HETEROAROMATIC MACROCYCLIC ETHER CHEMOTHERAPEUTIC AGENTS

§112 §DOUBLEPATENT

DETAILED ACTION Notice of Pre-AIA or AIA Status The inventor or joint inventor should note that the instant invention, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . Status of the Claims Claims 26, 27, 29 and 31-57 are pending in the instant invention. According to the Amendments to the Claims, filed September 4, 2026, claims 1-25, 28 and 30 were cancelled and claim 57 was added. Status of Priority This invention is a Divisional (DIV) of US Application No. 17/834,135, filed June 7, 2022 and now US 12,054,498, which is a Divisional (DIV) of US Application No. 17/514,877, filed October 29, 2021 and now US 11,542,278, which is a Continuation (CON) of International Application No. PCT/US2021/030842, filed May 5, 2021, which claims priority under 35 U.S.C. § 119(a-d) to International Application No. PCT/CN2020/088590, filed May 5, 2020, and under 35 U.S.C. § 119(e) to US Provisional Application No. 63/125,733, filed December 15, 2020. Restrictions / Election of Species PNG media_image1.png 200 400 media_image1.png Greyscale The inventor’s or joint inventor’s provisional election of the following, without traverse, in the reply filed on September 4, 2026, is acknowledged: a) Group I - claims 26, 29 and 31-57; and b) substituted macrocycle of Formula (I) - p. 245, Example 85, shown to the right below, and hereafter referred to PNG media_image2.png 200 400 media_image2.png Greyscale PNG media_image3.png 200 400 media_image3.png Greyscale PNG media_image4.png 200 400 media_image4.png Greyscale as (R)-1-chloro-3-(cyclopropylmethyl)-12-fluoro-10,16-dimethyl-3,10,16,18-tetrahydro-4,8-(metheno)benzo[l]pyrazolo[3,4-g][1,2,3]triazolo[4,5-j][1]oxa[4]azacyclotetradecin-7-amine, where Q = CH; R1 = -CH3; X is shown to the right, wherein, at C-1, R2 = -Cl and at N3, R2 = -CH2-cyclopropyl; Y is shown to the left below, wherein R3 = - CH3; R4 = -F; and Z = -CR5, wherein R5 = -H. Claims 26, 29, 31-49 and 53 read on the elected species. Affirmation of this election must be made by the inventor or joint inventor in replying to this Office action. Similarly, the inventor or joint inventor should further note that the requirement is still deemed proper and is therefore made FINAL. Likewise, the inventor or joint inventor should further note that the elected species, shown to the right above, was found to be free of the prior art. Thus, the examiner has expanded the forthcoming prosecution to include all claims relevant to the genus of Group I, for a first Office action and prosecution on the merits. Moreover, the inventor or joint inventor should further note that claim 27 was withdrawn from further consideration, pursuant to 37 CFR 1.142(b), as being drawn to a nonelected or cancelled invention, there being no allowable generic or linking claim. Thus, a first Office action and prosecution on the merits of claims 26, 29 and 31-57 is contained within. Specification Objection - Disclosure The inventor or joint inventor is advised to format the specification according to 37 CFR 1.77(c). Revisions should particularly address bold-type, underline, and/or upper case formatting. Appropriate correction may be required. Claim Objections Claim 26 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), the existing recitation should be replaced with the following recitation: A method for selectively inhibiting c-ros avian UR2 sarcoma virus oncogene homolog 1 (ROS1) over tropomyosin receptor kinase (TRK) in a subject suffering from cancer, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I): PNG media_image5.png 200 400 media_image5.png Greyscale (I) or a pharmaceutically acceptable salt, enantiomer, or tautomer thereof, wherein: Q is CH or N; R1 is H, CH3, or CH2OH; R4 is H or F; Z is CR5 or N; R5 is H or F; X is a 5-membered heteroarylene; wherein the 5-membered heteroarylene is attached to the aromatic ring comprising Q and -CH2- on adjacent atoms; wherein the 5-membered heteroarylene comprises 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and wherein the 5-membered heteroarylene is substituted with 0, 1, or 2 independently selected R2 substituents; each R2 is independently H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, CH2-C3-4 cycloalkyl, OC1-4 alkyl, C3-6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; Y is a 5- or 6-membered heteroarylene; wherein the 5- or 6-membered heteroarylene is attached to -CH2- and the aromatic ring comprising Z on adjacent atoms; wherein the 5- or 6-membered heteroarylene ring atom alpha to the -CH2- and beta to the aromatic ring comprising Z is nitrogen; wherein the 5- or 6-membered heteroarylene comprises 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and wherein the 5- or 6-membered heteroarylene is substituted with 0, 1, or 2 independently selected R3 substituents; and each R3 is independently H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, or OC1-4 alkyl. Appropriate correction is required. See MPEP § 2173.02. Claim 29 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), the existing recitation should be replaced with the following recitation: A method for selectively inhibiting c-ros avian UR2 sarcoma virus oncogene homolog 1 (ROS1) over tropomyosin receptor kinase (TRK) in a subject suffering from cancer, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I): PNG media_image5.png 200 400 media_image5.png Greyscale (I) or a pharmaceutically acceptable salt, enantiomer, or tautomer thereof, wherein: Q is CH or N; R1 is H, CH3, or CH2OH; R4 is H or F; Z is CR5 or N; R5 is H or F; X is a 5-membered heteroarylene; wherein the 5-membered heteroarylene is attached to the aromatic ring comprising Q and -CH2- on adjacent atoms; wherein the 5-membered heteroarylene comprises 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and wherein the 5-membered heteroarylene is substituted with 0, 1, or 2 independently selected R2 substituents; each R2 is independently H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, CH2-C3-4 cycloalkyl, OC1-4 alkyl, C3-6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; Y is a heteroarylene selected from the group consisting of 2*,3-substituted-pyrrolylene, 1*,5-substituted-pyrazolylene, 3*,4-substituted-pyrazolylene, 1,2*-substituted-imidazolylene, 4*,5-substituted-imidazolylene, 4,5*-substituted-imidazolylene, 3*,4-substituted-isoxazolylene, 4*,5-substituted-oxazolylene, 3*,4-substituted-isothiazolylene, 4*,5-substituted-thiazolylene, 4*,5-substituted-1,2,3-oxadiazolylene, 3*,4-substituted-1,2,5-oxadiazolylene, 4*,5-substituted-1,2,3-thiadiazolylene, 3*,4-substituted-1,2,5-thiadiazolylene, 4*,5-substituted-1,2,3-triazolylene, 1*,5-substituted-1,2,4-triazolylene, 1,5*-substituted-1,2,4-triazolylene, 3*,4-substituted-1,2,4-triazolylene, 1*,5-substituted-1,2,3,4-tetrazolylene, 2*,3-substituted-pyridinylene, 4*,5-substituted-pyrimidinylene, 3*,4-substituted-pyridazinylene, 2*,3-substituted-pyrazinylene, 4*,5-substituted-1,2,3-triazinylene, 5*,6-substituted-1,2,4-triazinylene, 5,6*-substituted-1,2,4-triazinylene, and 5*,6-substituted-1,2,3,4-tetrazinylene; wherein * indicates the point of attachment of the heteroarylene to -CH2-; wherein the heteroarylene ring atom alpha to the -CH2- and beta to the aromatic ring comprising Z is nitrogen; and wherein the heteroarylene is substituted with 0, 1, or 2 independently selected R3 substituents; and each R3 is independently H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, or OC1-4 alkyl. Appropriate correction is required. See MPEP § 2173.02. Claim 31 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation: The method of claim 26, wherein X is a 5-membered heteroarylene selected from the group consisting of pyrazolylene, imidazolylene, isoxazolylene, isothiazolylene, or triazolylene, wherein the 5-membered heteroarylene is substituted with 0, 1, or 2 independently selected R2 substituents. Appropriate correction is required. See MPEP § 2173.02. Claim 32 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation: The method of claim 31, wherein X is a 5-membered heteroarylene selected from the group consisting of 1*,5-substituted-pyrazolylene, 4*,5-substituted-pyrazolylene, 4,5*-substituted-pyrazolylene, 1*,5-substituted-imidazolylene, 4*,5-substituted-imidazolylene, 3*,4-substituted-isoxazolylene, 4*,5-substituted-isoxazolylene, 4,5*-substituted-isoxazolylene, 3*,4-substituted-isothiazolylene, 4*,5-substituted-isothiazolylene, 4,5*-substituted-isothiazolylene, 1*,5-substituted-triazolylene, and 4*,5-substituted-triazolylene; wherein * indicates the point of attachment of the 5-membered heteroarylene to -CH2-; and wherein the 5-membered heteroarylene is substituted with 0, 1, or 2 independently selected R2 substituents. Appropriate correction is required. See MPEP § 2173.02. Claim 33 is objected to because of the following informalities: for brevity, clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation: The method of claim 32, wherein X is a 5-membered heteroarylene selected from the group consisting of: PNG media_image6.png 135 193 media_image6.png Greyscale , PNG media_image7.png 144 193 media_image7.png Greyscale , PNG media_image8.png 193 193 media_image8.png Greyscale , PNG media_image9.png 197 193 media_image9.png Greyscale , PNG media_image10.png 142 193 media_image10.png Greyscale , PNG media_image11.png 144 197 media_image11.png Greyscale , PNG media_image12.png 195 191 media_image12.png Greyscale , PNG media_image13.png 140 193 media_image13.png Greyscale , PNG media_image14.png 138 193 media_image14.png Greyscale , PNG media_image15.png 147 209 media_image15.png Greyscale , PNG media_image16.png 138 193 media_image16.png Greyscale , PNG media_image17.png 147 201 media_image17.png Greyscale , and PNG media_image18.png 154 206 media_image18.png Greyscale ; wherein * indicates the point of attachment of the 5-membered heteroarylene to -CH2-. Appropriate correction is required. See MPEP § 2173.02. Claim 34 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation: The method of claim 26, wherein Y is a 5- or 6-membered heteroarylene selected from the group consisting of 1*,5-substituted-pyrazolylene, 3*,4-substituted-pyrazolylene, 1,2*-substituted-imidazolylene, 4*,5-substituted-imidazolylene, 4,5*-substituted-imidazolylene, 4*,5-substituted-thiazolylene, 1*,5-substituted-1,2,3-triazolylene, 4*,5-substituted-1,2,3-triazolylene, 1*,5-substituted-1,2,4-triazolylene, 1,5*-substituted-1,2,4-triazolylene, 2*,3-substituted-pyridinylene, 4*,5-substituted-pyrimidinylene, and 2*,3-substituted-pyrazinylene; wherein * indicates the point of attachment of the 5- or 6-membered heteroarylene to -CH2-; and wherein the 5- or 6-membered heteroarylene is substituted with 0, 1, or 2 independently selected R3 substituents. Appropriate correction is required. See MPEP § 2173.02. Claim 35 is objected to because of the following informalities: for brevity, clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation: The method of claim 34, wherein Y is a 5- or 6-membered heteroarylene selected from the group consisting of: PNG media_image19.png 164 142 media_image19.png Greyscale , PNG media_image20.png 124 174 media_image20.png Greyscale , PNG media_image21.png 165 142 media_image21.png Greyscale , PNG media_image22.png 167 142 media_image22.png Greyscale , PNG media_image23.png 126 177 media_image23.png Greyscale , PNG media_image24.png 124 174 media_image24.png Greyscale , PNG media_image25.png 145 121 media_image25.png Greyscale , PNG media_image26.png 147 154 media_image26.png Greyscale , PNG media_image27.png 124 178 media_image27.png Greyscale , PNG media_image28.png 164 140 media_image28.png Greyscale , PNG media_image29.png 165 142 media_image29.png Greyscale , PNG media_image30.png 163 142 media_image30.png Greyscale , PNG media_image31.png 128 177 media_image31.png Greyscale , PNG media_image32.png 147 163 media_image32.png Greyscale , PNG media_image33.png 124 160 media_image33.png Greyscale , and PNG media_image34.png 144 161 media_image34.png Greyscale ; wherein * indicates the point of attachment of the 5- or 6-membered heteroarylene to -CH2-. Appropriate correction is required. See MPEP § 2173.02. Claim 37 is objected to because of the following informalities: for brevity, clarity and precision, the existing recitation should be replaced with the following recitation: The method of claim 26, wherein the compound is of Formula (I-B): PNG media_image35.png 200 400 media_image35.png Greyscale (I-B) or a pharmaceutically acceptable salt thereof. Appropriate correction is required. See MPEP § 2173.02. Claim 38 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation: The method of claim 37, wherein each R2 is independently H, Cl, CH3, CH2CH3, CH2CH(CH3)2, CHF2, CF3, CH2CH2F, CH2CHF2, CH2-cyclopropyl, OCH3, cyclopropyl, cyclobutyl, or oxetanyl. Appropriate correction is required. See MPEP § 2173.02. Claim 39 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation: The method of claim 38, wherein each R3 is independently H, F, Cl, CN, CH3, or CH2CH3. Appropriate correction is required. See MPEP § 2173.02. Claim 43 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation: The method of claim 26, wherein the cancer is selected from the group consisting of angiosarcoma, bile duct cancer, breast cancer, cholangiocarcinoma, colon cancer, colorectal cancer, epithelioid hemangioendothelioma, esophageal cancer, gastric cancer, glioblastoma, an inflammatory myofibroblastic tumor (IMT), kidney cancer, lung cancer, melanoma, neuroblastoma, ovarian cancer, a spitzoid tumor, and thyroid cancer. Appropriate correction is required. See MPEP § 2173.02. Claim 47 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation: The method of claim 46, wherein the hematologic malignancy is selected from the group consisting of anaplastic large cell lymphoma (ALCL), diffuse large B-cell lymphoma (DLBCL), and large B-cell lymphoma. Appropriate correction is required. See MPEP § 2173.02. Claim 48 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation: The method of claim 26, wherein the cancer is a c-ros avian UR2 sarcoma virus oncogene homolog 1 (ROS1) positive cancer. Appropriate correction is required. See MPEP § 2173.02. Claim 49 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation: The method of claim 48, wherein the c-ros avian UR2 sarcoma virus oncogene homolog 1 (ROS1) positive cancer has a G2032R mutation. Appropriate correction is required. See MPEP § 2173.02. Claim 50 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation: The method of claim 26, wherein the enantiomer of the compound is: PNG media_image36.png 200 400 media_image36.png Greyscale , or a pharmaceutically acceptable salt or tautomer thereof. Appropriate correction is required. See MPEP § 2173.02. Claim 51 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation: The method of claim 44, wherein the enantiomer of the compound is: PNG media_image36.png 200 400 media_image36.png Greyscale , or a pharmaceutically acceptable salt or tautomer thereof. Appropriate correction is required. See MPEP § 2173.02. Claim 52 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation: The method of claim 45, wherein the enantiomer of the compound is: PNG media_image36.png 200 400 media_image36.png Greyscale , or a pharmaceutically acceptable salt or tautomer thereof. Appropriate correction is required. See MPEP § 2173.02. Claim 53 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(a), 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation: A method for selectively inhibiting c-ros avian UR2 sarcoma virus oncogene homolog 1 (ROS1) over tropomyosin receptor kinase (TRK) in a subject suffering from cancer, wherein the method comprises administering to the subject in need thereof a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a therapeutically effective amount of a compound of Formula (I): PNG media_image5.png 200 400 media_image5.png Greyscale (I) or a pharmaceutically acceptable salt, enantiomer, or tautomer thereof, wherein: Q is CH or N; R1 is H, CH3, or CH2OH; R4 is H or F; Z is CR5 or N; R5 is H or F; X is a 5-membered heteroarylene; wherein the 5-membered heteroarylene is attached to the aromatic ring comprising Q and -CH2- on adjacent atoms; wherein the 5-membered heteroarylene comprises 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and wherein the 5-membered heteroarylene is substituted with 0, 1, or 2 independently selected R2 substituents; each R2 is independently H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, CH2-C3-4 cycloalkyl, OC1-4 alkyl, C3-6 cycloalkyl, or 3- to 6-membered heterocycloalkyl; Y is a 5- or 6-membered heteroarylene; wherein the 5- or 6-membered heteroarylene is attached to -CH2- and the aromatic ring comprising Z on adjacent atoms; wherein the 5- or 6-membered heteroarylene ring atom alpha to the -CH2- and beta to the aromatic ring comprising Z is nitrogen; wherein the 5- or 6-membered heteroarylene comprises 1, 2, or 3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and wherein the 5- or 6-membered heteroarylene is substituted with 0, 1, or 2 independently selected R3 substituents; and each R3 is independently H, halo, CN, C1-4 alkyl, C1-4 haloalkyl, or OC1-4 alkyl. Appropriate correction is required. See MPEP § 2173.02. Claim 54 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation: The method of claim 53, wherein the enantiomer of the compound is: PNG media_image36.png 200 400 media_image36.png Greyscale , or a pharmaceutically acceptable salt or tautomer thereof. Appropriate correction is required. See MPEP § 2173.02. Claim 55 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation: The method of claim 54, wherein the cancer is lung cancer. Appropriate correction is required. See MPEP § 2173.02. Claim 56 is objected to because of the following informalities: for clarity, precision and to avoid issues under 35 U.S.C. § 112(b) and/or 35 U.S.C. § 112(d), the existing recitation should be replaced with the following recitation: The method of claim 55, wherein the lung cancer is non-small cell lung cancer. Appropriate correction is required. See MPEP § 2173.02. Claim 57 is objected to because of the following informalities: for clarity and precision, the existing recitation should be replaced with the following recitation: The method of claim 26, wherein the compound is: PNG media_image37.png 292 367 media_image37.png Greyscale , or a pharmaceutically acceptable salt, enantiomer, or tautomer thereof. Appropriate correction is required. See MPEP § 2173.02. Claim Rejections - 35 U.S.C. § 112(a) The following is a quotation of the first paragraph of 35 U.S.C. § 112: (a) IN GENERAL. The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. Method for selectively inhibiting ROS1 over TRK… said method comprising administering… a substituted macrocycle of the Formula (I), or a pharmaceutical composition thereof Claims 26, 29, 31, 34-49 and 53 are rejected under 35 U.S.C. § 112(a) because the specification, while being enabling for performing a method for selectively inhibiting ROS1 over TRK… said method comprising administering… a substituted macrocycle of the Formula (I), wherein the 5-membered heteroarylene of X is attached to the aromatic ring comprising Q and -CH2- on adjacent atoms, or a pharmaceutical composition thereof, does not reasonably provide enablement for performing a method for selectively inhibiting ROS1 over TRK… said method comprising administering… a substituted macrocycle of the Formula (I), wherein the 5-membered heteroarylene of X is not attached to the aromatic ring comprising Q and -CH2- on adjacent atoms, or a pharmaceutical composition thereof. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. A method for selectively inhibiting ROS1 over TRK… said method comprising administering… a substituted macrocycle of the Formula (I), wherein the 5-membered heteroarylene of X is not attached to the aromatic ring comprising Q and -CH2- on adjacent atoms, or a pharmaceutical composition thereof, as recited in claims 26, 29 and 53, respectively, has not been adequately enabled in the specification to allow any person having ordinary skill in the art, at the time this invention was made, to make and/or use (perform) a method for selectively inhibiting ROS1 over TRK… said method comprising administering… a substituted macrocycle of the Formula (I), wherein the 5-membered heteroarylene of X is not attached to the aromatic ring comprising Q and -CH2- on adjacent atoms, or a pharmaceutical composition thereof. There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: (a) breadth of the claims; (b) nature of the invention; (c) state of the prior art; (d) level of one of ordinary skill in the art; (e) level of predictability in the art; (f) amount of direction provided by the inventor or joint inventor; (g) existence of working examples; and (h) quantity of experimentation needed to make or use the invention based on the content of the disclosure. {See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986); and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988)}. The above factors, regarding the instant invention, are summarized as follows: PNG media_image1.png 200 400 media_image1.png Greyscale (a) Breadth of the claims - the breadth of the claims includes a method for selectively inhibiting ROS1 over TRK… said method comprising administering… a substituted macrocycle of the Formula (I), shown to the right, or a pharma-ceutical composition thereof; (b) Nature of the invention - the nature of the invention is performance of a method for selectively inhibiting ROS1 over TRK… said method comprising administering… a substituted macrocycle of the Formula (I), shown to the right above, or a pharmaceutical composition thereof; (c) State of the prior art - Nature Reviews: Drug Discovery offers a snapshot of the state of the drug development art. Herein, drug development is stated to follow the widely accepted Ehrlich model which includes: (1) development of a broad synthetic organic chemistry program; (2) subsequent testing of compounds in an appropriate laboratory model for the disease to be treated; and (3) screening of compounds with low toxicity in prospective clinical trials (Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205). Moreover, WO 21/226208, as provided in the file and cited on the IDS, provides a synthesis of the substituted macrocycles of the Formula (I) administered within the instantly recited method for selectively inhibiting ROS1 over TRK {Tang, et al. WO 21/226208, 2021}; (d) Level of one of ordinary skill in the art - the artisans performing the inventor’s or joint inventor’s method for selectively inhibiting ROS1 over TRK… said method comprising administering… a substituted macrocycle of the Formula (I), wherein the 5-membered heteroarylene of X is not attached to the aromatic ring comprising Q and -CH2- on adjacent atoms, or a pharmaceutical composition thereof, would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience; (e) Level of predictability in the art - Synthetic organic chemistry is quite unpredictable (See In re Marzocchi and Horton 169 USPQ at 367 ¶3). Similarly, it is unclear based on the combination of the instant specification, and Tang, et al. in WO 21/226208, as provided in the file and cited on the IDS, whether the substituted macrocycles of the Formula (I) administered within the instantly recited method for selectively inhibiting ROS1 over TRK, wherein the 5-membered heteroarylene of X is not attached to the aromatic ring comprising Q and -CH2- on adjacent atoms, or a pharmaceutical composition thereof, are enabled. Moreover, the following excerpt is taken from Dörwald, which has relevance to the synthesis of substituted macrocycles of the Formula (I) administered within the instantly recited method for selectively inhibiting ROS1 over TRK, wherein the 5-membered heteroarylene of X is not attached to the aromatic ring comprising Q and -CH2- on adjacent atoms, or a pharmaceutical composition thereof (Dörwald, F. Zaragoza. Side Reactions in Organic Synthesis: A Guide to Successful Synthesis Design, Weinheim: WILEY-VCH Verlag GmbH & Co. KGaA, 2005, Preface): Most non-chemists would probably be horrified if they were to learn how many attempted syntheses fail, and how inefficient research chemists are. The ratio of successful to unsuccessful chemical experiments in a normal research laboratory is far below unity, and synthetic research chemists, in the same way as most scientists, spend most of their time working out what went wrong, and why. Despite the many pitfalls lurking in organic synthesis, most organic chemistry textbooks and research articles do give the impression that organic reactions just proceed smoothly and that the total synthesis of complex natural products, for instance, is maybe a labor-intensive but otherwise undemanding task. In fact, most syntheses of structurally complex natural products are the result of several years of hard work by a team of chemists, with almost every step requiring careful optimization. The final synthesis usually looks quite different from that originally planned, because of unexpected difficulties encountered in the initially chosen synthetic sequence. Only the seasoned practitioner who has experienced for himself the many failures and frustrations which the development (sometimes even the repetition) of a synthesis usually implies will be able to appraise such work. Chemists tend not to publish negative results, because these are, as opposed to positive results, never definite (and far too copious). (f) Amount of direction provided by the inventor - the invention lacks direction with respect to making and/or using (performing) a method for selectively inhibiting ROS1 over TRK… said method comprising administering… a substituted macrocycle of the Formula (I), wherein the 5-membered heteroarylene of X is not attached to the aromatic ring comprising Q and -CH2- on adjacent atoms, or a pharmaceutical composition thereof; (g) Existence of working examples - the inventor or joint inventor has provided sufficient guidance to make and/or use (perform) a method for selectively inhibiting ROS1 over TRK… said method comprising administering… a substituted macrocycle of the Formula (I), wherein the 5-membered heteroarylene of X is attached to the aromatic ring comprising Q and -CH2- on adjacent atoms, or a pharmaceutical composition thereof; however, the disclosure is insufficient to allow extrapolation of the limited examples to enable performing the instantly recited method for selectively inhibiting ROS1 over TRK… said method comprising administering… a substituted macrocycle of the Formula (I), wherein the 5-membered heteroarylene of X is not attached to the aromatic ring comprising Q and -CH2- on adjacent atoms, or a pharmaceutical composition thereof. The specification lacks working examples of performing a method for selectively inhibiting ROS1 over TRK… said method comprising administering… a substituted macrocycle of the Formula (I), wherein the 5-membered heteroarylene of X is not attached to the aromatic ring comprising Q and -CH2- on adjacent atoms, or a pharmaceutical composition thereof. Within the specification, [A]t least one specific operative embodiment or example of the invention must be set forth. The example(s) and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula. See MPEP § 608.01(p) and MPEP § 2173.05. (h) Quantity of experimentation needed to make or use the invention based on the content of the disclosure - predicting whether a recited compound, and/or a pharmaceutical composition thereof, is in fact one that produces a desired physiological effect at a therapeutic concentration and with useful kinetics, is filled with experimental uncertainty, and without proper guidance, would involve a substantial amount of experimentation (Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205-213). Similarly, the specification, as originally filed, including any references incorporated therein, fails to provide the necessary support required by 35 U.S.C. § 112(a) to enable performing the instantly recited method for selectively inhibiting ROS1 over TRK… said method comprising administering… a substituted macrocycle of the Formula (I), wherein the 5-membered heteroarylene of X is not attached to the aromatic ring comprising Q and -CH2- on adjacent atoms, or a pharmaceutical composition thereof. Thus, it is unclear, based on the guidance provided by the specification, whether a substituted macrocycle of the Formula (I) administered within the instantly recited method for selectively inhibiting ROS1 over TRK, wherein the 5-membered heteroarylene of X is not attached to the aromatic ring comprising Q and -CH2- on adjacent atoms, or a pharmaceutical composition thereof, is either synthetically feasible or possesses utility as a therapeutic agent, useful in a method for selectively inhibiting ROS1 over TRK… said method comprising administering… a substituted macrocycle of the Formula (I), or a pharmaceutical composition thereof. A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the invention was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. {See In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)}. The determination that undue experimentation would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. (See In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404). These factual considerations are discussed comprehensively in MPEP § 2164.08 (scope or breadth of the claims), § 2164.05(a) (nature of the invention and state of the prior art), § 2164.05(b) (level of one of ordinary skill), § 2164.03 (level of predictability in the art and amount of direction provided by the inventor or joint inventor), § 2164.02 (the existence of working examples) and § 2164.06 (quantity of experimentation needed to make or use the invention based on the content of the disclosure). Based on a preponderance of the evidence presented herein, the conclusion that the inventor or joint inventor is insufficiently enabled for making and/or using (performing) a method for selectively inhibiting ROS1 over TRK… said method comprising administering… a substituted macrocycle of the Formula (I), wherein the 5-membered heteroarylene of X is not attached to the aromatic ring comprising Q and -CH2- on adjacent atoms, or a pharmaceutical composition thereof, is clearly justified. The examiner suggests amending the claims, particularly as stated in the section above entitled Claim Objections, to overcome this rejection. Claim Rejections - 35 U.S.C. § 112(b) The following is a quotation of the second paragraph of 35 U.S.C. § 112: (b) CONCLUSION. The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or joint inventor regards as the invention. Claims 43-45, 51 and 52 are rejected under 35 U.S.C. § 112(b) as being indefinite for failing to set forth the subject matter which the inventor or joint inventor regards as the invention. The inventor or joint inventor should note that claim 43 recites the limitation, The method of claim 42, wherein the cancer is…, in line 1 of the claim. There is insufficient antecedent basis, in claim 42, for this limitation, with respect to the method for selectively inhibiting ROS1 over TRK. According to claim 42, the cancer is recited as a solid tumor, with respect to the method for selectively inhibiting ROS1 over TRK. Moreover, the inventor or joint inventor should further note that [C]laims which depend from indefinite claims are also indefinite. {See Ex parte Cordova, 10 USPQ 2d 1949, 1952 (PTO Bd. App. 1989)}. The examiner suggests amending the claims, particularly as stated in the section above entitled Claim Objections, to overcome this rejection. Claim 49 is rejected under 35 U.S.C. § 112(b) as being indefinite for failing to set forth the subject matter which the inventor or joint inventor regards as the invention. The inventor or joint inventor should note that claim 49 recites the limitation, The method of claim 46, wherein the ROS1 positive cancer has a G2032R mutation, in lines 1-2 of the claim. There is insufficient antecedent basis, in claim 46, for this limitation, with respect to the method for selectively inhibiting ROS1 over TRK. According to claim 46, a ROS1 positive cancer is not recited, with respect to the method for selectively inhibiting ROS1 over TRK. The examiner suggests amending the claim, particularly as stated in the section above entitled Claim Objections, to overcome this rejection. Claim Rejections - Obviousness-type 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 obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined invention claim is not patentably distinct from the reference claims because the examined invention claim is either anticipated by, or would have been obvious over, the reference claims. {See 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); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969)}. US Patent No. 11,542,278 PNG media_image1.png 200 400 media_image1.png Greyscale PNG media_image4.png 200 400 media_image4.png Greyscale PNG media_image1.png 200 400 media_image1.png Greyscale PNG media_image3.png 200 400 media_image3.png Greyscale Consequently, claims 26, 29 and 31-57 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over at least claims 1-6, 9 and 21 of US Patent No. 11,542,278. Although the conflicting claims are not identical, they are not patentably distinct from each other because claim 1 in US 11,542,278 recites substituted macrocycles of the Formula (I), shown to the left above, where Q = CH; R1 = -CH3; X is shown to the right above, wherein, at C-3, R2 = -halo and at N3, R2 = -CH2-C3-4 cycloalkyl; Y is shown to the left, wherein R3 = -C1-4 alkyl; R4 = -F; and Z = -CR5, wherein R5 = -H, respectively, which are administered within the instantly recited method for selectively inhibiting ROS1 over TRK… comprising administering… a substituted macrocycle of the Formula (I), shown to the right above, where Q = CH; R1 = -CH3; X = -5-membered heteroarylene, substituted with 0, 1, or 2 R2 substituents; R2 = -halo and R2 = -CH2-C3-4 cycloalkyl; Y = -5- or 6-membered heteroarylene, substituted with 0, 1, or 2 R3 substituents; R3 = -C1-4 alkyl; R4 = -F; and Z = -CR5, wherein R5 = -H, respectively. The inventor or joint inventor should note that [T]he discovery of a previously unappreciated property of a prior art compound, or of a scientific explanation for the prior art’s functioning, does not render the old compound patentably new to the discoverer. {See Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999)}. Similarly, the inventor or joint inventor should further note that [T]he claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. {See In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977); and In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004)}. Likewise, the inventor or joint inventor should note that [W]hen the claim recites using an old compound and the use is directed to a result or property of that compound, then the claim is anticipated. {See In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978); and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966)}. Next, the inventor or joint inventor should further note that [P]roducts of identical chemical composition may not have mutually exclusive properties. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties the inventor or joint inventor discloses and/or claims are necessarily present. {See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990)}. Moreover, the inventor or joint inventor should further note that [A] claim to a method of using a composition is not patentably distinct from an earlier claim to the identical composition in a patent disclosing the identical use. {See Sun Pharmaceuticals Industries Ltd. v. Eli Lilly and Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010); Pfizer, Inc. v. Teva Pharmaceuticals USA, Inc., 518 F.3d 1353, 1363, 86 USPQ2d 1001 (Fed. Cir. 2008); and Geneva PNG media_image38.png 1 1 media_image38.png Greyscale Pharmaceuticals, Inc. v. GlaxoSmithKline PLC, PNG media_image38.png 1 1 media_image38.png Greyscale 349 F.3d 1373, 68 USPQ2d 1865, (Fed. Cir. 2003)}. US Patent No. 11,667,649 PNG media_image1.png 200 400 media_image1.png Greyscale PNG media_image1.png 200 400 media_image1.png Greyscale At least claims 26, 29, 31-49 and 53 are further rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over at least claims 1-5, 18 and 31 of US Patent No. 11,667,649. Although the conflicting claims are not identical, they are not patentably distinct from each other because claim 1 in US 11,667,649 recites substituted macrocycles of the Formula (I), shown to the left above, where Q = CH; R1 = -CH3; X = -pyrazolylene, substituted with 0, 1, or 2 R2 substituents; R2 = -halo and R2 = -C3-4 cycloalkylmethyl; Y = -pyrazolylene, substituted with 0, 1, or 2 R3 substituents; R3 = -C1-4 alkyl; R4 = -F; and Z = -CR5, wherein R5 = -H, respectively, which are administered within the instantly recited method for selectively inhibiting ROS1 over TRK… comprising administering… a substituted macrocycle of the Formula (I), shown to the right below, where Q = CH; R1 = -CH3; X = -5-membered heteroarylene, substituted with 0, 1, or 2 R2 substituents; R2 = -halo and R2 = -CH2-C3-4 cycloalkyl; Y = -5- or 6-membered heteroarylene, substituted with 0, 1, or 2 R3 substituents; R3 = -C1-4 alkyl; R4 = -F; and Z = -CR5, wherein R5 = -H, respectively. The inventor or joint inventor should note that [T]he discovery of a previously unappreciated property of a prior art compound, or of a scientific explanation for the prior art’s functioning, does not render the old compound patentably new to the discoverer. {See Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999)}. Similarly, the inventor or joint inventor should further note that [T]he claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. {See In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977); and In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004)}. Likewise, the inventor or joint inventor should note that [W]hen the claim recites using an old compound and the use is directed to a result or property of that compound, then the claim is anticipated. {See In re May, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978); and In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966)}. Next, the inventor or joint inventor should further note that [P]roducts of identical chemical composition may not have mutually exclusive properties. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties the inventor or joint inventor discloses and/or claims are necessarily present. {See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990)}. Then, the inventor or joint inventor should further note that [A] claim to a method of using a composition is not patentably distinct from an earlier claim to the identical composition in a patent disclosing the identical use. {See Sun Pharmaceuticals Industries Ltd. v. Eli Lilly and Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010); Pfizer, Inc. v. Teva Pharmaceuticals USA, Inc., 518 F.3d 1353, 1363, 86 USPQ2d 1001 (Fed. Cir. 2008); and Geneva PNG media_image38.png 1 1 media_image38.png Greyscale Pharmaceuticals, Inc. v. GlaxoSmithKline PLC, PNG media_image38.png 1 1 media_image38.png Greyscale 349 F.3d 1373, 68 USPQ2d 1865, (Fed. Cir. 2003)}. Moreover, the inventor or joint inventor should further note that a timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 37 CFR 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground, provided the conflicting invention or patent either is shown to be commonly owned with this invention, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. Furthermore, the inventor or joint inventor should also note that the USPTO internet Web site contains terminal disclaimer forms which may be used, and the inventor or joint inventor is encouraged to visit http://www.uspto.gov/forms/, where (i) the filing date of the invention will determine what form should be used, and (ii) a web-based eTerminal Disclaimer may be filled out completely online using web-screens, respectively. Also, the inventor or joint inventor should further note that an eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. Finally, for more information about eTerminal Disclaimers, the inventor or joint inventor should refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp. Allowable Subject Matter No claims are allowed. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOUGLAS M. WILLIS, whose telephone number is 571-270-5757. The examiner may normally be reached on Monday thru Thursday from 8:00-6:00 EST. The examiner is also available on alternate Fridays. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Mr. Jeffrey Murray, may be reached on 571-272-9023. The fax phone number for the organization where this invention or proceeding is assigned is 571-273-8300. Information regarding the status of an invention may be obtained from Patent Center. For more information about Patent Center, see https://www.uspto.gov/patents/apply/patent-center. Should you have questions on access to Patent Center, contact the Patent Electronic Business Center (PEBC) at 866-217-9197 (toll-free) or ebc@uspto.gov. /DOUGLAS M WILLIS/ Primary Examiner, Art Unit 1624