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 .
Specification
The use of the term “X’Pert Pro MPD” and “X’Celerator”, which are trade names or marks used in commerce, has been noted in this application. See specification page 5 line 7 and page 8 lines 20 – 21. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 3 is objected to because of the following informalities: missing a conjunction between “22.28” and “24.89” in line 7 of the claim. Appropriate correction is required.
Claim 4 is objected to because of the following informalities: missing a conjunction between “22.28” and “24.89” in line 4 of the claim. Appropriate correction is required.
Claim 16 is objected to because of the following informalities: missing a conjunction between “14.78” and “15.09” in line 7 of the claim. Appropriate correction is required.
Claims 2 – 4, 6, 8, and 11 – 16 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim5, 9 – 10, and 17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 5 and 17 contain the trademark/trade names “X’Pert Pro MPD” and “X’Celerator”. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe the x-ray diffractor and detector and, accordingly, the identification/description is indefinite.
Regarding claim 9, the phrase "for example," in lines 3 – 4 of the claim renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 10, the phrase "for example," in lines 3 – 4 of the claim renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
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.
Claims 1, 7, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. US 9108983 B2 to Le Tiran et. al. (Le Tiran’983) in view of Elder et. al., ((2013), Use of pharmaceutical salts and cocrystals, International Journal of Pharmaceutics, 453, 88-100; cited on the IDS dated August 27th, 2024).
Regarding claims 1, 7, and 9, Le Tiran’983 teach a compound of Formula I,
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. See column 1 lines 51 – 67. Furthermore, Le Tiran’983 teach the HCl salt of compound example 386, with the chemical name 5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-( 4-hydroxyphenyl)-1,2-dimethyl-1 H-pyrrole-3-carboxamide hydrochloride. See column 122 lines 53 – 57. See examined claim 1 limitation for 5-(5-Chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-( 4-hydroxyphenyl)-1,2-dimethyl-1 H-pyrrole-3-carboxamide hydrochloride. Moreover, Le Tiran’983 teach that a pharmaceutically acceptable acid, sulfuric acid can be added to compounds of the disclosure, which include compound 386, to form the hydrogen sulfate salts. See column 3 line 28. See examined claim 1 limitation for the hydrogen sulfate salt.
Additionally, Le Tiran’983 teach the use of the compounds of the disclosure, which include compound 386 and the hydrogen sulfate salt of compound 386, in treating cancers, autoimmune diseases and diseases of the immune system. See column 9 lines 42 – 45. Furthermore, Le Tiran’983 teach that the cancer treatment includes cancers of the bladder, brain, breast and uterus, chronic lymphoid leukemias, colorectal cancer, cancers of the esophagus and liver, lymphoblastic leukemias, non-Hodgkin lymphomas, melanomas, malignant hemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer and small-cell lung cancer. See column 9 lines 50 – 57. See examined claim 9 limitation for a method of treating conditions selected from bladder cancer, brain cancer, breast cancer, uterus cancer, chronic lymphoid leukaemias, colorectal cancer, cancers of the esophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemia, lymphomas, for example non-Hodgkin's B-cell lymphoma and diffuse large B-cell lymphoma, melanomas, malignant haemopathies, including myelodysplastic syndrome, myelomas, including multiple myeloma, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.
Moreover, Le Tiran’983 teach pharmaceutical compositions comprising at least one compounds of the disclosure, which include compound 386 and the hydrogen sulfate salt of compound 386, in combination with one or more pharmaceutically acceptable excipients. See column 9 lines 61 – 64. See examined claim 7 limitation for a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients.
However, while Le Tiran’983 fail to explicitly exemplify the hydrogen sulfate salt; Le Tiran’983 does teach the HCl salt of form. Moreover, Le Tiran’983 does teach that a pharmaceutically acceptable acid, sulfuric acid can be added to compounds of the disclosure, which include compound 386, to form the hydrogen sulfate salts. See column 3 line 28.
Nevertheless, Elder et. al. teach the use of salt formations as a simple and cost-effective strategy to address poor solubility in water and the enhance bioavailability. See page 88 column 1 paragraph 1. Furthermore, Elder et. al. teach that the strong inorganic acid sulfuric acid can be used to make sulfates, that is hydrogen sulfate salts. See page 96 Table 2. Moreover, Elder et. al. teach that the formation of active pharmaceutical ingredient (API) salts, which include hydrogen sulfate salts, have enhanced crystallinity compared to the free or unsalted molecule. See page 96 Table 2. Furthermore, Elder et. al. teach that the enhanced crystallinity of the sulfate salts lead to increased hydrolytic stability when compared to the free or unsalted molecule. See page 96 Table 2. Thus, Elder et. al. suggest that by improving the hydrolytic stability of an API, through salt formation, more of the API is available in the body leading, which in turn leads to lower effective therapeutic amounts needed to be administered. Accordingly, Elder et. al. suggest that the formation of API salts, which include hydrogen sulfate salts, would be an improvement over the free molecule in terms of hydrolytic stability.
Therefore it would have been obvious before the effective filing date of the instant application to modify Le Tiran’983, that is for the compound 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4- hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, in view of Elder et. al. to form the hydrogen sulfate salt. One of ordinary skill in the art would be motivated to make this modification to enhance the crystallinity of the compound. Lastly one of ordinary skill in the art would have a reasonable expectation of success because the enhanced crystal form had increased hydrolytic stability. Thus by improving the hydrolytic stability of a compound more of the compound is available in the body leading to lower effective therapeutic amounts needed to be administered.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 7, and 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 3,5 – 7, 10 – 12, and 14 – 18 of U.S. Patent No. US 9108983 B2 to Le Tiran et. al. (Le Tiran’983; cited on the IDS dated August 27th, 2024) in view of Elder et. al., ((2013), Use of pharmaceutical salts and cocrystals, International Journal of Pharmaceutics, 453, 88-100; cited on the IDS dated August 27th, 2024).
Le Tiran’983 recite a compound of formula (I):
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wherein (reference) R3-5, W, A1-2, T, and Ra-d. See reference claims 1 – 3, 5 – 7, and 10 – 12. Specifically, Le Tiran’983 recite a method where the compound is 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxypheny1)-1,2-dimethyl-1H-pyrrole-3-carboxamide or an enantiomer, a diastereoisomer, or an addition salt thereof with a pharmaceutically acceptable acid or base. See reference claim 14. See examined claim 1. Le Tiran’983 recite a pharmaceutical composition comprising a compound according to (reference) claim 1 in combination with one or more pharmaceutically acceptable excipients. See refernece claim 15. See examined claim 7. Additionally, Le Tiran’983 recite a composition comprising a compound according (reference) claim 1 in combination with an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies. See reference claim 16. Furthermore, Le Tiran’983 recite the composition of (reference) claim 16 further comprising one or more pharmaceutically acceptable excipients. See reference claim 17. Moreover, Le Tiran’983 recite a combination comprising the compound according to (reference) claim 1 and an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies. See reference claim 18.
However, while Le Tiran’983 recite that the selectedc compound can be in the form of an acid addition salt; Le Tiran’983 fail to recite a compound where the compound is a hydrogen sulfate salt. See examined claim 1. Moreover, Le Tiran’983 fail to to recite whether the compound can be used in a method of treating a condition selected from those recited in examined claim 9.
Nevertheless, Le Tiran’983 does recite in reference claims 17 – 18 that the compound can be made into a composition or combination with an anti-cancer agent. Thus given that the skill level of one of ordinary skill in the pharmactuical art is relatively higher, being that of an M.D. or Ph. D., it would have been within the skill and purview of such artican to administer the composition and/or combination comprising the 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxypheny1)-1,2-dimethyl-1H-pyrrole-3-carboxamide and an anti-cancer agent in a method to treat a condition selected from those recited in examined claim 9 which include cancers.
However, while Le Tiran’983 recite that the selected compound can be in the form of an acid addition salt; Le Tiran’983 fail to recite a compound where the compound is a hydrogen sulfate salt. See examined claim 1.
Nevertheless, Elder et. al. teach the use of salt formations as a simple and cost-effective strategy to address poor solubility in water and the enhance bioavailability. See page 88 column 1 paragraph 1. Furthermore, Elder et. al. teach that the strong inorganic acid sulfuric acid can be used to make sulfates, that is hydrogen sulfate salts. See page 96 Table 2. Moreover, Elder et. al. teach that the formation of active pharmaceutical ingredient (API) salts, which include hydrogen sulfate salts, have enhanced crystallinity compared to the free or unsalted molecule. See page 96 Table 2. Furthermore, Elder et. al. teach that the enhanced crystallinity of the sulfate salts lead to increased hydrolytic stability when compared to the free or unsalted molecule. See page 96 Table 2. Thus, Elder et. al. suggest that by improving the hydrolytic stability of an API, through salt formation, more of the API is available in the body leading, which in turn leads to lower effective therapeutic amounts needed to be administered. Accordingly, Elder et. al. suggest that the formation of API salts, which include hydrogen sulfate salts, would be an improvement over the free molecule in terms of hydrolytic stability.
Therefore it would have been obvious before the effective filing date of the instant application to modify the invention of Le Tiran’983, that is 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4- hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, in view of Elder et. al. to form the hydrogen sulfate salt. One of ordinary skill in the art would be motivated to make this modification to enhance the crystallinity of the compound. Lastly one of ordinary skill in the art would have a reasonable expectation of success because the enhanced crystal form had increased hydrolytic stability. Thus by improving the hydrolytic stability of a compound more of the compound is available in the body leading to lower effective therapeutic amounts needed to be administered.
Claims 1, 7, and 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 3, 5 – 7, 10 – 12, and 14 – 19 of U.S. Patent No. 9598427 B2 to Le Tiran et. al. (Le Tiran’427) in view of Elder et. al., ((2013), Use of pharmaceutical salts and cocrystals, International Journal of Pharmaceutics, 453, 88-100; cited on the IDS dated August 27th, 2024).
Le Tiran’427 recite a method of treating cancer where the cancer is selected from bladder, brain, breast and uterus, chronic lymphoid leukaemias, colorectal cancer, cancers of the esophagus and liver, lymphoblastic leukaemias, non-Hodgkin lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, and small-cell lung cancer, comprising administration of an effective amount of a compound of formula (I):
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wherein (reference) R3-5, A1-2, T, and Ra-d. See reference claims 1 – 3, 5 – 7, 10 – 12, and 18 – 19. See examined claim 9. Specifically, Le Tiran’427 recite a method where the compound is 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxypheny1)-1,2-dimethyl-1H-pyrrole-3-carboxamide or an enantiomer, a diastereoisomer, or an addition salt thereof with a pharmaceutically acceptable acid or base. See reference claim 14. See examined claim 1. Le Tiran’427 recite a pharmaceutical composition comprising a compound according to (reference) claim 1 in combination with one or more pharmaceutically acceptable excipients. See refernece claim 15. See examined claim 7. Moreover, Le Tiran’427 recite the method according to (reference) claim 1 where the compound according to formula (I) is administered with an an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies. See reference claim 16. Additionally, Le Tiran’427 recite the method according to (reference) claim 1 where the compound of formula (I) is administered in combination with radiotherapy. See reference claim 17.
However, while Le Tiran’427 recite that the selected compound can be in the form of an acid addition salt; Le Tiran’427 fail to recite a compound where the compound is a hydrogen sulfate salt. See examined claim 1.
Nevertheless, Elder et. al. teach the use of salt formations as a simple and cost-effective strategy to address poor solubility in water and the enhance bioavailability. See page 88 column 1 paragraph 1. Furthermore, Elder et. al. teach that the strong inorganic acid sulfuric acid can be used to make sulfates, that is hydrogen sulfate salts. See page 96 Table 2. Moreover, Elder et. al. teach that the formation of active pharmaceutical ingredient (API) salts, which include hydrogen sulfate salts, have enhanced crystallinity compared to the free or unsalted molecule. See page 96 Table 2. Furthermore, Elder et. al. teach that the enhanced crystallinity of the sulfate salts lead to increased hydrolytic stability when compared to the free or unsalted molecule. See page 96 Table 2. Thus, Elder et. al. suggest that by improving the hydrolytic stability of an API, through salt formation, more of the API is available in the body leading, which in turn leads to lower effective therapeutic amounts needed to be administered. Accordingly, Elder et. al. suggest that the formation of API salts, which include hydrogen sulfate salts, would be an improvement over the free molecule in terms of hydrolytic stability.
Therefore it would have been obvious before the effective filing date of the instant application to modify the claimed invention of Le Tiran’427 for a method pf treating cancer using 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4- hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, in view of Elder et. al., that is to use the hydrogen sulfate salt form of 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4- hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide. One of ordinary skill in the art would be motivated to make this modification to enhance the crystallinity of the compound. Lastly one of ordinary skill in the art would have a reasonable expectation of success because the enhanced crystal form had increased hydrolytic stability. Thus by improving the hydrolytic stability of a compound more of the compound is available in the body leading to lower effective therapeutic amounts needed to be administered.
Claims 1, and 7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 3, 5 – 7, 10 – 12, and 14 – 15 of U.S. Patent No. 10265323 B2 to Le Tiran et. al. (Le Tiran’323) in view of Elder et. al., ((2013), Use of pharmaceutical salts and cocrystals, International Journal of Pharmaceutics, 453, 88-100; cited on the IDS dated August 27th, 2024).
Le Tiran’323 recite a method of treating immune and autoimmune diseases in a subject in need thereof, comprising administration of an effective amount of a compound of formula (I):
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wherein (reference) R3-5, A1-2, T, and Ra-d. See reference claims 1 – 3, 5 – 7, and 10 – 12. Specifically, Le Tiran’323 recite a method where the compound is 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxypheny1)-1,2-dimethyl-1H-pyrrole-3-carboxamide or an enantiomer, a diastereoisomer, or an addition salt thereof with a pharmaceutically acceptable acid or base. See reference claim 14. See examined claim 1. Le Tiran’323 recite a method according to (reference) claim 1 where the compound of formula (I) is administered as a pharmactuical composition comprsing a compoind of formula (i) in combination with one or more pharmaceutically acceptable excipients. See refernece claim 15. See examined claim 7.
However, while Le Tiran’323 recite that the selected compound can be in the form of an acid addition salt; Le Tiran’323 fail to recite a compound where the compound is a hydrogen sulfate salt. See examined claim 1.
Nevertheless, Elder et. al. teach the use of salt formations as a simple and cost-effective strategy to address poor solubility in water and the enhance bioavailability. See page 88 column 1 paragraph 1. Furthermore, Elder et. al. teach that the strong inorganic acid sulfuric acid can be used to make sulfates, that is hydrogen sulfate salts. See page 96 Table 2. Moreover, Elder et. al. teach that the formation of active pharmaceutical ingredient (API) salts, which include hydrogen sulfate salts, have enhanced crystallinity compared to the free or unsalted molecule. See page 96 Table 2. Furthermore, Elder et. al. teach that the enhanced crystallinity of the sulfate salts lead to increased hydrolytic stability when compared to the free or unsalted molecule. See page 96 Table 2. Thus, Elder et. al. suggest that by improving the hydrolytic stability of an API, through salt formation, more of the API is available in the body leading, which in turn leads to lower effective therapeutic amounts needed to be administered. Accordingly, Elder et. al. suggest that the formation of API salts, which include hydrogen sulfate salts, would be an improvement over the free molecule in terms of hydrolytic stability.
Therefore it would have been obvious before the effective filing date of the instant application to modify the claimed invention of Le Tiran’323, that is for a method of treating either an immune disease or an autoimmune disease using 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4- hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, in view of Elder et. al. to use the hydrogen sulfate salt form of the compound. One of ordinary skill in the art would be motivated to make this modification to enhance the crystallinity of the compound. Lastly one of ordinary skill in the art would have a reasonable expectation of success because the enhanced crystal form had increased hydrolytic stability. Thus by improving the hydrolytic stability of a compound more of the compound is available in the body leading to lower effective therapeutic amounts needed to be administered.
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 6, 7, 8, and 11 – 15 of U.S. Patent No. 10688101 B2 to Le Tiran et. al. (Le Tiran’101) in view of Elder et. al., ((2013), Use of pharmaceutical salts and cocrystals, International Journal of Pharmaceutics, 453, 88-100; cited on the IDS dated August 27th, 2024).
Le Tiran’101 recite a method of the preparation of a compound of formula (I):
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wherein (reference) R3-5, A1-2, T, and Ra-d. See reference claims 3, 6, 7, 8, and 11 – 14. Specifically, Le Tiran’323 recite a method where the compound is 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxypheny1)-1,2-dimethyl-1H-pyrrole-3-carboxamide or an enantiomer, a diastereoisomer, or an addition salt thereof with a pharmaceutically acceptable acid or base. See reference claim 15. See examined claim 1.
However, while Le Tiran’101 recite that the selected compound can be in the form of an acid addition salt; Le Tiran’101 fail to recite a compound where the compound is a hydrogen sulfate salt. See examined claim 1.
Nevertheless, Elder et. al. teach the use of salt formations as a simple and cost-effective strategy to address poor solubility in water and the enhance bioavailability. See page 88 column 1 paragraph 1. Furthermore, Elder et. al. teach that the strong inorganic acid sulfuric acid can be used to make sulfates, that is hydrogen sulfate salts. See page 96 Table 2. Moreover, Elder et. al. teach that the formation of active pharmaceutical ingredient (API) salts, which include hydrogen sulfate salts, have enhanced crystallinity compared to the free or unsalted molecule. See page 96 Table 2. Furthermore, Elder et. al. teach that the enhanced crystallinity of the sulfate salts lead to increased hydrolytic stability when compared to the free or unsalted molecule. See page 96 Table 2. Thus, Elder et. al. suggest that by improving the hydrolytic stability of an API, through salt formation, more of the API is available in the body leading, which in turn leads to lower effective therapeutic amounts needed to be administered. Accordingly, Elder et. al. suggest that the formation of API salts, which include hydrogen sulfate salts, would be an improvement over the free molecule in terms of hydrolytic stability.
Therefore it would have been obvious before the effective filing date of the instant application to modify the invention of Le Tiran’101, that is for a method of preparing 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4- hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, in view of Elder et. al., that is to form the hydrogen sulfate salt. One of ordinary skill in the art would be motivated to make this modification to enhance the crystallinity of the compound. Lastly one of ordinary skill in the art would have a reasonable expectation of success because the enhanced crystal form had increased hydrolytic stability. Thus by improving the hydrolytic stability of a compound more of the compound is available in the body leading to lower effective therapeutic amounts needed to be administered.
Claim 1 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3 – 4, 6 – 7, and 9 – 11 of U.S. Patent No. 11058689 B2 to Le Tiran et. al. (Le Tiran’689) in view of Elder et. al., ((2013), Use of pharmaceutical salts and cocrystals, International Journal of Pharmaceutics, 453, 88-100; cited on the IDS dated August 27th, 2024).
Le Tiran’689 recite a method of the preparation of a compound of formula (I’):
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wherein (reference) R3-5, A1-2, T, and Ra-d that can be selected to form 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinolin-2(1H)-yl]-carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4-hydroxypheny1)-1,2-dimethyl-1H-pyrrole-3-carboxamide or an enantiomer, a diastereoisomer, or an addition salt thereof with a pharmaceutically acceptable acid or base. See reference claims 1, 3 – 4, 6 – 7, and 9 – 11. See examined claim 1.
However, while Le Tiran’689 recite that the selected compound can be in the form of an acid addition salt; Le Tiran’689 fail to recite a compound where the compound is a hydrogen sulfate salt. See examined claim 1.
Nevertheless, Elder et. al. teach the use of salt formations as a simple and cost-effective strategy to address poor solubility in water and the enhance bioavailability. See page 88 column 1 paragraph 1. Furthermore, Elder et. al. teach that the strong inorganic acid sulfuric acid can be used to make sulfates, that is hydrogen sulfate salts. See page 96 Table 2. Moreover, Elder et. al. teach that the formation of active pharmaceutical ingredient (API) salts, which include hydrogen sulfate salts, have enhanced crystallinity compared to the free or unsalted molecule. See page 96 Table 2. Furthermore, Elder et. al. teach that the enhanced crystallinity of the sulfate salts lead to increased hydrolytic stability when compared to the free or unsalted molecule. See page 96 Table 2. Thus, Elder et. al. suggest that by improving the hydrolytic stability of an API, through salt formation, more of the API is available in the body leading, which in turn leads to lower effective therapeutic amounts needed to be administered. Accordingly, Elder et. al. suggest that the formation of API salts, which include hydrogen sulfate salts, would be an improvement over the free molecule in terms of hydrolytic stability.
Therefore it would have been obvious before the effective filing date of the instant application to modify the invention of Le Tiran’689, that is for a method of preparing 5-(5-chloro-2-{[(3S)-3-(morpholin-4-ylmethyl)-3,4- dihydroisoquinolin-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)-N-(4- hydroxyphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide, in view of Elder et. al., that is to form the hydrogen sulfate salt. One of ordinary skill in the art would be motivated to make this modification to enhance the crystallinity of the compound. Lastly one of ordinary skill in the art would have a reasonable expectation of success because the enhanced crystal form had increased hydrolytic stability. Thus by improving the hydrolytic stability of a compound more of the compound is available in the body leading to lower effective therapeutic amounts needed to be administered.
Conclusion
Claims 1, 5, 7, 9 – 10, and 17 are rejected. Claims 2 – 4, 6, 8, and 11 – 16 are objected.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
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