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/Restrictions
Applicant's election with traverse of Group I, drawn to a cocrystal of a compound of formula (I) and fumaric acid, and a pharmaceutical composition comprising said compound and one or more pharmaceutically acceptable excipient; and a crystalline form in the reply filed on October 14, 2025 is acknowledged; and a crystalline form characterized by an X-ray powder diffraction pattern comprising at least three peaks at 2θ angles of: 5.0±0.2, 10.0±0.2, 10.5±0.2, 15.0±0.2, 18.7±0.2, and 19.8±0.2 as the elected species of cocrystal of a compound of formula (I) and fumaric acid are maintained.
Claims 20, 28, 31-37, 40 and 49 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 October 14, 2025.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on May 14, 2026, wherein claims 1-3, 6-8, 11, 13, 15-16, 21-27, 29-30, 38-39, 41-47 and 50-54 are cancelled; claims 4-5, 9-10, 12, 14, 17-20, 28, 31-37, 40 and 48-49 are unchanged; and claims 55-56 are newly added.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 4-5, 9-10, 12, 14, 17-20, 28, 31-37, 40, 48-49, and 55-56 are pending.
Claims 20, 28, 31-37, 40 and 49 remain withdrawn.
Claims 4-5, 9-10, 12, 14, 17-19, 48 and 55-56 are under examination in accordance with the elected species.
Information Disclosure Statement
The information disclosure statement filed on May 14, 2026 fails to comply with the provisions of 37 CFR 1.98(a)(4) because it lacks the appropriate size fee assertion. It has been placed in the application file, but the information referred to therein has not been considered as to the merits.
Priority
The instant application 18/257,962 filed on June 16, 2023 is a 371 of PCT/IB2021/061895 filed
on December 17, 2021, which claims priority to, and the benefits of Foreign Application No.
IN202041055174 filed on December 18, 2020.
Action Summary
The objection to the claims previously set forth in the Non-Final Office Action mailed on February 20, 2026 are withdrawn.
Claims 4-5, 9 and 48 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph,
as failing to comply with the written description requirement have been maintained, but revisited and modified upon further consideration for the reasons set forth herein.
Claims 4-5 and 48 rejected under 35 U.S.C. 103 as being unpatentable over Kumar et al. (WO 2022/084930 A2; cited in the IDS filed on 1/24/2024), in view of Gupta et al. (Molecules [Basel, Switzerland], 2018. Vol. 23, 7:1 719), as evidenced by Anderson (Academic Press, 2012: pp. 329-364) are withdrawn in light of the statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, i.e., December 18, 2020, that the subject matter disclosed in the reference Kumar et al. and the claimed invention were owned by, or subject to an obligation of assignment to, the same entity as Aurigene Discovery Technologies Limited, which was later renamed Aurigene Oncology Limited (the Applicant of the instant application), at the time the claimed invention was effectively filed (see page 9-10 of the reply filed on May 14, 2026).
Applicant’s arguments, see page 10-12, filed on May 14, 2026, with respect to the rejection(s) of claims 4-5 and 48 under 35 U.S.C. 103 as being unpatentable over Samajdar et al. (WO 2016/193939 A1), in view of Gupta et al. (Molecules [Basel, Switzerland], 2018. Vol. 23, 7:1 719), as evidenced by Anderson (Academic Press, 2012: pp. 329-364) have been fully considered; and applicant’s arguments with respect to Gupta et al. are found persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Samajdar et al. (WO 2016/193939 A1) and Yang et al. (ACS Omega, 2020. Vol. 5(14): 8283-8292) for the reasons set forth below.
Applicant’s arguments, see page 12, filed on May 14, 2026, with respect to the rejection(s) of claims 4-5 and 48 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, 12 of U.S. Patent No. 10,689,347 B2 in view of Gupta et al. (Molecules [Basel, Switzerland], 2018. Vol. 23, 7:1 719), as evidenced by Anderson (Academic Press, 2012: pp. 329-364) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Yang et al. (ACS Omega, 2020. Vol. 5(14): 8283-8292) and Orola et al. (CrystEngComm, 2009. Vol. 11(3): 415).
Claims 4-5 and 48 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 18 and 22 of copending Application No. 18/032,919 in view of Gupta et al. (Molecules [Basel, Switzerland], 2018. Vol. 23, 7:1 719), as evidenced by Anderson (Academic Press, 2012: pp. 329-364) are withdrawn in light of the abandonment of copedning application.
Claim Interpretation
The claimed term “cocrystal”, when reasonably construed in light of the special definition provided in the instant specification (see p. 7, line 32 to p. 8, line 4), is taken to include hydrate, solvates and clathrates.
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.
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.
Claim 48 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and, (8) the quantity of experimentation necessary. All of the Wands factors have been considered and discussed below:
(1, 5) The breadth of the claims and the Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
Instant claim 48 recites a pharmaceutical composition comprising the cocrystal of claim 4 and one of more pharmaceutically acceptable excipients. Therefore, the breadth of the claim covers a full genus of pharmaceutical composition, comprising the co-crystal of claim 4 and any one or more pharmaceutically acceptable excipients, and that encompass a broad API concentration ranges, multiple excipients classes and alternatives with broad concentration ranges, and numerous potential formulations.
(2, 3, 4) The state of the prior art, the level of skill in the art, and the predictability or lack
thereof in the art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the
art would have known, at the time the application was filed, about the subject matter to which the
claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art
refers to the skill of those in the art in relation to the subject matter to which the claimed invention
pertains at the time the application was filed.”
According to Chavan et al. (Cureus, 2024. Vol. 16(9): e70328), interactions with excipients may cause cocrystals to dissociate, alter cocrystal stoichiometry, replace the conformer, or convert the cocrystal back to the less soluble parent drug during formulation or dissolution (see e.g., p. 9, 1st paragraph). Chavan et al. further teaches that cocrystal stability depends upon numerous variables, including pH, surfactant levels, ion concentration, polymorphism, excipient selection, and processing conditions (see e.g., p. 9, 1st paragraph; p. 7, line 9-12 and last paragraph). In other words, one skilled in the art would have known that pharmaceutical formulation of cocrystals is highly dependent upon formulation variables. While the level of skilled in the art with respect to forming a pharmaceutical composition would have been high, there is lack of predictability surrounding cocrystal behavior in manufacturing the claimed genus of pharmaceutical composition.
(6, 7, 8) The amount of guidance given, the presence of working example and the quantitation
of experimentation required:
In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the claimed invention. Although the specification generally describes pharmaceutical compositions and lists numerous pharmaceutical acceptable excipients (see e.g., page 23, line 10-18 of the specification), it fails to teach how to formulate the full scope of the claimed cocrystal genus in a pharmaceutical composition while maintaining the claimed cocrystal in the presence of the broad range of excipients and dosage forms. In this case, the breadth of claim 48 is substantial, the specification provides only general guidance regarding pharmaceutical formulations, and the quantity of experimentation required to identify suitable excipients and formulation conditions that preserve the claimed cocrystal throughout the full scope of the claim would be undue in view of the unpredictability of pharmaceutical cocrystal behavior during formulation and dissolution.
Accordingly, one of ordinary skill in the art would be required to engage in substantial experimentation to identify compatible excipients and formulation conditions capable of preserving the claimed cocrystal across the full scope of pharmaceutical compositions encompassed by claim 48. Because the specification provides only generalized formulation guidance and does not teach how to formulate the full scope of the claimed pharmaceutical compositions without loss of the claimed cocrystal, the specification does not enable the full scope of claim 48 without undue experimentation.
Claims 4-5, 9-10, 12, 14, 17-19, 48 and 55-56 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, 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 claimed invention.
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
In this case, instant claims promise a broad genus cocrystal of a compound of formula (I):
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and fumaric acid. The specification defines the claimed term "cocrystal(s)" to encompass hydrates, solvates, and clathrates (see e.g., p. 7, line 32 to p. 8, line 4), and further recognizes that different crystalline forms may possess different crystal lattices (e.g., unit cells) and different physical properties (see e.g., p. 8, line 5-9). Therefore, Applicant's own disclosure contemplates a genus of distinct crystalline forms.
In contrast, the specification does not reasonably convey to one of ordinary skill in the art that Applicant was in possession of the full scope of the claimed cocrystal. The instant specification only exemplified a single representative cocrystal species, i.e., a cocrystal of a compound of formula (I) and fumaric acid referred to therein as “Form 1” having an X-ray powder diffraction pattern described in Table 1 and Fig. 2; thermogravimetric analysis in Fig. 4; dynamic vapor sorption in Fig. 8; and endotherm in Fig. 3. Said cocrystal species is also described therein to have an equimolar of compound of formula (I) and fumaric acid, i.e., a molar ratio of 1:1 (see e.g., p. 39, line 1-5 of instant specification); and the preparations of said cocrystal species is further described in Example 2. In other words, while applicant is in possession of the Form 1 noted above, the specification fails to identify any other particular cocrystal species, any particular hydrate forms, solvate forms, and clathrate forms coupled with their physical properties. Although applicant does not have to exemplify each and every possible species of cocrystal of a compound of formula (I) and fumaric acid to satisfy the written description requirement, applicant needs to provide enough representative species from different corners of the range to represent the claimed genus fairly. Since the instant claim pertain to a cocrystal genus, including a wide variety of cocrystals with different crystal lattices and physical properties, applicant must provide a reasonable sampling of them so that a relevant artisan can see applicant truly envisioned the whole genus.
To the extent that the limitation(s) as claimed in claims 5, 9-10, 12, 14, 17-19, 55 and 56 are referring to a hydrate, solvate, or clathrate as broadly encompassed by the claimed term “cocrystal”, the specification provide no guidance identifying which hydrates, solvates, and clathrates of cocrystal can retain the same characteristic(s) claimed, including the claimed X-ray powder diffraction pattern, endotherm transition, thermogravimetric analysis, and dynamic vapor sorption; nor provides any guidance for preparing these particular hydrates, solvates, and clathrate without changing their stoichiometric ratio of 1:1 and their physical characteristic(s). Therefore, applicant is not in possession of the full scope of “cocrystal” coupled with the claimed physical or structural characteristic(s).
With respect to claim 48, the claim incorporates by dependency the broad cocrystal genus of claim 4. Since the specification does not reasonably convey to one skilled in the art that applicant was in possession of the full scope of that cocrystal genus for the reasons set forth above, the claimed pharmaceutical composition which contains the same scope of cocrystal genus also does not reasonably convey to one skilled in the art that applicant is in possession of the full scope of pharmaceutical composition.
Accordingly, the specification does not reasonably convey possession of the full scope of the claims.
Response to Arguments
Applicant's arguments filed on May 14, 2026 with respect the rejection of claims 4-5, 9 and 48 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement have been fully considered but they are not persuasive. Upon further consideration and in light of the claim amendments, the rejection has been revisited and modified for the reasons set forth above.
Applicant newly added claims 55-56, and that necessitate a modification of the rejection of record.
In Summary, applicant argues there is no requirement to disclose every possible cocrystal of a compound of formula (I) and fumaric acid to satisfy the written description requirement, because every cocrystal of a compound of formula (I) and fumaric acid shares this formula; and, based on the formula, a person of ordinary skill in the art using routine techniques would have been able to recognize any species of the cocrystal and distinguish it from other cocrystals, thereby permitting them to recognize the identity of the members of the genus. Applicant further argues one of ordinary skill in the art would have been able to use the disclosed XRPD characteristics, combined with the defined structural features of the cocrystal disclosed in the specification to identify the characteristics of the claimed genus. Applicant further argues to satisfy the written description requirement, there is no requirement for a claim to recites sufficient information to meet an arbitrary standard to solve the crystal structure, and there is no legal authority establishing that a minimum number of XRPD peaks is required.
In response, applicant’s arguments are not found persuasive. The mere fact that the instant specification states the term “cocrystal(s)”, encompass hydrates, solvates and clathrates (see e.g., p. 7, line 32 to p. 8, line 4), and recognized that different crystalline forms of the same substance may possess different crystal lattices (e.g., unit cells) and different physical properties (see e.g., p. 8, line 5-9), it does not reasonably convey to one skilled in the relevant art that applicant is in possession of the full scope of cocrystal genus, including each and every distinct crystalline forms as broadly encompassed by the instant claim(s). As noted in the rejection above, the claims are drawn to a genus of cocrystal; However, the disclosure only exemplified a single representative cocrystal species (“Form 1” at Table 1, Fig. 2-4, and 8 of the specification). A person skilled in the art would recognize that different cocrystals with the same chemical formula (i.e., formula (I) and fumaric acid) can exhibits different physical and chemical properties due to polymorphism, different stoichiometric ratios, or varying internal crystal packing arrangement; and that single cocrystal species “Form 1” disclosed by Applicant is not representative of the genus claimed which embraces vast variety of crystalline forms such as hydrates, solvates and clathrates with any distinct properties. Since applicant only describe a single species of cocrystal (i.e., “Form 1”), there may be unpredictability in the results obtained from species other than those specifically enumerated. Although applicant does not have to exemplify each and every possible species of cocrystal of a compound of formula (I) and fumaric acid to satisfy the written description requirement, applicant needs to provide enough representative species from different corners of the range to represent the claimed genus fairly. Given that the cocrystal formation is highly unpredictable and there is no reason to expect, nor is it possible to predict, that the full scope of cocrystal as broadly encompassed by the claims will all have the same physical properties instantly claimed, e.g., molar ratio and X-ray powder diffraction pattern. The specification fails to identify which hydrates, solvates, and clathrates of cocrystal can retain the same characteristic(s) claimed, including the claimed X-ray powder diffraction pattern, endotherm transition, thermogravimetric analysis, and dynamic vapor sorption; nor provides any guidance for preparing these particular hydrates, solvates, and clathrate without changing their stoichiometric ratio of 1:1 and their physical characteristic(s). Therefore, while applicant disclosed a single X-ray powder diffraction pattern associated with the Form 1, it is not sufficient to represent the claimed genus.
In addition, while applicant is in possession of the Form 1 noted above, the claim(s) only reciting its chemical formula (i.e., formula(I) and fumaric acid) or the chemical formula in addition to a molar ratio without any characteristics (e.g., X-ray powder diffraction pattern) are not sufficient to identify this specific cocrystal species (“Form 1”). In other words, having a sufficient number of peaks in the X-ray powder diffraction pattern is often required for one of ordinary skill in the art to distinguish the cocrystal species. That being said, instant claim(s) are drawn to a genus of distinct crystalline forms that lacks adequate description support, thus, applicant’s argument are not found persuasive.
Claim Rejections - 35 USC § 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 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 4 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Samajdar et al. (WO 2016/193939 A1; cited in the IDS filed on 1/24/2024), in view of Yang et al. (ACS Omega, 2020. Vol. 5(14): 8283-8292).
Samajdar et al. teaches a compound 44, (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl) amino)-3-methyl-1-oxobutan-2-yl) phenyl) pyridin-2-yl)-4-morpholinobut-2-enamide, having the structure of:
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, or a pharmaceutically acceptable salt or a stereoisomer thereof is an exemplary compound of formula (I) useful for inhibiting CDK7 kinase activity ; and for treating diseases and/or disorders mediated by selective transcriptional CDKs selected from the group consisting of, inter alia, a cancer, an inflammatory disorder, an auto-inflammatory disorder and an infectious disease (see e.g., p. 25, Compound No. 44; p. 28, last line; p. 102, 1st line under the “biochemical assay for CDK7” section; and Table 5; claims 25-26). Samajdar et al. further teaches a pharmaceutical composition comprising the compound 44 or a pharmaceutically acceptable salt or a stereoisomer thereof and at least one pharmaceutically acceptable excipient (see e.g., claims 17-18). Samajdar et al. further teaches the term "stereoisomers" refers to any enantiomers, diastereoisomers, or geometrical isomers of the compounds of Formula (I), (IA), (IB), (IC), (ID), (IE), (IF) and (IG), wherever they are chiral or when they bear one or more double bonds; when the compounds of the formula (I), (IA), (IB), (IC), (ID), (IE), (IF) and (IG) are chiral, they can exist in racemic or in optically active form; individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art; and the present invention includes all isomers as well as the appropriate mixtures thereof (see e.g., p. 9, line 22 to p. 10, line 9).
Samajdar et al. does not teach the cocrystal species of a compound of formula (I) and fumaric acid.
Yang et al. teaches cocrystal formation is a recent research focus that seeks to improve the solubility of insoluble or slightly soluble drugs; cocrystals can not only improve the solubility but also have a positive impact on stability by introducing an appropriate cocrystal former (CCF) (see e.g., p. 8283, right column, line 4-8). Yang et al. further teaches fumaric acid (FA) is a typical CCF which is commonly used as pharmaceutical excipient in pharmaceutical field (see e.g., p. 8284, left column, line 4-5). Yang et al. further teaches berberine (BB) was found to have a wide range of pharmacological activities, such as antimicrobial, anti-inflammatory, and antitumor activities (see e.g., p. 8283, left column, 1st paragraph); However, low bioavailability due to low water solubility seriously limits its further clinical use; and clinical application of berberine is mostly as chloride salt, but the actual solubility is still not ideal (see e.g., p. 8283, left column, 2nd paragraph). Yang et al. further teaches a total of 33 related crystal structures of BB were retrieved; only six cocrystals are of BBC, and the rest are BB salts and their hydrates (see e.g., p. 8283, right column, 2nd paragraph). Yang et al. further teaches the slurry method and recrystallization were chosen to form cocrystal of BBC with fumaric acid (see e.g., p. 8284, left column, “2.1. synthesis and crystallization”). Yang et al. further teaches different technical methods were performed for the characterization and structural analysis of this new cocrystal, such as single-crystal X-ray diffraction (SXRD), powder X-ray diffraction (PXRD), thermogravimetry (TG), and differentia scanning calorimetry (DSC), and dynamic vapor sorption (DVS) (see e.g., p. 8284, left column, line 8-17).
In the present case, the difference between the compound 44 of Samajdar et al. and the claimed invention is that the prior art compound is a racemic rather than an individual stereoisomer claimed, and it is not a cocrystal form with fumaric acid; However, Samajdar et al. teaches compound 44 can exists in racemic form, and individual stereoisomers of said compound can be obtained by preparation of mixtures of enantiomeric products followed by separation. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by separating the individual stereoisomers of compound 44 of Samajdar et al., and then form a cocrystal of each stereoisomer with fumaric acid as the appropriate cocrystal former as taught by of Yang et al. One would have been motivated to do so, because the compound 44 of Samajdar et al., including individual stereoisomers, and berberine of Yang et al. are each taught by the prior art to have anti-inflammatory and antitumor activities; and Yang et al. teaches cocrystal formation is routinely employed to improve solubility and stability of an active pharmaceutical ingredient, and fumaric acid is a typical cocrystal former that can be employed in slurry method and recrystallization for preparing new cocrystals, and said cocrystal can be characterized, including SXRD, PXRD, TG and DSC. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the known active pharmaceutical ingredient together with fumaric acid using routine cocrystallization techniques can successfully identify pharmaceutical useful crystalline forms possessing improved solid-state properties, such as solubility or stability.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed.
Claims 4-5 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Samajdar et al. (WO 2016/193939 A1; cited in the IDS filed on 1/24/2024), in view of Yang et al. (ACS Omega, 2020. Vol. 5(14): 8283-8292) as applied to claims 4 and 48 above, and further in view of Orola et al. (CrystEngComm, 2009. Vol. 11(3): 415).
The teachings of Samajdar et al. and Yang et al. are set forth above and applies as before.
Samajdar et al. and Yang et al. does not teach molar ratio of compound of formula (I) to fumaric acid is 1:1 as claimed in claim 5.
Orola et al. teaches cocrystal synthesis may be achieved using stoichiometric amounts of the cocrystal formers (see e.g., p. 415, first paragraph). Orola et al. further teaches cocrystals with different stoichiometries can have different physical properties; For example, nicotinamide (nc) and fumaric acid (fa) cocrystals with two different stoichiometries, nic-fa (1 : 1) cocrystals and nic-fa (2 : 1) cocrystals, each has a unique powder pattern (see e.g., p. 415, 2nd paragraph); and the melting point of nic-fa (1 : 1) is higher than nic-fa (2 : 1), and would be expected to be thermally more stable (see e.g., p. 417, left column, last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by modifying the stoichiometric ratio of the cocrystal of Samajdar et al. and Yang et al. set forth above through routine optimization, because Orola et al. demonstrates that the ratio itself is a result-effective-variable during pharmaceutical cocrystal screening because different stoichiometries produce different physical properties, including thermal stability. Accordingly, optimizing the API-to-coformer ratio, including evaluating the conventional equimolar (1:1) ratio, would have been routine. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed equimolar ratio, because Orola demonstrates that equimolar (1:1) stoichiometry is one of the conventional stoichiometries successfully employed in pharmaceutical cocrystal formation, and that varying the stoichiometric ratio is a routine means of optimizing solid-state properties. One would have reasonably recognized that the equimolar ratio (1:1) is one of the stoichiometric ratios routinely explored during cocrystal synthesis to identify cocrystals possessing improved physical properties, such as satiability.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed.
Response to Arguments
Applicant’s arguments, see page 10-12, filed on May 14, 2026, with respect to the rejection(s) of claims 4-5 and 48 under 35 U.S.C. 103 as being unpatentable over Samajdar et al. (WO 2016/193939 A1), in view of Gupta et al. (Molecules [Basel, Switzerland], 2018. Vol. 23, 7:1 719), as evidenced by Anderson (Academic Press, 2012: pp. 329-364) have been fully considered.
In Summary, applicant argues salt formation is distinct from cocrystal formation, and the fumarate taught by Gupta et al. is a counterion for salt formation rather than a cocrystal conformer. Applicant further argues while Samajdar et al. teaches a racemic compound in Example 44, the prior art does not refer to any specific stereoisomer nor indicate a preference for one stereochemical configuration over another; thus, one would not have selected the specific (S)-enantiomer of compound 44. Applicant further argues the claimed invention demonstrate unexpectedly improved stability, purity, and hygroscopicity compared to the free form of the compound of formula (I).
In response, applicant’s arguments with respect to Gupta et al. have been fully considered and are found persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Samajdar et al. (WO 2016/193939 A1) and Yang et al. (ACS Omega, 2020. Vol. 5(14): 8283-8292) for the reason set forth below and for the reasons set forth herein.
While applicant’s arguments with respect to Gupta et al. are found persuasive, applicant’s arguments with respect to Samajdar et al. are not found persuasive. According to MPEP 2141.02, “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004)”. Same logic is applicable to instant product claim(s), the mere fact that Samajdar et al. teaches compound species other than compound of Example 44 and/or other stereoisomers that are contemplated for use in the claimed invention, it does not constitute a teaching away from incorporating any individual stereoisomers of compound of Example 44 (referred to herein as “Compound 44”) because such disclosure does not criticize, discredit, or otherwise discourage the incorporation of any individual stereoisomers. In fact, MPEP 2141.02 states: “[a] prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention”; and in present case, Samajdar et al. clearly teaches the compounds of the formula (I), including compound 44, can exist in racemic, and individual stereoisomers of the compound can be prepared by preparation of mixture of enantiomeric products followed by separation (see e.g., p. 9, line 22 to p. 10, line 9). In other words, there is clearly a suggestion in the prior art to include each individual stereoisomers of compound 44.
In addition, Applicant’s assertion of unexpected results (“the cocrystal of claim 4 exhibits unexpectedly improved stability, purity, and hygroscopicity compared to the free form of the compound of formula (I)”, see page 12, line 23-25 of the reply) is not commensurate in scope with the claimed invention. It is respectfully noted that applicant does not particularly point out which working examples disclosed therein demonstrate these unexpected results. For instance, Example 5 compares the solubility of compound of formula (I) free base and compound of formula (I) fumarate, but does not specifically indicate whether the “compound of formula (I) fumarate” is referring to a fumarate salt of compound of formula (I) or cocrystal of compound of formula (I) and fumaric acid (see e.g., p. 40 of the specification). It is further noted that the term “formula (I) fumarate” in step-6 of Example 1 is referring to salt formation of formula (I) and fumarate, which was then used in Example 2 for crystallization. To the extent that applicant is referring to Example 4 disclosed in the specification, the cocrystal of formula (I) fumarate referred therein is drawn to “Form I” (see e.g., p. 4, Fig.6A, 6B and 7-8), and that “Form 1” has an X-ray powder diffraction pattern described in Table 1 and Fig. 2; thermogravimetric analysis in Fig. 4; dynamic vapor sorption in Fig. 8; and endotherm in Fig. 3.
According to MPEP 716.02(d), “whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the ‘objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support.’ In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980)”.
In the present case, instant claim 4 promise a broad genus cocrystal of a compound of formula (I) and fumaric acid. The specification defines the claimed term "cocrystal(s)" to encompass hydrates, solvates, and clathrates (see e.g., p. 7, line 32 to p. 8, line 4), and further recognizes that different crystalline forms may possess different crystal lattices (e.g., unit cells) and different physical properties (see e.g., p. 8, line 5-9). Therefore, the instant claims pertain to a full genus of distinct crystalline forms.
In contrast, Applicant expressly defines “cocrystal(s)” to encompass hydrates, solvates, and clathrates, and further recognizes that different crystalline forms possess different crystal lattices and physical properties. Therefore, claim 4 encompasses a genus of distinct crystalline forms, whereas the relied-upon evidence pertains to only Form 1.
Upon further consideration, a new ground of rejection is made for the reasons set forth herein.
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 4-5 and 48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7 and 12 of U.S. Patent No. 10,689,347 B2 (reference patent) in view of Yang et al. (ACS Omega, 2020. Vol. 5(14): 8283-8292) and Orola et al. (CrystEngComm, 2009. Vol. 11(3): 415).
The claims of the reference patent are drawn to a compound having the structure:
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or a pharmaceutically acceptable salt, or an enantiomer thereof; which the compound is an enantiomer of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide or a pharmaceutically acceptable salt thereof; and a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier or excipient.
The claims of the reference patent do not teach the cocrystal species of a compound of formula (I) and fumaric acid. The claims of the reference patent also do not teach the molar ratio of compound of formula (I) to fumaric acid is 1:1 as claimed in claim 5.
Yang et al. teaches cocrystal formation is a recent research focus that seeks to improve the solubility of insoluble or slightly soluble drugs; cocrystals can not only improve the solubility but also have a positive impact on stability by introducing an appropriate cocrystal former (CCF) (see e.g., p. 8283, right column, line 4-8). Yang et al. further teaches fumaric acid (FA) is a typical CCF which is commonly used as pharmaceutical excipient in pharmaceutical field (see e.g., p. 8284, left column, line 4-5). Yang et al. further teaches berberine (BB) was found to have a wide range of pharmacological activities, such as antimicrobial, anti-inflammatory, and antitumor activities (see e.g., p. 8283, left column, 1st paragraph); However, low bioavailability due to low water solubility seriously limits its further clinical use; and clinical application of berberine is mostly as chloride salt, but the actual solubility is still not ideal (see e.g., p. 8283, left column, 2nd paragraph). Yang et al. further teaches a total of 33 related crystal structures of BB were retrieved; only six cocrystals are of BBC, and the rest are BB salts and their hydrates (see e.g., p. 8283, right column, 2nd paragraph). Yang et al. further teaches the slurry method and recrystallization were chosen to form cocrystal of BBC with fumaric acid (see e.g., p. 8284, left column, “2.1. synthesis and crystallization”). Yang et al. further teaches different technical methods were performed for the characterization and structural analysis of this new cocrystal, such as single-crystal X-ray diffraction (SXRD), powder X-ray diffraction (PXRD), thermogravimetry (TG), and differentia scanning calorimetry (DSC), and dynamic vapor sorption (DVS) (see e.g., p. 8284, left column, line 8-17).
Orola et al. teaches cocrystal synthesis may be achieved using stoichiometric amounts of the cocrystal formers (see e.g., p. 415, first paragraph). Orola et al. further teaches cocrystals with different stoichiometries can have different physical properties; For example, nicotinamide (nc) and fumaric acid (fa) cocrystals with two different stoichiometries, nic-fa (1 : 1) cocrystals and nic-fa (2 : 1) cocrystals, each has a unique powder pattern (see e.g., p. 415, 2nd paragraph); and the melting point of nic-fa (1 : 1) is higher than nic-fa (2 : 1), and would be expected to be thermally more stable (see e.g., p. 417, left column, last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by forming a cocrystal of each enantiomer of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl) amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide of reference patent with fumaric acid as the appropriate cocrystal former as taught by of Yang et al. One would have been motivated to do so, because the reference patent teaches the compound can be an enantiomer; and Yang et al. teaches cocrystal formation is routinely employed to improve solubility and stability of an active pharmaceutical ingredient, and fumaric acid is a typical cocrystal former that can be employed in slurry method and recrystallization for preparing new cocrystals, and said cocrystal can be characterized, including SXRD, PXRD, TG and DSC. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the known active pharmaceutical ingredient together with fumaric acid using routine cocrystallization techniques can successfully identify pharmaceutical useful crystalline forms possessing improved solid-state properties, such as solubility or stability;
Regarding the limitation of “wherein molar ratio of compound of formula (I) to fumaric acid is 1:1” in claim 2, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by modifying the stoichiometric ratio of the cocrystal of reference patent and Yang et al. set forth above through routine optimization, because Orola et al. teaches cocrystals with different stoichiometries can have different physical properties, and demonstrates fumaric acid can successfully form cocrystals with nicotinamide as an active pharmaceutical ingredient at multiple stoichiometric ratios, including 1:1 and 2:1, in which 1 : 1 ratio is thermally more stable. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed equimolar ratio, because one would have reasonably recognized that the equimolar ratio (1:1) is one of the stoichiometric ratios routinely explored during cocrystal synthesis to identify cocrystals possessing improved physical properties, such as satiability.
Therefore, the nonstatutory double patenting rejection applies.
Response to Arguments
Applicant's arguments filed on May 14, 2026 with respect to the rejection of claims 4-5 and 48 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7 and 12 of U.S. Patent No. 10,689,347 B2, in view of Gupta et al. (Molecules [Basel, Switzerland], 2018. Vol. 23, 7:1 719), as evidenced by Anderson (Academic Press, 2012: pp. 329-364) have been fully considered. Applicant’s arguments with respect to Gupta et al. are found persuasive; therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Yang et al. (ACS Omega, 2020. Vol. 5(14): 8283-8292) and Orola et al. (CrystEngComm, 2009. Vol. 11(3): 415) for the reasons set forth herein.
Claims 4-5 and 48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 8, 10, 14-15 of U.S. Patent No. 12,331,023 B2 (reference patent) in view of Yang et al. (ACS Omega, 2020. Vol. 5(14): 8283-8292), Orola et al. (CrystEngComm, 2009. Vol. 11(3): 415) and Samajdar et al. (WO 2016/193939 A1).
The claims of the reference patent are drawn to a method of preparing a compound of formula (IC-1), including compound 44: (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide having the structure of:
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, and further comprising isolating an enantiomer of (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide (see e.g., claim 15).
The claims of the reference application does not teach the cocrystal species of a compound of formula (I) and fumaric acid. The claims of the reference application also does not teach the molar ratio of compound of formula (I) to fumaric acid is 1:1 as claimed in claim 5. The claims of the reference application does not teach one or more pharmaceutically acceptable excipients as claimed in claim 48.
Yang et al. teaches cocrystal formation is a recent research focus that seeks to improve the solubility of insoluble or slightly soluble drugs; cocrystals can not only improve the solubility but also have a positive impact on stability by introducing an appropriate cocrystal former (CCF) (see e.g., p. 8283, right column, line 4-8). Yang et al. further teaches fumaric acid (FA) is a typical CCF which is commonly used as pharmaceutical excipient in pharmaceutical field (see e.g., p. 8284, left column, line 4-5). Yang et al. further teaches berberine (BB) was found to have a wide range of pharmacological activities, such as antimicrobial, anti-inflammatory, and antitumor activities (see e.g., p. 8283, left column, 1st paragraph); However, low bioavailability due to low water solubility seriously limits its further clinical use; and clinical application of berberine is mostly as chloride salt, but the actual solubility is still not ideal (see e.g., p. 8283, left column, 2nd paragraph). Yang et al. further teaches a total of 33 related crystal structures of BB were retrieved; only six cocrystals are of BBC, and the rest are BB salts and their hydrates (see e.g., p. 8283, right column, 2nd paragraph). Yang et al. further teaches the slurry method and recrystallization were chosen to form cocrystal of BBC with fumaric acid (see e.g., p. 8284, left column, “2.1. synthesis and crystallization”). Yang et al. further teaches different technical methods were performed for the characterization and structural analysis of this new cocrystal, such as single-crystal X-ray diffraction (SXRD), powder X-ray diffraction (PXRD), thermogravimetry (TG), and differentia scanning calorimetry (DSC), and dynamic vapor sorption (DVS) (see e.g., p. 8284, left column, line 8-17).
Orola et al. teaches cocrystal synthesis may be achieved using stoichiometric amounts of the cocrystal formers (see e.g., p. 415, first paragraph). Orola et al. further teaches cocrystals with different stoichiometries can have different physical properties; For example, nicotinamide (nc) and fumaric acid (fa) cocrystals with two different stoichiometries, nic-fa (1 : 1) cocrystals and nic-fa (2 : 1) cocrystals, each has a unique powder pattern (see e.g., p. 415, 2nd paragraph); and the melting point of nic-fa (1 : 1) is higher than nic-fa (2 : 1), and would be expected to be thermally more stable (see e.g., p. 417, left column, last paragraph).
Samajdar et al. teaches a compound 44, (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl) amino)-3-methyl-1-oxobutan-2-yl) phenyl) pyridin-2-yl)-4-morpholinobut-2-enamide, having the structure of:
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useful for treating diseases and/or disorders mediated by selective transcriptional CDKs selected from the group consisting of, inter alia, a cancer (see e.g., p. 25, Compound No. 44; p. 28, last line; p. 102, 1st line under the “biochemical assay for CDK7” section; and Table 5; claims 25-26); and a pharmaceutical composition comprising the compound 44 or a pharmaceutically acceptable salt or a stereoisomer thereof and at least one pharmaceutically acceptable excipient (see e.g., claims 17-18). Samajdar et al. further teaches the term "stereoisomers" refers to any enantiomers, diastereoisomers, or geometrical isomers of the compounds (see e.g., p. 9, line 22 to p. 10, line 9).
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by forming a cocrystal of each enantiomer of Compound 44 of reference patent with fumaric acid as the appropriate cocrystal former as taught by of Yang et al. One would have been motivated to do so, because the reference patent teaches the compound can be an enantiomer; and Yang et al. teaches cocrystal formation is routinely employed to improve solubility and stability of an active pharmaceutical ingredient, and fumaric acid is a typical cocrystal former that can be employed in slurry method and recrystallization for preparing new cocrystals, and said cocrystal can be characterized, including SXRD, PXRD, TG and DSC. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the known active pharmaceutical ingredient together with fumaric acid using routine cocrystallization techniques can successfully identify pharmaceutical useful crystalline forms possessing improved solid-state properties, such as solubility or stability.
Regarding the limitation of “wherein molar ratio of compound of formula (I) to fumaric acid is 1:1” in claim 2, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by modifying the stoichiometric ratio of the cocrystal of reference patent and Yang et al. set forth above through routine optimization, because Orola et al. teaches cocrystals with different stoichiometries can have different physical properties, and demonstrates fumaric acid can successfully form cocrystals with nicotinamide as an active pharmaceutical ingredient at multiple stoichiometric ratios, including 1:1 and 2:1, in which 1 : 1 ratio is thermally more stable. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed equimolar ratio, because one would have reasonably recognized that the equimolar ratio (1:1) is one of the stoichiometric ratios routinely explored during cocrystal synthesis to identify cocrystals possessing improved physical properties, such as satiability.
Regarding claim 48, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by combining the cocrystal of reference patent and Yang et al. set forth above with one or more pharmaceutically acceptable excipients, because Samajdar et al. teaches stereoisomer of compound 44, including enantiomers, and at least one pharmaceutically acceptable excipient can arrive at a pharmaceutical composition useful for treating cancer. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the cocrystal of reference application and Yang et al. and one or more pharmaceutically acceptable excipients can successfully arrive at a pharmaceutical composition.
This is a provisional nonstatutory double patenting rejection.
Claims 4-5 and 48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 18, 22, 40 and 42 of copending Application No. 18/564,384 (reference application) in view of Yang et al. (ACS Omega, 2020. Vol. 5(14): 8283-8292), Orola et al. (CrystEngComm, 2009. Vol. 11(3): 415), and Samajdar et al. (WO 2016/193939 A1).
The claims of the reference application is drawn a method of treating and/or preventing cancer in a subject, comprising administering to the subject a compound of formula (Ib), including Compound 44A: (S)-(E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl)amino)-3-methyl-1-oxobutan-2-yl)phenyl)pyridin-2-yl)-4-morpholinobut-2-enamide.
The claims of the reference application does not teach the cocrystal species of a compound of formula (I) and fumaric acid. The claims of the reference application also does not teach the molar ratio of compound of formula (I) to fumaric acid is 1:1 as claimed in claim 5. The claims of the reference application does not teach one or more pharmaceutically acceptable excipients as claimed in claim 48.
Yang et al. teaches cocrystal formation is a recent research focus that seeks to improve the solubility of insoluble or slightly soluble drugs; cocrystals can not only improve the solubility but also have a positive impact on stability by introducing an appropriate cocrystal former (CCF) (see e.g., p. 8283, right column, line 4-8). Yang et al. further teaches fumaric acid (FA) is a typical CCF which is commonly used as pharmaceutical excipient in pharmaceutical field (see e.g., p. 8284, left column, line 4-5). Yang et al. further teaches berberine (BB) was found to have a wide range of pharmacological activities, such as antimicrobial, anti-inflammatory, and antitumor activities (see e.g., p. 8283, left column, 1st paragraph); However, low bioavailability due to low water solubility seriously limits its further clinical use; and clinical application of berberine is mostly as chloride salt, but the actual solubility is still not ideal (see e.g., p. 8283, left column, 2nd paragraph). Yang et al. further teaches a total of 33 related crystal structures of BB were retrieved; only six cocrystals are of BBC, and the rest are BB salts and their hydrates (see e.g., p. 8283, right column, 2nd paragraph). Yang et al. further teaches the slurry method and recrystallization were chosen to form cocrystal of BBC with fumaric acid (see e.g., p. 8284, left column, “2.1. synthesis and crystallization”). Yang et al. further teaches different technical methods were performed for the characterization and structural analysis of this new cocrystal, such as single-crystal X-ray diffraction (SXRD), powder X-ray diffraction (PXRD), thermogravimetry (TG), and differentia scanning calorimetry (DSC), and dynamic vapor sorption (DVS) (see e.g., p. 8284, left column, line 8-17).
Orola et al. teaches cocrystal synthesis may be achieved using stoichiometric amounts of the cocrystal formers (see e.g., p. 415, first paragraph). Orola et al. further teaches cocrystals with different stoichiometries can have different physical properties; For example, nicotinamide (nc) and fumaric acid (fa) cocrystals with two different stoichiometries, nic-fa (1 : 1) cocrystals and nic-fa (2 : 1) cocrystals, each has a unique powder pattern (see e.g., p. 415, 2nd paragraph); and the melting point of nic-fa (1 : 1) is higher than nic-fa (2 : 1), and would be expected to be thermally more stable (see e.g., p. 417, left column, last paragraph).
Samajdar et al. teaches a compound 44, (E)-N-(5-(3-(1-((5-cyclopropyl-1H-pyrazol-3-yl) amino)-3-methyl-1-oxobutan-2-yl) phenyl) pyridin-2-yl)-4-morpholinobut-2-enamide, having the structure of:
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useful for treating diseases and/or disorders mediated by selective transcriptional CDKs selected from the group consisting of, inter alia, a cancer (see e.g., p. 25, Compound No. 44; p. 28, last line; p. 102, 1st line under the “biochemical assay for CDK7” section; and Table 5; claims 25-26); and a pharmaceutical composition comprising the compound 44 or a pharmaceutically acceptable salt or a stereoisomer thereof and at least one pharmaceutically acceptable excipient (see e.g., claims 17-18). Samajdar et al. further teaches the term "stereoisomers" refers to any enantiomers, diastereoisomers, or geometrical isomers of the compounds (see e.g., p. 9, line 22 to p. 10, line 9).
It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by forming a cocrystal of Compound 44A of reference application with fumaric acid as the appropriate cocrystal former as taught by of Yang et al. One would have been motivated to do so, because Yang et al. teaches cocrystal formation is routinely employed to improve solubility and stability of an active pharmaceutical ingredient, and fumaric acid is a typical cocrystal former that can be employed in slurry method and recrystallization for preparing new cocrystals, and said cocrystal can be characterized, including SXRD, PXRD, TG and DSC. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the known active pharmaceutical ingredient together with fumaric acid using routine cocrystallization techniques can successfully identify pharmaceutical useful crystalline forms possessing improved solid-state properties, such as solubility or stability.
Regarding the limitation of “wherein molar ratio of compound of formula (I) to fumaric acid is 1:1” in claim 2, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by modifying the stoichiometric ratio of the cocrystal of reference application and Yang et al. set forth above through routine optimization, because Orola et al. teaches cocrystals with different stoichiometries can have different physical properties, and demonstrates fumaric acid can successfully form cocrystals with nicotinamide as an active pharmaceutical ingredient at multiple stoichiometric ratios, including 1:1 and 2:1, in which 1 : 1 ratio is thermally more stable. One would have a reasonable expectation of success to arrive at the claimed invention through routine optimization, including the claimed equimolar ratio, because one would have reasonably recognized that the equimolar ratio (1:1) is one of the stoichiometric ratios routinely explored during cocrystal synthesis to identify cocrystals possessing improved physical properties, such as satiability.
Regarding claim 48, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to arrive at the claimed invention by combining the cocrystal of reference application and Yang et al. set forth above with one or more pharmaceutically acceptable excipients, because Samajdar et al. teaches stereoisomer of compound 44, including enantiomers, and at least one pharmaceutically acceptable excipient can arrive at a pharmaceutical composition useful for treating cancer. One would have a reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the cocrystal of reference application and Yang et al. and one or more pharmaceutically acceptable excipients can successfully arrive at a pharmaceutical composition.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
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