. Bingham et al., Chem. Commun. 603-604 (2001). A typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20° C. to about 25° C., then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration. Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvate in a crystal of the solvate.”
Consequently, Wang teaches salts, solvates, hydrates and crystalline solids of compounds of Formula I.
Wang does not explicitly teach the characterization of crystalline solids of formula I and particularly of crystal form B via XRD, TGA, and DSC as per claims 1, 5, 6 and 7.
Wang also teaches that compounds of formula I can be formulated in pharmaceutical compositions as per column 166, lines 17-29 and columns 173- 174.
Papadakis teaches that “crystallization tasks are usually employed for the purification and recovery steps of the APIs (page 447, paragraph 3, lines 1-2).”
Papadakis also teaches that methanol, acetonitrile, ethyl acetate and acetone are commonly used solvents in pharmaceutical processes as used in instant invention(page 449, Table 2).
Newman teaches “Polymorph screens focus on finding new forms of an API and can include unsolvated, solvated, hydrated, and even amorphous materials. Salt, cocrystal, and amorphous dispersion screens use additional materials, such as counterions, cocrystal formers, and polymers, respectively. For all solid forms, small screens in early development may lead to medium size screens for phase II or III trials and a more comprehensive screen near launch. It should be noted that, once a new salt or cocrystal is targeted for development, a polymorph screen should be performed on that material to determine the possible forms, the thermodynamically stable form, and how this new form best fits within the development plan.”
Consequently, Newman teaches that screening for polymorphs is an important part of routine optimization in developing pharmaceuticals.
Newman also teaches that methanol, acetonitrile, ethyl acetate and acetone are common solvents used for a stable form screen as used in instant invention (Table 1).
Thorson teaches that “A key challenge to identify salts of parent compounds (PCs) is screening an extensive number of salt formers (SFs) under a variety of crystallization conditions with limited material. Extensive screens are traditionally conducted at various conditions to identify salts with suitable properties for formulation development because many parameters influence crystallization of salts, including SF identity, PC to SF ratios, solvents employed, pH, and temperature. To carry out high-throughput screens, automated robotic systems have been developed, which improve efficiency and reduce turnaround time… This study presents a microfluidic approach that addresses these challenges by enabling extensive salt screenings with reduced sample requirement and much improved control over the crystallization processes.”
Thorson also teaches “The microfluidic platform reported here can also find its application in salt screening using evaporation and/or antisolvent modes. Other high throughput crystallization applications include the screening for crystal habit, polymorphs or co-crystals covering wide ranges of conditions while using minimal amounts of material. Furthermore, modifications to the microfluidic chips, specifically the mixing zone and chamber geometries, would change the rate of supersaturation, thereby influencing crystallization events. In summary, with simple modifications, this platform could be used to study the nucleation, polymorphism and crystal habit of drugs and other compounds.”
Consequently, Thorson teaches that salt and polymorph screening of pharmaceutical compounds, including using antisolvent modes can be achieved with improved efficiency and requiring minimal material via routine optimization using a microfluidic platform and/or automated robotic systems.
Consequently, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the teachings of Wang, Papadakis, Newman and Thorson towards accessing crystalline solids and crystalline form B of instant invention because Wang discloses the identical compound and teaches that the compound can be crystallized, converted into pharmaceutically acceptable salts and used in pharmaceutical compositions, because Papadakis teaches that crystallization is a commonly used process for purifying API (active pharmaceutical ingredients) and that methanol, acetonitrile, ethyl acetate and acetone are commonly used solvents in pharmaceutical processes and Newman similarly teaches common solvents used in a stable form screen and that such a screen is routine optimization in pharmaceutical sciences. Thorson additionally teaches that polymorph screening can be achieved with improved efficiency as a routine optimization using automation.
A person of ordinary skill in the art of process chemistry and/or pharmaceutical sciences would have been motivated to purify Wang’s compound 59 using common crystallization techniques and to routinely screen the list of common solvents taught by Papadakis and Newman to arrive at the claimed invention as part of pharmaceutical scale-up and manufacturing process optimization. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success in arriving at the claiming invention as a highly predictable result with a reasonable expectation of success.
It would have been also prima facie obvious to perform standard characterization of Crystalline form B such as XRD, DSC and TGA as part of crystallization optimization process as is well-known in the art as standard analytical techniques to characterize API in scale-up, recrystallization and process optimization in the pharmaceutical sciences.
Finally, it would have been further prima facie obvious to develop pharmaceutical compositions using crystal form B as a highly predictable result with a reasonable expectation of success as Wang teaches pharmaceutical compositions using the identical compounds and its pharmaceutically acceptable salts and such experimentation would be part of routine optimization in the drug development process in preparing pharmaceutical compositions for methods of treatment.
Consequently, an ordinarily-skilled artisan would arrive at the claimed inventions as a predictable result with a reasonable expectation of success.
Consequently Claims 1, 5-7 and 25 are rejected on grounds of obviousness based on the beneficial teachings of Wang, Papadakis, Newman and Thorson.
Conclusion
Claims 1, 5-7 and 25 are under consideration and are rejected. No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROLYN L. LADD whose telephone number is (703)756-5313. The examiner can normally be reached M-Th, 7:00 am to 5:30 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached at 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.L.L./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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