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 with traverse of Group I (including claims 1, 5, 10-11, 21, and 70-71) and the compound of formula IV, in the reply filed on 6/22/26 is acknowledged. The traversal is on the ground(s) that Zhao does not disclose or teach the claimed nanocrystal formulation and that Applicant discovered its very poor solubility. This is not found persuasive because Zhao et al. expressly teach the claimed compound and all crystalline forms of the compound, which includes nanocrystalline forms, as well as adding a stabilizer such as lactose or mannitol. The very poor solubility is simply an inherent characteristic of the compound. See Atlas Powder, 190 F.3d at 1347 (“[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art's function, does not render the old composition patentably new to the discoverer.”). Applicant states: “It is generally understood in the art that most poorly soluble compounds cannot have their solubility improved by being formulated as nanocrystals (for instance, some drugs cannot be prepared as nanocrystals due to factors such as stability, or they remain poorly soluble even after being converted into nanocrystals).” However, not only has Applicant not cited any evidence to support that statement but also it is in conflict with the general teachings in the nanocrystal art. Kawakami et al. teach: “the dissolution rate of drug particles is proportional to the surface area of the particles in contact with the dissolution medium. A decrease in drug crystal size results in an increased surface area to volume ratio…; therefore, reducing the crystal size of a drug powder will increase its dissolution rate. For example, if the crystal size is reduced from 1 μm to 100 nm, the surface area increases 10-fold, which should lead to a 10-fold enhancement of the dissolution rate.” (Page 4, 3.2 CRYSTAL SIZE: NANOSIZING in: Kawakami et al. ([online] retrieved on 7/30/26 from: https://basicmedicalkey.com/improving-the-water-solubility-of-poorly-soluble-drugs/; 2017:7 pages). Thus, while the special technical feature appears novel, it requires no inventive step in view of the teachings of Zhao et al.
The requirement is still deemed proper and is therefore made FINAL.
Claims 55-56, 62-66 and 69 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected groups, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 6/22/26.
Claim Status
Claims 2-4, 6-9, 12-20, 22-54, 57-61, 67 and 68 are cancelled.
Claims 1, 5, 10, 11, 21, 55-56, 62-66 and 69-71 are pending.
Claims 55-56, 62-66 and 69 are withdrawn.
Claims 1, 5, 10, 11, 21, 70 and 71 are presented for examination on the merits.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
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The foreign priority documents are not in English. Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 8/8/24, 9/29/25 and 3/16/26 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1, 5, 10, 11, 21, 70 and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. (WO2019001572; of record) and Joshi et al. (Pharmaceutical Nanotechnology, 2019, 7, 259-278; of record) and Kawakami et al. ([online] retrieved on 7/30/26 from: https://basicmedicalkey.com/improving-the-water-solubility-of-poorly-soluble-drugs/; 2017:7 pages) and Censi et al. (Molecules 2015, 20, 18759-18776) and Jenkins et al. (WO2007033239).
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103, the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103.
Applicant claims, for example:
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Level of Ordinary Skill in the Art
(MPEP 2141.03)
MPEP 2141.03 (I) states: “The “hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988). The level of skill is that of a pharmaceutical research scientist, as is the case here, then one can assume comfortably that such an educated artisan will draw conventional ideas from pharmaceutical formulation and possess conventional knowledge in drug delivery, material science, and physical chemistry to convert active pharmaceutical ingredients (APIs) into stable, effective medicines. They understand how to select excipients (inactive ingredients), optimize stability, and ensure compliance with regulatory standards (FDA, GMP). Their expertise covers formulation development, dosage form design, and manufacturing processes.
In addition, the prior art itself reflects an appropriate level (MPEP 2141.03(II)).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Regarding claim 1, Zhao et al. teach pharmaceutical compositions of a Rho-associated protein kinase (ROCK) inhibitor (Abstract) and expressly teach the same ROCK inhibitor compound in the claims on page 353:
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Zhao et al. teach: “a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof, N-oxide, an isotopically labeled compound, a metabolite or prodrug, and one or more pharmaceutically acceptable carriers” (Page 3, last paragraph; page 5, last 3 paragraphs; page 6, first 2 paragraphs; claims 10-12).
Zhao et al. teach that all possible crystalline forms or polymorphs of the compounds are encompassed (Page 9, 3rd paragraph).
Regarding claims 5 and 10-11, Zhao et al. teach that the pharmaceutically acceptable carrier include mannitol, lactose, wetting agents, emulsifying agents, magnesium stearate, glycerin, silica gel (silicon dioxide), talc and cellulose (Page 23, paragraphs 3-4), where lactose and mannitol can serve as stabilizers thus meeting definition i) of claim 5 and definition ii) of claim 11, and be in the form of tablets, powders and suspensions (Page 23, paragraph 7), thus meeting definition iv) of claim 10.
Regarding claim 70, Zhao et al. teach the hydrochloride salt (Page 9, paragraphs 5 and 6).
Regarding claim 71, Zhao et al. teach water as a solvate (Page 9 last paragraph through page 10 first paragraph), thus making a hydrate.
Regarding claims 1, 5, 10, 11 and 21, Joshi et al. teach that most pharmaceutical actives have poor water solubility that leads to poor bioavailability (Abstract; Introduction). Joshi et al. teach that nanocrystals “not only enhance dissolution rate velocity, it also improves saturation solubility as well and hence, a higher bioavailability can be logically achieved due to their high surface to volume ratio, which ultimately increases both the dissolution rate and saturation solubility of active pharmaceutical ingredients” and have a size from 10 to 1000 nm (Page 260, left column). Joshi et al. teach methods of preparation (Page 261, 2.1.; Figures 2-3). Joshi et al. teach dispersed particles in nanosuspensions that need to be stabilized by addition of surfactants such as SDS, polysorbates, vitamin E TPGS, sorbitan esters, HPMC, HPC, MC, PVP and poloxamers (Page 267, 3.). Joshi et al. teach that NCs are “noticeably easy to prepare” and that: “Physically stable nanocrystalline formulations are obtained when the weight ratio of drug to stabilizer is 20:1 to 2:1. Too little stabilizer induces agglomeration or aggregation and too much stabilizer promotes Ostwald ripening. The process of identifying an appropriate stabilizer(s) for a drug candidate is empirical and can be accomplished using amount of drug in milligram. Pharmaceutical excipients such as the polysorbates, cellulosic, povidones and pluronic are usually used that are acceptable stabilizers for creating physically stable nanoparticle dispersions.” (Page 267, 3.).
Regarding claims 1 and 5, Kawakami et al. teach adding ionic surfactants such as sodium lauryl sulfate and sodium docusate to confer added stability to nanocrystals (3.2.1 Stabilization).
Regarding claims 1, 70 and 71, Censi et al. is directed to drugs with low water solubility which might be overcome through an appropriate formulation of the drug. (Abstract). Censi et al. teach that: “the Food and Drug Administration (FDA) and the International Conference on Harmonization (ICH) has required preliminary and exhaustive screening studies to identify and characterize all the polymorph crystal forms for each drug.” (Abstract) Censi et al. teach: “For approval of a new drug, the drug substance guideline of the US Food and Drug Administration (FDA) states that “appropriate” analytical procedures need to be used to detect polymorphs, hydrates and amorphous forms of the drug substance and also stresses the importance of controlling the crystal form of the drug substance during the various stages of product development.” (Page 18769, 6. Regulatory Considerations). Censi et al. stress the importance of solubility on the bioavailability of drugs stating: “solubility is one of the most critical and important parameters influencing drug bioavailability” (Page 18760, 2.)
Regarding claims 1, 5, 10, 11 and 21, Jenkins et al. teach crystalline compositions (Claims 1 and 2) with about 0.001% to about 99.5% active agent and about 0.5% to about 99.999% of stabilizer (Claim 7; [0113]), a particles sizes ranging from less than about 1000 nm or less than about 500 nm or less than about 300 nm (Claim 3; [0107]), hence nanocrystalline, and formulated as a dispersion/suspension (Claim 4; [0128, 0135, 0137]), with one or more pharmaceutically acceptable excipients/carriers (Claim 6). Jenkins et al. claim a wide variety of stabilizers including hypromellose, sodium lauryl sulfate, poloxamers, wax, polyvinylpyrrolidone (povidone), silicon dioxide, polyvinyl alcohol, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters TWEEN20 and TWEEN80 (polysorbates), docusate sodium (Claims 9-10; [0072-0075, 0089-0092, 0095]) with Table 1 teaching commercially available povidone K values [0094]. Jenkins et al. also teach adding preservatives [0097] such as methylparaben and propylparaben [0101, 0115]. Further regarding the particles size, Jenkins et al. teach: “the nanoparticle size can be manipulated to give the desirable blood level profiles and duration of action when administered by either IM or SC routes” [0115].
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
1. The difference between the instant application and Zhao et al. is that Zhao et al. do not expressly teach a nanocrystal formulation of the claimed ROCK2 inhibitor with the claimed stabilizers in the particle sizes claimed, amounts claimed, weight ratios claimed, excipients claimed and their amounts claimed. This deficiency in Zhao et al. is cured by the teachings of Censi et al., Kawakami et al., Jenkins et al. and Joshi et al.
1. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make a nanocrystalline formulation of the ROCK2 inhibitor taught by Zhao et al. with the claimed stabilizers in the particle sizes claimed, amounts claimed, weight ratios claimed, excipients and their amounts claimed, as suggested by Censi et al., Kawakami et al., Jenkins et al. and Joshi et al., and produce the instant invention. One of ordinary skill in the art would have been motivated to do this because for the following sound articulated reasoning with rational underpinning based upon the evidence. The claimed ROCK2 inhibitor is an N-methylated indole compound with an expectation of very poor water solubility. Required conventional solubility testing of the crystalline form, as taught by Censi et al., would ascertain the solubility. The artisan would then seek to improve the solubility for bioavailability reasons and produce nanocrystalline suspensions of the ROCK2 inhibitor where the particle size is 10-1000 nm, as taught by Joshi et al. and Jenkins et al., and overlaps the claimed particle size ranges. The artisan would also add stabilizers in a drug:stabilizer ratio of 20:1 to 2:1, as suggested by Joshi et al., which overlaps the claimed range and Jenkins et al. provide additional guidance on which stabilizers and preservatives to add and in overlapping amounts by weight. Consequently, having 1-10% of ROCK2 inhibitor and 1-10% of stabilizer of any combination of stabilizers and excipients as found in claims 5, 11 and 21 is obvious over the combined references. See MPEP 2144.05 (II) (A): “[W]here 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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)…see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.").
The test for obviousness is "what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 4I3, 425 (CCPA I98I) (MPEP 2145(III)). In the present case, the combined references render obvious each and every claimed limitation. The ordinary artisan would have a reasonable expectation of success in formulating the crystalline embodiment of compound TD101470 of Zhao et al. as a nanocrystalline suspension formulation with the claimed stabilizers and excipients in the amounts claimed in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the combined references, especially in the absence of evidence to the contrary.
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, 11, 21, 70 and 71 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6-8 of U.S. Patent No. 11390609 (common assignee Beijing Tide Pharmaceutical Co., LTD.) in view of Zhao et al. (WO2019001572; of record) and Joshi et al. (Pharmaceutical Nanotechnology, 2019, 7, 259-278; of record) and Kawakami et al. ([online] retrieved on 7/30/26 from: https://basicmedicalkey.com/improving-the-water-solubility-of-poorly-soluble-drugs/; 2017:7 pages) and Censi et al. (Molecules 2015, 20, 18759-18776) and Jenkins et al. (WO2007033239). Although the claims at issue are not identical, they are not patentably distinct from each other because the patent teaches in claims 6-8:
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The patent does not expressly teach which pharmaceutically acceptable carriers to use to make the pharmaceutical composition as a nanocrystalline suspension with stabilizers as claimed. However, as discussed in detail above and incorporated by reference, the combined teachings of Zhao et al., Censi et al., Kawakami et al., Jenkins et al. and Joshi et al. render obvious the instantly claimed subject matter. In view of the combined references, the ordinary artisan would have recognized the obvious variation of the claimed subject matter over the patented subject matter.
Claims 1, 5, 10, 11, 21, 70 and 71 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11-17 of copending Application No. 18691908 (common inventors and assignee) and claims 1, 5, 10, 11, 21 and 70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 29-46 of copending Application No. 18023394 (NOA filed 4/24/26 and not assigned patent number yet and common inventors and assignee) both in view of Zhao et al. (WO2019001572; of record) and Joshi et al. (Pharmaceutical Nanotechnology, 2019, 7, 259-278; of record) and Kawakami et al. ([online] retrieved on 7/30/26 from: https://basicmedicalkey.com/improving-the-water-solubility-of-poorly-soluble-drugs/; 2017:7 pages) and Censi et al. (Molecules 2015, 20, 18759-18776) and Jenkins et al. (WO2007033239). Both applications are directed to the same compound as claimed and pharmaceutical compositions thereof with one or more pharmaceutically acceptable carriers. The copending applications do not expressly teach which pharmaceutically acceptable carriers to use to make the pharmaceutical composition as a nanocrystalline suspension with stabilizers as claimed. However, as discussed in detail above and incorporated by reference, the combined teachings of Zhao et al., Censi et al., Kawakami et al., Jenkins et al. and Joshi et al. render obvious the instantly claimed subject matter. In view of the combined references, the ordinary artisan would have recognized the obvious variation of the claimed subject matter over the copending subject matter.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNST V ARNOLD whose telephone number is (571)272-8509. The examiner can normally be reached M-F 7-3:30.
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/ERNST V ARNOLD/Primary Examiner, Art Unit 1613
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