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 .
Status of the Claims
Claims 1-27 are pending in the application. Claims 1-27 are examined herein.
Priority
This application claims priority to PRO 63/526,327 filed 07/12/2023.
The subject matter of the instant claims are supported by PRO 63/526,327. Accordingly, the effective filing date of instant claims 1-27 is 07/12/2023.
Information Disclosure Statement
The information disclosure statement submitted 01/16/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 7-10 and 13-14 are objected to because of the following informalities:
In claims 7-10 and 13-14, line 1 of these claims, suggest amending the claims to read “The compound of claim …, further having a characteristic absorption peak …” for clarity of claim language.
Appropriate correction is required.
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.
Claims 21 and 23-27 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.
Regarding claim 21, the claim recites “… arthritis (rheumatoid and psoriatic), multiple sclerosis, …”. The presence of limitations in parentheses renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Thus, the metes and bounds of the claim are indefinite.
For the purposes of applying prior art, claim 21 has been interpreted to read “… rheumatoid arthritis, [[(rheumatoid and psoriatic)]]and psoriatic arthritis, multiple sclerosis, …”.
Regarding claims 23-27, the claims recite “A method of making the crystalline compound of … using crystal seeding”. The method does not recite any positive method steps. There is no way of knowing how to synthesize the respective crystalline forms since the method claim does not recite what the starting material is or how the seeding process is performed. Does the seeding process involve seeds in dry or slurry form?, What is the seed loading amount?, etc. Therefore, the metes and bounds of claims 23-27 are indefinite.
For the purposes of applying prior art, the method of claims 23-27 have been given the broadest reasonable interpretation to involve any method of crystalline solid form preparation involving a seeding procedure to arrive at the recited crystalline forms.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or 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 1-3 and 16-22 are rejected under 35 U.S.C. 103 as being unpatentable over Jackson et al. (WO 2019/147862 A1, 01 August 2019, in the IDS, hereinafter Jackson, in the IDS) in view of Karagianni et al. (Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs, published 25 January 2018, hereinafter Karagianni).
Regarding instant claims 1-2, Jackson teaches compounds and methods of use for the modulation of certain chemokine receptor activity (Abstract). Jackson teaches a compound having structural Formula (I) or a pharmaceutically acceptable salt thereof, with variables as defined (Para. [0003]).
PNG
media_image1.png
125
312
media_image1.png
Greyscale
Jackson teaches an exemplary compound in an embodiment, as shown below (Para. [0664], Pg. 213; Para. [0790]; Claim 71).
PNG
media_image2.png
214
244
media_image2.png
Greyscale
The above compound of Jackson is (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-
dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-
methylcyclobutane-1-carboxylic acid and thus, anticipates the compound of claim 1. Jackson teaches the compounds exist as salts that include tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures) among various other salts (Para. [0056]). Jackson teaches certain compounds may exist in multiple crystalline forms as well as solvated or hydrated forms (Para. [0059).
Jackson does not explicitly teach that the disclosed compound, (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid exists in a crystalline salt form and have not attempted to crystallize any of the compounds.
Karagianni teaches the optimization of properties including solubility, dissolution rate, mechanical properties, hygroscopicity, physical stability and chemical stability is of strategic importance in determining the physical form in which active pharmaceutical ingredients (APIs) will be administered (Pg. 1, first paragraph). Karagianni teaches various solid-phase modifications that include a multi-component crystalline form, specifically “hydrated/solvated salts and their polymorphs” (Pg. 1, last paragraph; Figure 1). Karagianni teaches salt formation is common between acidic and basic or zwitter-ionic substances, and is a simple, cost-effective method for improving low water solubility and enhancing an API’s bioavailability (Pg. 2, last paragraph). Karagianni teaches an instance of improved bioavailability of a poorly soluble drug, Merck L-883555, on forming a cocrystal with L-tartaric acid (Pg. 12, last paragraph – Pg. 13, continued paragraph).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Jackson and Karagianni, to have synthesized a crystalline salt form of (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid, wherein the salt is a tartaric acid salt, to arrive at the crystalline salt form of the instant claims with a reasonable expectation of success. Jackson anticipates the compound of instant claims 1-2. Jackson teaches the compounds exist as salts that include tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures). Jackson teaches certain compounds may exist in multiple crystalline forms as well as solvated or hydrated forms. Karagianni teaches the optimization of properties including solubility, dissolution rate, mechanical properties, hygroscopicity, physical stability and chemical stability is of strategic importance in determining the physical form in which active pharmaceutical ingredients (APIs) will be administered. Karagianni teaches various solid-phase modifications that include a multi-component crystalline form, specifically “hydrated/solvated salts and their polymorphs”. Karagianni teaches salt formation is common between acidic and basic or zwitter-ionic substances, and is a simple, cost-effective method for improving low water solubility and enhancing an API’s bioavailability, with tartaric acid as a key example.
Therefore, one of ordinary skill in the art would be motivated to synthesize a crystalline form of (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid tartaric acid salt. The motivation being for improving low water solubility and enhancing an API’s bioavailability (Karagianni, Pg. 2, last paragraph).
According to MPEP 2144.05(II)(A), "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions. See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007)". In the instant case, tartaric acid is among a finite list of commonly screened salts forms of (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid taught by Jackson (Para. [0056]), rendering it prima facie obvious.
Regarding instant claim 3, the combined teachings of Jackson and Karagianni render obvious the crystalline form of (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid tartaric acid salt. Karagianni teaches various solid-phase modifications that include a multi-component crystalline form, specifically “hydrated/solvated salts and their polymorphs” (Pg. 1, last paragraph; Figure 1). Karagianni teaches the hydrates are viable forms for drug products as there are no safety concerns surrounding water as a crystal adduct (Pg. 2, last paragraph).
Therefore, one of ordinary skill in the art would be motivated to synthesize a hemi-L-tartaric acid crystalline salt form of (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid, to arrive at the compound of the instant claims with a reasonable expectation of success. The motivation being to synthesize a viable form of the drug with no safety concerns surrounding the crystal adduct (Karagianni, Pg. 2, last paragraph).
According to MPEP 2144.05(II)(A), "It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions. See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007)". In the instant case, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to optimize the stoichiometric salt ratio, e.g., mono- vs. hemi- tartaric acid, to arrive at the hemi-L-tartrate hydrate of (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid, given the teachings of Jackson and Karagianni.
Regarding instant claims 16-17, the combined teachings of Jackson and Karagianni render obvious the crystalline form of (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid salt. Jackson teaches a pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound or a pharmaceutically acceptable salt thereof, wherein the excipient is a suitable vehicle (Para. [0680]; Claim 44). Jackson teaches the compositions in various dosage forms for oral administration (Para. [0061]; Para. [0092]). This renders the limitations of instant claims 16-17 prima facie obvious.
Regarding instant claims 18-22, the combined teachings of Jackson and Karagianni render obvious the crystalline form of (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid salt. Jackson teaches the compounds as inhibitors of C-C chemokine receptor type 4 (CCR4) (Para. [0013]). Jackson teaches a method of treating or preventing a disease or disorder mediated by CCR4, including administering to a subject in need thereof a therapeutically effective amount of a compound, wherein the disease or disorder is an immune or inflammatory disorder (Paras. [0690]-[0691; Para. [0694]; Para. [0696]; Paras. [0073-[0074]; [0081]). Jackson teaches embodiments wherein the disease or disorder is cancer (Para. [0693]; Para. [0696]; Paras. [0075]-[0080]). Jackson teaches the disease or disorder of the instant claims 18-22, rendering them prima facie obvious.
Claims 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Jackson et al. (WO 2019/147862 A1, 01 August 2019, in the IDS, hereinafter Jackson, in the IDS) in view of Karagianni et al. (Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs, published 25 January 2018, hereinafter Karagianni) as applied to claims 1-3 and 16-22 above, and further in view of Parambil et al. (Seeding in Crystallisation, 2017, hereinafter Parambil).
The teachings of Jackson and Karagianni are set forth in the obviousness rejection above and incorporated herein by reference.
Regarding instant claims 23-25, the combined teachings of Jackson and Karagianni render obvious the crystalline form of (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid salt as in instant claims 1-3. Karagianni teaches various methods of cocrystal preparation (Pg. 14, first full paragraph - Pg. 20, last paragraph) (Some of these methods, such solvent evaporation or slurry conversion can be used in the preparation of salt hydrates of the instant claims).
Jackson and Karagianni do not teach preparing the crystalline compound by crystal seeding.
Parambil teaches seeding as one of the most critical steps in optimising the crystallization process that involves the process of adding homogeneous or heterogeneous crystals to a crystallising solution to nucleate and/or grow more crystals (Abstract). Parambil teaches that seeding separates crystal nucleation from growth in large-scale processes (section 13.3). Parambil teaches this controls crystal size and polymorphism while avoiding difficult nucleation control by optimising critical factors, such as seed amount, temperature, size, shape, surface area, porosity, and chemistry (section 13.3). Parambil teaches an aptly designed seeding technique would ensure product reproducibility between batches or over time (Abstract).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, in view of the teachings of Jackson, Karagianni and Parambil, to have synthesized the crystalline form of (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid salt, to arrive at the method of the instant claims with a reasonable expectation of success. The combined teachings of Jackson and Karagianni render obvious the crystalline form of (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid salt as in instant claims 1-3. Karagianni teaches various methods of cocrystal preparation that can be applied to the preparation of the instant crystalline salt forms. Parambil teaches seeding as one of the most critical steps in optimising the crystallization process. Parambil teaches an aptly designed seeding technique would ensure product reproducibility between batches or over time.
Therefore, one of ordinary skill in the art would be motivated to prepare the crystalline form of (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid salt using the process of crystal seeding. The motivation being to ensure product reproducibility between batches or over time (Parambil, Abstract).
Claims 4-15 and 26-27 objected to as being dependent upon a rejected base claim.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-3 and 16-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10 and 17-18 of U.S. Patent No. 10,683,280 B2 in view of Jackson et al. (WO 2019/147862 A1, 01 August 2019, in the IDS, hereinafter Jackson, in the IDS), Karagianni et al. (Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs, published 25 January 2018, hereinafter Karagianni) and Parambil et al. (Seeding in Crystallisation, 2017, hereinafter Parambil).
Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid or a pharmaceutically acceptable salt thereof.
The instant claims are drawn to crystalline salt forms of (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid.
The claims of the reference ‘280 patent are drawn to a compound having the formula shown below, or a pharmaceutically acceptable salt thereof.
PNG
media_image3.png
369
307
media_image3.png
Greyscale
The above compound anticipates (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid of the instant claims. The reference ‘280 patent does not teach a crystalline salt form of the above compound; a crystalline form of the tartaric acid salt thereof; a crystalline form of the hemi-L-tartrate hydrate salt thereof; a pharmaceutical composition thereof; methods of treatment thereof; or a method of making thereof as recited in the instant claims.
Jackson anticipates the instant compound, (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid and teaches the compounds exist as salts that include tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures) among various other salts (Para. [0056]). Jackson teaches certain compounds may exist in multiple crystalline forms as well as solvated or hydrated forms (Para. [0059).
Karagianni teaches various solid-phase modifications that include a multi-component crystalline form, specifically “hydrated/solvated salts and their polymorphs” (Pg. 1, last paragraph; Figure 1). Karagianni teaches salt formation is common between acidic and basic or zwitter-ionic substances, and is a simple, cost-effective method for improving low water solubility and enhancing an API’s bioavailability (Pg. 2, last paragraph). Karagianni teaches an instance of improved bioavailability of a poorly soluble drug, Merck L-883555, on forming a cocrystal with L-tartaric acid (Pg. 12, last paragraph – Pg. 13, continued paragraph). Using a similar rationale as that of the 35 U.S.C. 103 rejection above, the synthesis of the tartaric acid salt crystalline form and hemi-L-tartrate hydrate crystalline form, are rendered prima facie obvious. See MPEP 2144.05(II)(A) cited above for routine optimization.
Jackson teaches a pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound or a pharmaceutically acceptable salt thereof, wherein the excipient is a suitable vehicle (Para. [0680]; Claim 44). Jackson teaches the compositions in various dosage forms for oral administration (Para. [0061]; Para. [0092]). Jackson teaches the compounds as inhibitors of C-C chemokine receptor type 4 (CCR4) (Para. [0013]). Jackson teaches a method of treating or preventing a disease or disorder mediated by CCR4, including administering to a subject in need thereof a therapeutically effective amount of a compound, wherein the disease or disorder is an immune or inflammatory disorder (Paras. [0690]-[0691; Para. [0694]; Para. [0696]; Paras. [0073-[0074]; [0081]). Jackson teaches embodiments wherein the disease or disorder is cancer (Para. [0693]; Para. [0696]; Paras. [0075]-[0080]).
Therefore, the teachings of the reference ‘280 patent in view of Jackson and Karagianni render the pharmaceutical composition of instant claims 16-17 and the method of instant claims 18-22, prima facie obvious.
Karagianni teaches various methods of cocrystal preparation (Pg. 14, first full paragraph - Pg. 20, last paragraph) (Some of these methods, such solvent evaporation or slurry conversion can be used in the preparation of salt hydrates of the instant claims). Parambil teaches seeding as one of the most critical steps in optimising the crystallization process that involves the process of adding homogeneous or heterogeneous crystals to a crystallising solution to nucleate and/or grow more crystals (Abstract). Parambil teaches that seeding separates crystal nucleation from growth in large-scale processes (section 13.3). Parambil teaches an aptly designed seeding technique would ensure product reproducibility between batches or over time (Abstract).
Therefore, the teachings of the reference ‘280 patent in view of Jackson, Karagianni and Parambil, render the method of instant claims 23-25, prima facie obvious.
The instant claims 1-3 and 16-25 and claims 1, 10 and 17-18 of U.S. Patent No. 10,683,280 B2 are therefore not patentably distinct, in view of Jackson, Karagianni and Parambil.
This is a nonstatutory double patenting rejection.
Claims 1-3 and 16-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 15-16 and 24 of U.S. Patent No. 11,384,064 B2 in view of Jackson et al. (WO 2019/147862 A1, 01 August 2019, in the IDS, hereinafter Jackson, in the IDS), Karagianni et al. (Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs, published 25 January 2018, hereinafter Karagianni) and Parambil et al. (Seeding in Crystallisation, 2017, hereinafter Parambil).
Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid or a pharmaceutically acceptable salt thereof.
The instant claims are drawn to crystalline salt forms of (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid.
The claims of the reference ‘064 patent are drawn to a method of treating or preventing inflammation in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a compound of structural Formula (IIb), with specific species of the compound embodied in claims 15-16 and 24 (structure shown below).
PNG
media_image4.png
390
375
media_image4.png
Greyscale
The above compound anticipates (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid of the instant claims. The reference ‘064 patent does not teach a crystalline salt form of the above compound; a crystalline form of the tartaric acid salt thereof; a crystalline form of the hemi-L-tartrate hydrate salt thereof; a pharmaceutical composition thereof; methods of treatment of other immune-related and cancer-related disease or disorder; or a method of making thereof, as recited in the instant claims.
Jackson anticipates the instant compound, (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid and teaches the compounds exist as salts that include tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures) among various other salts (Para. [0056]). Jackson teaches certain compounds may exist in multiple crystalline forms as well as solvated or hydrated forms (Para. [0059).
Karagianni teaches various solid-phase modifications that include a multi-component crystalline form, specifically “hydrated/solvated salts and their polymorphs” (Pg. 1, last paragraph; Figure 1). Karagianni teaches salt formation is common between acidic and basic or zwitter-ionic substances, and is a simple, cost-effective method for improving low water solubility and enhancing an API’s bioavailability (Pg. 2, last paragraph). Karagianni teaches an instance of improved bioavailability of a poorly soluble drug, Merck L-883555, on forming a cocrystal with L-tartaric acid (Pg. 12, last paragraph – Pg. 13, continued paragraph). Using a similar rationale as that of the 35 U.S.C. 103 rejection above, the synthesis of the tartaric acid salt crystalline form and hemi-L-tartrate hydrate crystalline form, are rendered prima facie obvious. See MPEP 2144.05(II)(A) cited above for routine optimization.
Jackson teaches a pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound or a pharmaceutically acceptable salt thereof, wherein the excipient is a suitable vehicle (Para. [0680]; Claim 44). Jackson teaches the compositions in various dosage forms for oral administration (Para. [0061]; Para. [0092]). Jackson teaches the compounds as inhibitors of C-C chemokine receptor type 4 (CCR4) (Para. [0013]). Jackson teaches a method of treating or preventing a disease or disorder mediated by CCR4, including administering to a subject in need thereof a therapeutically effective amount of a compound, wherein the disease or disorder is an immune or inflammatory disorder (Paras. [0690]-[0691; Para. [0694]; Para. [0696]; Paras. [0073-[0074]; [0081]). Jackson teaches embodiments wherein the disease or disorder is cancer (Para. [0693]; Para. [0696]; Paras. [0075]-[0080]).
Therefore, the teachings of the reference ‘064 patent in view of Jackson and Karagianni render the pharmaceutical composition of instant claims 16-17 and the method of instant claims 18-22, prima facie obvious.
Karagianni teaches various methods of cocrystal preparation (Pg. 14, first full paragraph - Pg. 20, last paragraph) (Some of these methods, such solvent evaporation or slurry conversion can be used in the preparation of salt hydrates of the instant claims). Parambil teaches seeding as one of the most critical steps in optimising the crystallization process that involves the process of adding homogeneous or heterogeneous crystals to a crystallising solution to nucleate and/or grow more crystals (Abstract). Parambil teaches that seeding separates crystal nucleation from growth in large-scale processes (section 13.3). Parambil teaches an aptly designed seeding technique would ensure product reproducibility between batches or over time (Abstract).
Therefore, the teachings of the reference ‘064 patent in view of Jackson, Karagianni and Parambil, render the method of instant claims 23-25, prima facie obvious.
The instant claims 1-3 and 16-25 and claims 1-2, 15-16 and 24 of U.S. Patent No. 11,384,064 B2 are therefore not patentably distinct, in view of Jackson, Karagianni and Parambil.
This is a nonstatutory double patenting rejection.
Claims 1-3 and 16-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 11 and 22-24 of U.S. Patent No. 12,098,139 B2 in view of Jackson et al. (WO 2019/147862 A1, 01 August 2019, in the IDS, hereinafter Jackson, in the IDS), Karagianni et al. (Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs, published 25 January 2018, hereinafter Karagianni) and Parambil et al. (Seeding in Crystallisation, 2017, hereinafter Parambil).
Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid or a pharmaceutically acceptable salt thereof.
The instant claims are drawn to crystalline salt forms of (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid.
The claims of the reference ‘139 patent are drawn to a method of treating or pain in a subject comprising administering to said subject a therapeutically effective amount of a compound of structural Formula (I), with specific species of the compound embodied in claim 11 (structure shown below).
PNG
media_image5.png
328
343
media_image5.png
Greyscale
The above compound anticipates (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid of the instant claims. The reference ‘139 patent does not teach a crystalline salt form of the above compound; a crystalline form of the tartaric acid salt thereof; a crystalline form of the hemi-L-tartrate hydrate salt thereof; methods of treatment of other immune-related and cancer-related disease or disorder; or a method of making thereof, as recited in the instant claims.
Jackson anticipates the instant compound, (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid and teaches the compounds exist as salts that include tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures) among various other salts (Para. [0056]). Jackson teaches certain compounds may exist in multiple crystalline forms as well as solvated or hydrated forms (Para. [0059).
Karagianni teaches various solid-phase modifications that include a multi-component crystalline form, specifically “hydrated/solvated salts and their polymorphs” (Pg. 1, last paragraph; Figure 1). Karagianni teaches salt formation is common between acidic and basic or zwitter-ionic substances, and is a simple, cost-effective method for improving low water solubility and enhancing an API’s bioavailability (Pg. 2, last paragraph). Karagianni teaches an instance of improved bioavailability of a poorly soluble drug, Merck L-883555, on forming a cocrystal with L-tartaric acid (Pg. 12, last paragraph – Pg. 13, continued paragraph). Using a similar rationale as that of the 35 U.S.C. 103 rejection above, the synthesis of the tartaric acid salt crystalline form and hemi-L-tartrate hydrate crystalline form, are rendered prima facie obvious. See MPEP 2144.05(II)(A) cited above for routine optimization.
Claims 22-14 of the reference ‘139 patent in view of Jackson and Karagianni renders obvious the pharmaceutical composition of instant claims 16-17.
Jackson teaches the compounds as inhibitors of C-C chemokine receptor type 4 (CCR4) (Para. [0013]). Jackson teaches a method of treating or preventing a disease or disorder mediated by CCR4, including administering to a subject in need thereof a therapeutically effective amount of a compound, wherein the disease or disorder is an immune or inflammatory disorder (Paras. [0690]-[0691; Para. [0694]; Para. [0696]; Paras. [0073-[0074]; [0081]). Jackson teaches embodiments wherein the disease or disorder is cancer (Para. [0693]; Para. [0696]; Paras. [0075]-[0080]).
Therefore, the teachings of the reference ‘139 patent in view of Jackson and Karagianni render the method of instant claims 18-22, prima facie obvious.
Karagianni teaches various methods of cocrystal preparation (Pg. 14, first full paragraph - Pg. 20, last paragraph) (Some of these methods, such solvent evaporation or slurry conversion can be used in the preparation of salt hydrates of the instant claims). Parambil teaches seeding as one of the most critical steps in optimising the crystallization process that involves the process of adding homogeneous or heterogeneous crystals to a crystallising solution to nucleate and/or grow more crystals (Abstract). Parambil teaches that seeding separates crystal nucleation from growth in large-scale processes (section 13.3). Parambil teaches an aptly designed seeding technique would ensure product reproducibility between batches or over time (Abstract).
Therefore, the teachings of the reference ‘139 patent in view of Jackson, Karagianni and Parambil, render the method of instant claims 23-25, prima facie obvious.
The instant claims 1-3 and 16-25 and claims 1, 3, 11 and 22-24 of U.S. Patent No. 12,098,139 B2 are therefore not patentably distinct, in view of Jackson, Karagianni and Parambil.
This is a nonstatutory double patenting rejection.
Claims 1-3 and 16-25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 85, 87 and 89 of co-pending Application No 18/808,638 in view of Jackson et al. (WO 2019/147862 A1, 01 August 2019, in the IDS, hereinafter Jackson, in the IDS), Karagianni et al. (Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs, published 25 January 2018, hereinafter Karagianni) and Parambil et al. (Seeding in Crystallisation, 2017, hereinafter Parambil).
Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid or a pharmaceutically acceptable salt thereof.
The instant claims are drawn to crystalline salt forms of (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid.
The claims of the co-pending ‘638 application are drawn to a method of using intermediates in the synthesis of a compound that anticipates the compound of the instant claims, wherein Riv is hydrogen.
PNG
media_image6.png
318
594
media_image6.png
Greyscale
The claims of the co-pending ‘638 application does not recite a crystalline salt form of the above compound; a crystalline form of the tartaric acid salt thereof; a crystalline form of the hemi-L-tartrate hydrate salt thereof; a pharmaceutical composition thereof; methods of treatment of other immune-related and cancer-related disease or disorder; or a method of making thereof, as recited in the instant claims.
Jackson anticipates the instant compound, (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid and teaches the compounds exist as salts that include tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures) among various other salts (Para. [0056]). Jackson teaches certain compounds may exist in multiple crystalline forms as well as solvated or hydrated forms (Para. [0059).
Karagianni teaches various solid-phase modifications that include a multi-component crystalline form, specifically “hydrated/solvated salts and their polymorphs” (Pg. 1, last paragraph; Figure 1). Karagianni teaches salt formation is common between acidic and basic or zwitter-ionic substances, and is a simple, cost-effective method for improving low water solubility and enhancing an API’s bioavailability (Pg. 2, last paragraph). Karagianni teaches an instance of improved bioavailability of a poorly soluble drug, Merck L-883555, on forming a cocrystal with L-tartaric acid (Pg. 12, last paragraph – Pg. 13, continued paragraph). Using a similar rationale as that of the 35 U.S.C. 103 rejection above, the synthesis of the tartaric acid salt crystalline form and hemi-L-tartrate hydrate crystalline form, are rendered prima facie obvious. See MPEP 2144.05(II)(A) cited above for routine optimization.
Jackson teaches a pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound or a pharmaceutically acceptable salt thereof, wherein the excipient is a suitable vehicle (Para. [0680]; Claim 44). Jackson teaches the compositions in various dosage forms for oral administration (Para. [0061]; Para. [0092]). Jackson teaches the compounds as inhibitors of C-C chemokine receptor type 4 (CCR4) (Para. [0013]). Jackson teaches a method of treating or preventing a disease or disorder mediated by CCR4, including administering to a subject in need thereof a therapeutically effective amount of a compound, wherein the disease or disorder is an immune or inflammatory disorder (Paras. [0690]-[0691; Para. [0694]; Para. [0696]; Paras. [0073-[0074]; [0081]). Jackson teaches embodiments wherein the disease or disorder is cancer (Para. [0693]; Para. [0696]; Paras. [0075]-[0080]).
Therefore, the teachings of the reference ‘638 application in view of Jackson and Karagianni render the pharmaceutical composition of instant claims 16-17 and the method of instant claims 18-22, prima facie obvious.
Karagianni teaches various methods of cocrystal preparation (Pg. 14, first full paragraph - Pg. 20, last paragraph) (Some of these methods, such solvent evaporation or slurry conversion can be used in the preparation of salt hydrates of the instant claims). Parambil teaches seeding as one of the most critical steps in optimising the crystallization process that involves the process of adding homogeneous or heterogeneous crystals to a crystallising solution to nucleate and/or grow more crystals (Abstract). Parambil teaches that seeding separates crystal nucleation from growth in large-scale processes (section 13.3). Parambil teaches an aptly designed seeding technique would ensure product reproducibility between batches or over time (Abstract).
Therefore, the teachings of the reference ‘638 application in view of Jackson, Karagianni and Parambil, render the method of instant claims 23-25, prima facie obvious.
The instant claims 1-3 and 16-25 and claims 85,87 and 89 of co-pending Application No 18/808,638 are therefore not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Objection to Claims, Allowable Subject Matter
The specific crystalline form of the hemi-L-tartrate hydrate salt of (1R,3r)-3-((R)-3-(1-(5-chloro-4-((R)-1-(2,4-dichlorophenyl)ethyl)amino)-6-methylpyrimidin-2-yl)azetidin-3-yl)piperidin-1-yl)-1-methylcyclobutane-1-carboxylic acid as in instant claims 6 and 12 are free of prior art.
Except for the above objections, 35 U.S.C. 112(b) rejection and statutory double patenting rejections, claims 4-15 and 26-27 would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Claims 1-3 and 16-27 are rejected.
Claims 4-15 and 26-27 are objected to.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PADMAJA S RAO whose telephone number is (571) 272-9918. The examiner can normally be reached 9:00-5:30 pm EDT.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney L Klinkel can be reached on (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/PADMAJA S RAO/Examiner, Art Unit 1627
Prosecution Insights