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 .
DETAILED ACTION
The preliminary amendment filed 06/12/2024, amended claim 15 and added claim 16.
Claims 1-16 are pending and examined on the merits herein.
Priority
This application claims the following priority:
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Title
See MPEP 606, “Novel” is a word that should not be included at the beginning of the title of the invention and will be deleted when the Office enters the title into the Office’s computer records.
Claim Rejections - 35 USC § 112(a)-Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 16 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for treating cancer, inflammatory diseases, autoimmune disease, or fibrosis, does not reasonably provide enablement for a method for preventing cancer, inflammatory diseases, autoimmune disease, or fibrosis. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The criteria for enablement set out in the In re Wands, MPEP 2164.01(a), considers the following factors:
Breadth of the Claims
Independent claim 16 is directed toward a method of treating any cancer, cany inflammatory disease, any autoimmune disease, or any fibrosis, comprising administering, to a subject in need thereof, and effective amount of:
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As such, the breadth of the claims is great.
Level of Skill in Art
The level of skill in the art is a clinician or an artisan with a PhD.
State of the Prior Art
While the prior art teaches methods of treating cancer, inflammatory diseases, autoimmune diseases, and fibrotic diseases, the prior art does not teach methods of preventing these diseases.
As taught by the University of Kansas Cancer Center (Prevention and Risk Reduction, PTO-892), no cancer is 100% preventable, though managing risk factors can lower one’s chance of developing certain cancers (pg. 1).
As taught by Boston Children’s Hospital (Autoimmune Diseases, PTO-892), there is nothing that can be done to prevent an autoimmune diseases (pgs. 4, 6).
While US 2019/0359617 to Lee (IDS of 08/04/2025) teaches pharmaceutical compositions comprising its compounds, i.e., (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, for the prevention or treatment of cancers, inflammatory diseases, autoimmune diseases, or fibrosis (pg. 70, claim 12), it merely exemplifies inhibitory IC50 value of its compounds for phosphoribosylpyrophosphate synthetase enzyme activity.
Predictability in the Art
In view of the teachings of the University of Kansas, Boston, Children’s Hospital, and Lee, it is not predictably in the art to prevent the instantly claimed diseases as recited in instant claim 16.
Working Examples
The instant specification provides zero examples of treating or preventing cancer, inflammatory disease, autoimmune disease, or fibrosis, with the instantly claimed compounds.
Direction and Guidance
In view of the unpredictability in the art, as established by the University of Kansas, Boston Children’s Hospital, and Lee, and in view of the lack of working examples, the instant specification fails to provide sufficient direction or guidance to use the instantly claimed compounds as claimed.
Quantity of Experimentation
The amount of experimentation required to determine which of the recited compounds at what dosages, in what dosing regimens, prevent which cancers, which inflammatory diseases, which autoimmune diseases, and which fibrosis, would be astronomical. This amounts to invention, not development; it is an undue amount of experimentation.
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 for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 9 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over US PG Pub 2019/0359617 to Lee (published 2019, IDS) in view of Gupta (Salts of Therapeutic Agents: Chemical, physicochemical, and Biological Considerations, Molecules, published 2018, PTO-892).
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Lee teaches:
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([423]-[432]).
Lee teaches the above species as compounds of
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, and pharmaceutically acceptable salts thereof.
Lee teaches that “the compounds of the present invention may exist in the form of a pharmaceutically acceptable salt,” and “both solvates and hydrates which can be prepared therefrom.” “The salts or solvates of the compound represented by Chemical Formula I can be prepared from the compounds represented by Chemical Formula I using conventional methods in the technical field to which the present invention pertains.” Lee exemplifies hydrochloric acid and maleic acid as such salts ([0262]-[0264]).
Lee teaches that “the compound represented by Chemical Formula I according to the present invention can be prepared in crystalline form or non-crystalline form. When the compound presented by Chemical Formula I is produced in crystalline form, it may be optionally hydrated or solvated. The present invention may include not only stoichiometric hydrates of the compound represented by Chemical Formula 1 but also compounds containing various amounts of water. The solvates of the compound represented by Chemical Formula 1 according to the present invention include both stoichiometric solvates and non-stoichiometric solvates” ([0265]).
While Lee teaches (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol and exemplifies the dihydrochloride salt thereof, it differs from that of instant claims 1, 3 and 9, in that it does not teach the monohydrochloride salt or maleate salt.
Gupta teaches that the physicochemical and biological properties of active pharmaceutical ingredients are greatly affected by their salts forms. The choice of a particular salt formulation is based on numerous factors such as active pharmaceutical ingredient (API) chemistry, intended dosage form, pharmacokinetics and pharmacodynamics. The appropriate salt can improve the overall therapeutic and pharmaceutical effect of an API (abstract, pg. 12, “Conclusions”).
Gupta teaches that a salt with the associated water of crystallization is considered as a hydrate form and that hydrate forms of APIs are quite common. Water molecules in pharmaceutical hydrates influence the internal energy thermodynamic activity hygroscopicity, solubility, dissolution rate, and stability (pg. 4, 2.5).
Gupta teaches hydrochloride salts as one of the most common methods to increase the solubility of weakly acidic and basic drugs (pgs. 5-6, 2.8).
Gupta teaches maleate as a validated counterion that is used to prepare salts of APIs (paragraph spanning pgs. 1-2, Table 1).
Gupta teaches chloride and maleate as some of the most commonly used anions for oral dosage forms (pg. 8, 3.3).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select a monohydrochloride salt or a maleate salt as the salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol of Lee, to arrive at instant claims 1, 3, and 9. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Lee teaches that salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol may exist in the form of a pharmaceutically acceptable salt,
-Lee teaches that salts can be prepared using conventional methods in the technical field
-Lee exemplifies hydrochloric acid and maleic acid as such salts, and
-Gupta teaches hydrochloride salts as one of the most common methods to increase the
solubility drugs,
- Gupta teaches chloride and maleate as two of the most commonly used anions for oral
dosage forms,
-Gupta teaches that the physicochemical and biological properties of active
pharmaceutical ingredients are greatly affected by their salt forms and that the appropriate salt can improve the overall therapeutic and pharmaceutical effects of an API.
As such, an ordinary skilled artisan would have been motivated to make such a
selection, to predictably arrive at salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol with similar or greater therapeutic or physiochemical effects than (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol.
Further regarding the ratio of salt to (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," MPEP 2144.05(II). As such, an ordinary skilled artisan would have been motivated to modify the ratio of salt to (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, to predictably arrive at a drug product that is optimized for stability and therapeutic effect.
Regarding claims 15 and 16, Lee teaches pharmaceutical compositions comprising its compounds for the prevention or treatment of cancers, inflammatory diseases, autoimmune diseases, or fibrosis (pg. 70, claim 12).
Claims 2, 10 and 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over US PG Pub 2019/0359617 to Lee (published 2019, IDS of 08/04/2025) and Gupta (Salts of Therapeutic Agents: Chemical, physicochemical, and Biological Considerations, Molecules, published 2018, PTO-892), as applied to claims 1, 3, 9 and 15-16 above, and further in view of Morissette (High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids, published 2004, PTO-892).
Regarding claims 2, 10, and 13-14, while the combination of Lee and Gupta teaches (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol monohydrochloride or maleate salt, it differs from that of the instantly claimed invention in that it does not teach endothermic onset temperatures, endothermic peak temperature’s, or the X-ray powder diffraction pattern of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol monohydrochloride.
Morissette teaches that active pharmaceutical ingredients (APIs) can exist in a variety of distinct solid forms, including polymorphs and other forms. Each form displays unique physicochemical properties that can profoundly influence the bioavailability, manufacturability, purification, stability and other performance characteristics of the drug. Discovery and characterization of the diversity of solid forms of a drug substance provide options from which to select a form that exhibits the appropriate balance of critical properties for development into the drug product (pg. 276, 1st paragraph).
Morissette teaches that most APIs and theirs salts are purified and isolated by crystallization from an appropriate solvent during the final step in the synthetic process. A large number of factors influence crystal nucleation and growth during this processes, wherein the most notable are:
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(pgs. 276, Col. 2- pg. 277, Table 1).
Morissette teaches high throughput (HT) crystallization, wherein HT crystallization methodology is capable of screening hundreds or thousands of crystallization conditions, enabling more comprehensive exploration of solid form diversity. (title, abstract, pg. 96, 1st full paragraph). Morissette teaches that use of these systems has the potential to facilitate drug development by saving valuable time in selecting the optimal physical or chemical form of a given compound (pg. 297, final paragraph).
Morissette teaches that preparation of salt forms of an active compound is commonly used to modulate physicochemical properties with the goal of increasing solubility, improving bioavailability, or enhancing manufacturability of poorly soluble ionizable compounds. Salts may also be employed to increase chemical stability or to reduce the solubility of a given compound for certain applications. The relevant physicochemical properties of each salt art characterized, including degree of crystallinity, hygroscopicity, aqueous solubility, crystal habit, and physical and chemical stability. Based on these properties of the salt forms, their suitability for development can be evaluated. HT crystallization technologies are used to more rapidly and comprehensively identify the range of salt forms that may be prepared for a given compound or series of compounds, and characterize their crystal form diversity (pgs. 285-287, 3.1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol monohydrochloride or maleate salts of the combination of Lee and Gupta, to arrive at the compounds of instant claims 2, 10, and 13-14. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-the combination of Lee and Gupta teach (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol monohydrochloride or maleate salts,
-Lee teaches crystalline forms of its compounds,
-Morissette teaches that APIs are known to exist in many solid forms, wherein each form has its own unique properties,
-Morissette teaches that HT crystallization screens compounds for the selection of optimal physical and/or chemical forms of a compound,
-Morissette teaches that preparation of salt forms of an active compound is commonly used to modulate physicochemical properties with the goal of increasing solubility, improving bioavailability, or enhancing manufacturability of poorly soluble ionizable compounds,
-Morissette teaches that salts are employed to increase chemical stability or to reduce the solubility of a given compound for certain applications, and
-Morissette teaches that HT crystallization technologies are used to more rapidly and comprehensively identify the range of slat forms that may be prepared for a given compound or series of compounds, and characterize their crystal form diversity.
As such, an artisan having ordinary skill in the art would have been motivated to make such modifications via HT crystallization technology, to predictably arrive at a crystalline salt form of the of teach (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol monohydrochloride or maleate, that provides the most stable product with the greatest therapeutic effect.
Moreover, a prima facie case of obvious may be made when chemical compounds have very close structural similarities and similar utilities. See MPEP 2114.09.
Claims 3-4, 7, 9 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over US PG Pub 2019/0359617 to Lee (published 2019) in view of Saal (Pharmaceutical salts: A summary on doses of salt formers from the Orange Book, published 2013, IDS of 10/27/2025).
Lee is applied as discussed above and incorporated herein.
While Lee teaches (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, and salts thereof, it differs from that of instant claims 3-4, 7 and 9, in that it does not teach the oxalate or maleate salt.
Saal teaches that over half of the active pharmaceutical ingredients currently approved within the US are pharmaceutical salts and that selection of suitable pharmaceutical salts is carried out during late research or early development based on physicochemical behavior, dissolution rate, and pharmacokinetics of a pharmaceutical salt (abstract).
Saal teaches that salt formation is widely used in the pharmaceutical industry to optimize properties of candidate compounds. Selection of pharmaceutical salts provides a means to improve solubility, dissolution rate, supersaturation, drug absorption, and bioavailability of drugs compared to the parent form of the drug, without changing the pharmacologically active moiety. Beyond optimization of properties related to bioavailability, physicochemical properties of active pharmaceutical ingredients can be improved by salt selection, such as hygroscopicity, melting point, crystallinity, chemical as well as physical stability, impurity profile, or crystal habit (pg. 615, 1st paragraph).
Saal teaches maleate and oxalate salts as salt formers of AP1s (pg. 617, 2.1; pg. 616, Table 1).
Saal teaches that a number of maleate salts are listed in the FDA’s Orange Book. Since maleate has more than one acidic group, diverse stoichiometries are possible for salt formulation, such as 1:1 or 2:1 salt to API ratios (pg. 619, 2.1.20).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select a oxalate or maleate salt as the salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, of Lee, to arrive at instant claims 3-4, 7, and 9. One of ordinary skill in the art would have been motivated to make such selections, with a reasonable expectation of success, because:
-Lee teaches salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol may exist in the form of a pharmaceutically acceptable salt,
-Lee teaches that salts can be prepared using conventional methods in the technical field
-Lee teaches maleic acid as such a salt,
- Saal teaches maleate and oxalate salts as salt formers of basic AP1s
-Saal teaches that salt formation is widely used in the pharmaceutical industry to optimize
properties pharmaceutical active ingredients,
-Saal teaches that selection of pharmaceutical salts provides a means to improve
solubility, dissolution rate, supersaturation, drug absorption, and bioavailability of drugs compared to the parent form of the drug, without changing the pharmacologically active moiety, and
-Saal teaches that the physicochemical properties of active pharmaceutical ingredients can be improved by salt selection.
As such, an ordinary skilled artisan would have been motivated to make such a
selection, to predictably arrive at salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol with similar therapeutic or physicochemical effects.
Further regarding the ratio of salt to (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," MPEP 2144.05(II). As such, an ordinary skilled artisan would have been motivated to modify the ratio of salt to (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, to predictably arrive at a product that is optimized for stability and therapeutic effect.
Regarding claim 15, Lee teaches pharmaceutical compositions comprising its compounds for the prevention or treatment of cancers, inflammatory diseases, autoimmune diseases, or fibrosis (pg. 70, claim 12).
Claims 5-6, 8, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over US PG Pub 2019/0359617 to Lee (published 2019) in view of Saal (Pharmaceutical salts: A summary on doses of salt formers from the Orange Book, published 2013, IDS of 10/27/2025), as applied to claims 3-4, 7, 9 and 15-16 above, and further in view of Morissette (High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids, published 2004, PTO-892).
Lee and Saal are applied as discussed above and incorporated herein.
Regarding claims 5-6, 8, and 10 while the combination of Lee and Saal teaches (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol oxalate and maleate salt, it differs from that of the instantly claimed invention in that it does not teach endothermic onset temperatures or endothermic peak temperatures of the compounds.
Morissette is applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol oxalate or maleate salts of the combination of Lee and Gupta, to arrive at the compounds of instant claims 5-6, 8, and 10. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-the combination of Lee and Gupta teaches (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol oxalate or maleate salts,
-Lee teaches crystalline forms of its compounds,
-Morissette teaches that active ingredients are known to exist in many solid forms, wherein each form has its own unique properties,
-Morissette teaches that HT crystallization screens compounds for the selection of optimal physical and/or chemical forms of a compound,
-Morissette teaches that preparation of salt forms of an active compound is commonly used to modulate physicochemical properties with the goal of increasing solubility, improving bioavailability, or enhancing manufacturability of poorly soluble ionizable compounds,
-Morissette teaches that salts are employed to increase chemical stability or to reduce the solubility of a given compound for certain applications, and
-Morissette teaches that HT crystallization technologies are used to more rapidly and comprehensively identify the range of slat forms that may be prepared for a given compound or series of compounds, and characterize their crystal form diversity.
As such, an artisan having ordinary skill in the art would have been motivated to make such modifications via HT crystallization technology, to predictably arrive at a crystalline salt form of the of teach (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol oxalate or maleate, that provides the most stable product with the greatest therapeutic effect.
Moreover, a prima facie case of obvious may be made when chemical compounds have very close structural similarities and similar utilities. See MPEP 2114.09.
Claims 3, 11 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over US PG Pub 2019/0359617 to Lee (published 2019, IDS of 08/04/2025) in view of Serajuddin (Salt formation to improve drug solubility, published 2007, PTO-892) and Williams (Lipophilic Salts-Opportunities & Applications in Oral Drug Delivery, published 2016, PTO-892).
Lee is applied as discussed above and incorporated herein.
While Lee teaches (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, and salts thereof, it differs from that of instant claims 3, 11, and 15, in that it does not teach a palmitate salt.
Serajuddin teaches salt formation to improve drug solubility (title, abstract). Serajuddin teaches that salt formation is the most commonly applied technique of increasing solubility and dissolution rate in drug product development (pg. 604, 1st paragraph).
Serajuddin teaches that pharmaceutical salts are sometimes used to slow dissolution rates. “For certain pharmaceutical uses, such as inhalation products, parenteral depot systems, etc., drug substances are converted to relatively less soluble forms by salt formation with long chain fatty acids like stearic acid, palmitic acid, etc.,” wherein these salt forms dissolve much more slowly than the free base and other salt forms (pg. 611, paragraph spanning Cols. 1-2).
Williams teaches that lipophilic salts have increased solubility in lipidic vehicles relative to free base or acid API forms, and that lipid formulations have proven applications in enhancing oral bioavailability and providing a rapid onset of action (pg. 8).
Williams teaches that due to their distinct physical and solution properties, lipophilic salts are used for circumventing crystal polymorphism issues, for increasing aqueous solubility for oral or parenteral drug delivery, for dual function salts combining anion and cation actives in one complex for combined, unique, or enhanced pharmacological/pharmacodynamics, or for biopharmaceutical effects, enhanced permeation across hydrophobic barriers, and/or for enhanced API loading in lipid-based formulations (pgs. 2-3).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select a palmitate salt as the salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol in Lee, to arrive at instant claims 3 and 11. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Lee teaches that salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol may exist in the form of a pharmaceutically acceptable salt,
-Lee teaches that salts can be prepared using conventional methods in the technical field
-Serajuddin teaches that salt formation is the most commonly applied technique of increasing solubility and dissolution rate in drug product development,
-Serajuddin teaches palmitic acid salts as salt forms of APIs that dissolve much more slowly than the free base and other salt forms,
-Williams teaches that lipophilic salts have increased solubility in lipidic vehicles relative to free base or acid API forms, and that lipid formulations have proven applications in enhancing oral bioavailability and providing a rapid onset of action, and
-Williams teaches that lipophilic salts are used for circumventing crystal polymorphism issues, increasing aqueous solubility for oral or parenteral drug delivery, for dual function salts combining anion and cation actives in one complex for combined, unique, or enhanced pharmacological/pharmacodynamics or biopharmaceutical effects, enhanced permeation across hydrophobic barriers, and/or for enhanced API loading in lipid-based formulations.
As such, an ordinary skilled artisan would have been motivated to make such
a modification, to predictably arrive at a salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol with similar therapeutic or physicochemical effects, such as increased solubility in lipophilic formulations and increased bioavailability.
Regarding claim 15, Lee teaches pharmaceutical compositions comprising its compounds for the prevention or treatment of cancers, inflammatory diseases, autoimmune diseases, or fibrosis (pg. 70, claim 12).
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over US PG Pub 2019/0359617 to Lee (published 2019, IDS of 08/04/2025), Serajuddin (Salt formation to improve drug solubility, published 2007, PTO-892) and Williams (Lipophilic Salts-Opportunities & Applications in Oral Drug Delivery, published 2016, PTO-892), as applied to claims 3, 11 and 15-16, and further in view of Morissette (High-throughput crystallization: polymorphs, salts, co-crystals and solvates of pharmaceutical solids, published 2004, PTO-892).
Lee, Serajuddin, and Williams are applied as discussed above and incorporated herein.
While the combination of Lee, Serajuddin, and Williams teaches (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol palmitate salt, it differs from that of the instantly claimed invention in that it does not teach endothermic onset temperatures, and endothermic peak temperature.
Morissette is applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol palmitate salt of the combination of Lee, Serajuddin, and Williams, to arrive at the compounds of instant claim 12. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-the combination of Lee, Serajuddin, and Williams teaches (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol palmitate salt,
-Lee teaches crystalline forms of its compounds,
-Morissette teaches that active ingredients are known to exist in many solid forms, wherein each form has its own unique properties,
-Morissette teaches that HT crystallization screens compounds for the selection of optimal physical and/or chemical forms of a compound,
-Morissette teaches that preparation of salt forms of an active compound is commonly used to modulate physicochemical properties with the goal of increasing solubility, improving bioavailability, or enhancing manufacturability of poorly soluble ionizable compounds,
-Morissette teaches that salts are employed to increase chemical stability or to reduce the solubility of a given compound for certain applications, and
-Morissette teaches that HT crystallization technologies are used to more rapidly and comprehensively identify the range of slat forms that may be prepared for a given compound or series of compounds, and characterize their crystal form diversity.
As such, an artisan having ordinary skill in the art would have been motivated to make such modifications via HT crystallization technology, to predictably arrive at a crystalline salt form of the of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol palmitate, that provides the most stable product with the greatest therapeutic effect.
Moreover, a prima facie case of obvious may be made when chemical compounds have very close structural similarities and similar utilities. See MPEP 2114.09.
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 and 15-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims1 and 4 of copending Application No. 18/577,071 (claim set dated 06/12/2026).
‘071 claims a method of treating SSC-ILD, a fibrosis diseases, by administering a composition comprising (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol and salts thereof (claim 1).
Regarding claims 1 and 15, ‘071 claims the hydrochloride salt (claim 4).
Claims 1, 3-4, 7, 9, and 15-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of copending Application No. 18/577,071, in view of US PG Pub 2019/0359617 to Lee (published 2019) in view of Saal (Pharmaceutical salts: A summary on doses of salt formers from the Orange Book, published 2013, IDS of 10/27/2025).
This is a provisional nonstatutory double patenting rejection.
‘071 is applied as discussed above and incorporated herein.
‘071 differs from that of the instantly claimed invention in that it does not teach maleate or oxalate salts.
Lee and Saal are applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol of ‘071, to a maleate or oxalate salt, to arrive at instant claims 3-4, 7, and 9. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Lee teaches salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol may exist in the form of a pharmaceutically acceptable salt,
-Lee teaches that salts can be prepared using conventional methods in the technical field
-Lee teaches maleic acid as such a salt,
- Saal teaches maleate and oxalate salts as salt formers of basic AP1s
-Saal teaches that salt formation is widely used in the pharmaceutical industry to optimize
properties pharmaceutical active ingredients,
-Saal teaches that selection of pharmaceutical salts provides a means to improve
solubility, dissolution rate, supersaturation, drug absorption, and bioavailability of drugs compared to the parent form of the drug, without changing the pharmacologically active moiety, and
-Saal teaches that the physicochemical properties of active pharmaceutical ingredients can be improved by salt selection.
As such, an ordinary skilled artisan would have been motivated to make such
modifications, to predictably arrive at salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol with similar therapeutic or physicochemical effects.
Further regarding the ratio of salt to (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," MPEP 2144.05(II). As such, an ordinary skilled artisan would have been motivated to modify the ratio of salt to (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, to predictably arrive at a product that is optimized for stability and therapeutic effect.
Claims 1, 3, 11, and 15-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of copending Application No. 18/577,071, in view of US PG Pub 2019/0359617 to Lee (published 2019, IDS of 08/04/2025), Serajuddin (Salt formation to improve drug solubility, published 2007, PTO-892) and Williams (Lipophilic Salts-Opportunities & Applications in Oral Drug Delivery, published 2016, PTO-892).
This is a provisional nonstatutory double patenting rejection.
‘071 is applied as discussed above and incorporated herein.
‘071 differs from that of the instantly claimed invention in that it does not teach a palmitate salt.
Lee, Serajuddin, and Williams are applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol in ‘071, to a palmitate salt, to arrive at instant claims 3 and 11. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Lee teaches that salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol may exist in the form of a pharmaceutically acceptable salt,
-Lee teaches that salts can be prepared using conventional methods in the technical field
- Serajuddin teaches that salt formation is the most commonly applied technique of increasing solubility and dissolution rate in drug product development,
-Serajuddin teaches palmitic acid salts as salt forms of APIs that dissolve much more slowly than the free base and other salt forms,
-Williams teaches that lipophilic salts have increased solubility in lipidic vehicles relative to free base or acid API forms, and that lipid formulations have proven applications in enhancing oral bioavailability and providing a rapid onset of action,
-Williams teaches that lipophilic salts are used for circumventing crystal polymorphism issues, increasing aqueous solubility for oral or parenteral drug delivery, for dual function salts combining anion and cation actives in one complex for combined, unique, or enhanced pharmacological/pharmacodynamics or biopharmaceutical effects, enhanced permeation across hydrophobic barriers, and/or for enhanced API loading in lipid-based formulations (pgs. 2-3).
As such, an ordinary skilled artisan would have been motivated to make such
a modification, to predictably arrive at a salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol with similar therapeutic or physicochemical effects, such as increased solubility in lipophilic formulations and increased bioavailability.
Claims 1, 3, 9 and 15-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims1 and 4 of copending Application No. 18/288,275 (claim set dated 05/11/2026) in view of US PG Pub 2019/0359617 to Lee (published 2019, IDS of 08/04/2025) in view of Gupta (Salts of Therapeutic Agents: Chemical, physicochemical, and Biological Considerations, Molecules, published 2018, PTO-892).
This is a provisional double patenting rejection.
Regarding claims 1 and 15-16, ‘275 claims a method of treating interstitial lung disease, a fibrosis disease, comprising administering a composition comprising (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol and salts thereof (claim 1).
‘275 differs from that of instant claims 1, 3, and 9, in that it does not teach monohydrochloride or maleate as the salt.
Lee and Gupta are applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the select monohydrochloride as the salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, of ‘275, to arrive at instant claims 1, 3, and 9. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Lee teaches that salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol may exist in the form of a pharmaceutically acceptable salt,
-Lee teaches that salts can be prepared using conventional methods in the technical field
-Lee exemplifies hydrochloric acid and maleic acid as such salts, and
-Gupta teaches hydrochloride salts as one of the most common methods to increase the
solubility of weakly acidic and basic drugs
- Gupta teaches chloride and maleate as one of the most commonly used anions for oral
dosage forms
-Gupta teaches that the physicochemical and biological properties of active
pharmaceutical ingredients are greatly affected by their salt forms and that the appropriate salt can improve the overall therapeutic and pharmaceutical effects of an API.
As such, an ordinary skilled artisan would have been motivated to make such
selections, to predictably arrive at salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol with similar or greater therapeutic or physiochemical effects.
Further regarding the ratio of salt to (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," MPEP 2144.05(II). As such, an ordinary skilled artisan would have been motivated to modify the ratio of salt to (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, to predictably arrive at a product that is optimized for stability and therapeutic effect.
Claims 1, 3-4, 7, 9, and 15-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of copending application no. 18/288,275 (claim set dated 10/15/2023), in view of US PG Pub 2019/0359617 to Lee (published 2019) in view of Saal (Pharmaceutical salts: A summary on doses of salt formers from the Orange Book, published 2013, IDS of 10/27/2025).
This is a provisional nonstatutory double patenting rejection.
‘275 is applied as discussed above and incorporated herein.
‘275 differs from that of the instantly claimed invention in that it does not teach maleate or oxalate salts.
Lee and Saal are applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol of ‘275, to a maleate or oxalate salt, to arrive at instant claims 3-4, 7, and 9. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Lee teaches salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol may exist in the form of a pharmaceutically acceptable salt,
-Lee teaches that salts can be prepared using conventional methods in the technical field
-Lee teaches maleic acid as such a salt,
- Saal teaches maleate and oxalate salts as salt formers of basic AP1s
-Saal teaches that salt formation is widely used in the pharmaceutical industry to optimize
properties pharmaceutical active ingredients,
-Saal teaches that selection of pharmaceutical salts provides a means to improve
solubility, dissolution rate, supersaturation, drug absorption, and bioavailability of drugs compared to the parent form of the drug, without changing the pharmacologically active moiety, and
-Saal teaches that the physicochemical properties of active pharmaceutical ingredients can be improved by salt selection.
As such, an ordinary skilled artisan would have been motivated to make such
modifications, to predictably arrive at salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol with similar therapeutic or physicochemical effects.
Further regarding the ratio of salt to (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," MPEP 2144.05(II). As such, an ordinary skilled artisan would have been motivated to modify the ratio of salt to (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, to predictably arrive at a product that is optimized for stability and therapeutic effect.
Claims 1, 3, 11, and 15-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of copending Application No. 18/288,275 (claim set dated 10/15/2023), in view of US PG Pub 2019/0359617 to Lee (published 2019, IDS of 08/04/2025), Serajuddin (Salt formation to improve drug solubility, published 2007, PTO-892) and Williams (Lipophilic Salts-Opportunities & Applications in Oral Drug Delivery, published 2016, PTO-892).
This is a provisional nonstatutory double patenting rejection.
‘275 is applied as discussed above and incorporated herein.
‘275 differs from that of the instantly claimed invention in that it does not teach a palmitate salt.
Lee, Serajuddin, and Williams are applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol in ‘275, to a palmitate salt, to arrive at instant claims 3 and 11. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Lee teaches that salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol may exist in the form of a pharmaceutically acceptable salt,
-Lee teaches that salts can be prepared using conventional methods in the technical field
- Serajuddin teaches that salt formation is the most commonly applied technique of increasing solubility and dissolution rate in drug product development,
-Serajuddin teaches palmitic acid salts as salt forms of APIs that dissolve much more slowly than the free base and other salt forms,
-Williams teaches that lipophilic salts have increased solubility in lipidic vehicles relative to free base or acid API forms, and that lipid formulations have proven applications in enhancing oral bioavailability and providing a rapid onset of action,
-Williams teaches that lipophilic salts are used for circumventing crystal polymorphism issues, increasing aqueous solubility for oral or parenteral drug delivery, for dual function salts combining anion and cation actives in one complex for combined, unique, or enhanced pharmacological/pharmacodynamics or biopharmaceutical effects, enhanced permeation across hydrophobic barriers, and/or for enhanced API loading in lipid-based formulations (pgs. 2-3).
As such, an ordinary skilled artisan would have been motivated to make such
a modification, to predictably arrive at a salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol with similar therapeutic or physicochemical effects, such as increased solubility in lipophilic formulations and increased bioavailability.
Claims 1 and 15-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims1 and 10-11 of copending Application No. 18/288,296 (claim set dated 04/06/2026).
This is a provisional double patenting rejection.
Regarding claims 1 ‘296 claims (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol and salts thereof , and claims hydrochloride as the salt (claims 1 and 10).
Regarding claim 15-16, ‘296 claims composition comprising the compounds (claim 11).
Claims 1, 3-4, 7, 9, and 15-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims1 and 10-11 of copending Application No. 18/288,296 (claim set dated 04/06/2026)., in view of US PG Pub 2019/0359617 to Lee (published 2019) in view of Saal (Pharmaceutical salts: A summary on doses of salt formers from the Orange Book, published 2013, IDS of 10/27/2025).
This is a provisional nonstatutory double patenting rejection.
‘296 is applied as discussed above and incorporated herein.
‘296 differs from that of the instantly claimed invention in that it does not teach maleate or oxalate salts.
Lee and Saal are applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol of ‘296, to a maleate or oxalate salt, to arrive at instant claims 3-4, 7, and 9. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Lee teaches salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol may exist in the form of a pharmaceutically acceptable salt,
-Lee teaches that salts can be prepared using conventional methods in the technical field
-Lee teaches maleic acid as such a salt,
- Saal teaches maleate and oxalate salts as salt formers of basic AP1s
-Saal teaches that salt formation is widely used in the pharmaceutical industry to optimize
properties pharmaceutical active ingredients,
-Saal teaches that selection of pharmaceutical salts provides a means to improve
solubility, dissolution rate, supersaturation, drug absorption, and bioavailability of drugs compared to the parent form of the drug, without changing the pharmacologically active moiety, and
-Saal teaches that the physicochemical properties of active pharmaceutical ingredients can be improved by salt selection.
As such, an ordinary skilled artisan would have been motivated to make such
modifications, to predictably arrive at salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol with similar therapeutic or physicochemical effects.
Further regarding the ratio of salt to (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," MPEP 2144.05(II). As such, an ordinary skilled artisan would have been motivated to modify the ratio of salt to (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, to predictably arrive at a product that is optimized for stability and therapeutic effect.
Claims 1, 3, 11, and 15-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10-11 of copending Application No. 18/288,296 (claim set dated 04/06/2026), in view of US PG Pub 2019/0359617 to Lee (published 2019, IDS of 08/04/2025), Serajuddin (Salt formation to improve drug solubility, published 2007, PTO-892) and Williams (Lipophilic Salts-Opportunities & Applications in Oral Drug Delivery, published 2016, PTO-892).
This is a provisional nonstatutory double patenting rejection.
‘296 is applied as discussed above and incorporated herein.
‘296 differs from that of the instantly claimed invention in that it does not teach a palmitate salt.
Lee, Serajuddin, and Williams are applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol in ‘296, to a palmitate salt, to arrive at instant claims 3 and 11. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Lee teaches that salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol may exist in the form of a pharmaceutically acceptable salt,
-Lee teaches that salts can be prepared using conventional methods in the technical field
- Serajuddin teaches that salt formation is the most commonly applied technique of increasing solubility and dissolution rate in drug product development,
-Serajuddin teaches palmitic acid salts as salt forms of APIs that dissolve much more slowly than the free base and other salt forms,
-Williams teaches that lipophilic salts have increased solubility in lipidic vehicles relative to free base or acid API forms, and that lipid formulations have proven applications in enhancing oral bioavailability and providing a rapid onset of action,
-Williams teaches that lipophilic salts are used for circumventing crystal polymorphism issues, increasing aqueous solubility for oral or parenteral drug delivery, for dual function salts combining anion and cation actives in one complex for combined, unique, or enhanced pharmacological/pharmacodynamics or biopharmaceutical effects, enhanced permeation across hydrophobic barriers, and/or for enhanced API loading in lipid-based formulations (pgs. 2-3).
As such, an ordinary skilled artisan would have been motivated to make such
a modification, to predictably arrive at a salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol with similar therapeutic or physicochemical effects, such as increased solubility in lipophilic formulations and increased bioavailability.
Claims 1, 3, 9, and 15-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11, 12, and 16 of U.S. Patent No. 10,981,917 (IDS of 06/12/2024) in view of US PG Pub 2019/0359617 to Lee (published 2019, IDS of 08/04/2025) in view of Gupta (Salts of Therapeutic Agents: Chemical, physicochemical, and Biological Considerations, Molecules, published 2018, PTO-892).
‘917 claims (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol and salts thereof (claim 11).
Regarding claim 15, ‘917 claims compositions comprising (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol and salts thereof (claim 12).
Regarding claim 16, ‘917 claims a method of treating inflammatory diseases, autoimmune diseases, or fibrosis comprising administering an effective amount of claim 1 (claim 16).
‘917 differs from that of instant claims 1, 3, and 9, in that it does not teach monohydrochloride or maleate as the salt.
Lee and Gupta are applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the select monohydrochloride as the salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, of ‘917, to arrive at instant claims 1, 3, and 9. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Lee teaches that salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol may exist in the form of a pharmaceutically acceptable salt,
-Lee teaches that salts can be prepared using conventional methods in the technical field
-Lee exemplifies hydrochloric acid and maleic acid as such salts, and
-Gupta teaches hydrochloride salts as one of the most common methods to increase the
solubility of weakly acidic and basic drugs
- Gupta teaches chloride and maleate as one of the most commonly used anions for oral
dosage forms
-Gupta teaches that the physicochemical and biological properties of active
pharmaceutical ingredients are greatly affected by their salt forms and that the appropriate salt can improve the overall therapeutic and pharmaceutical effects of an API.
As such, an ordinary skilled artisan would have been motivated to make such
selections, to predictably arrive at salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol with similar or greater therapeutic or physiochemical effects.
Further regarding the ratio of salt to (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," MPEP 2144.05(II). As such, an ordinary skilled artisan would have been motivated to modify the ratio of salt to (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, to predictably arrive at a product that is optimized for stability and therapeutic effect.
Claims 1, 3-4, 7, 9, and 15-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11 and 12 of U.S. Patent No. 10,981,917 (IDS of 06/12/2024), in view of US PG Pub 2019/0359617 to Lee (published 2019, IDS of 08/04/2025) in view of Saal (Pharmaceutical salts: A summary on doses of salt formers from the Orange Book, published 2013, IDS of 10/27/2025).
This is a provisional nonstatutory double patenting rejection.
‘917 is applied as discussed above and incorporated herein.
‘917 differs from that of the instantly claimed invention in that it does not teach maleate or oxalate salts.
Lee and Saal are applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol of ‘917, to a maleate or oxalate salt, to arrive at instant claims 3-4, 7, and 9. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Lee teaches salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol may exist in the form of a pharmaceutically acceptable salt,
-Lee teaches that salts can be prepared using conventional methods in the technical field
-Lee teaches maleic acid as such a salt,
- Saal teaches maleate and oxalate salts as salt formers of basic AP1s
-Saal teaches that salt formation is widely used in the pharmaceutical industry to optimize
properties pharmaceutical active ingredients,
-Saal teaches that selection of pharmaceutical salts provides a means to improve
solubility, dissolution rate, supersaturation, drug absorption, and bioavailability of drugs compared to the parent form of the drug, without changing the pharmacologically active moiety, and
-Saal teaches that the physicochemical properties of active pharmaceutical ingredients can be improved by salt selection.
As such, an ordinary skilled artisan would have been motivated to make such
modifications, to predictably arrive at salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol with similar therapeutic or physicochemical effects.
Further regarding the ratio of salt to (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," MPEP 2144.05(II). As such, an ordinary skilled artisan would have been motivated to modify the ratio of salt to (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol, to predictably arrive at a product that is optimized for stability and therapeutic effect.
Claims 1, 3, 11, and 15-16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11 and 12 of U.S. Patent No. 10,981,917 (IDS of 06/12/2024), in view of US PG Pub 2019/0359617 to Lee (published 2019 IDS of 08/04/2025), Serajuddin (Salt formation to improve drug solubility, published 2007, PTO-892) and Williams (Lipophilic Salts-Opportunities & Applications in Oral Drug Delivery, published 2016, PTO-892).
This is a provisional nonstatutory double patenting rejection.
‘917 is applied as discussed above and incorporated herein.
‘917 differs from that of the instantly claimed invention in that it does not teach a palmitate salt.
Lee, Serajuddin, and Williams are applied as discussed above and incorporated herein.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol in ‘275, to a palmitate salt, to arrive at instant claims 3 and 11. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Lee teaches that salt forms of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol may exist in the form of a pharmaceutically acceptable salt,
-Lee teaches that salts can be prepared using conventional methods in the technical field
- Serajuddin teaches that salt formation is the most commonly applied technique of increasing solubility and dissolution rate in drug product development,
-Serajuddin teaches palmitic acid salts as salt forms of APIs that dissolve much more slowly than the free base and other salt forms,
-Williams teaches that lipophilic salts have increased solubility in lipidic vehicles relative to free base or acid API forms, and that lipid formulations have proven applications in enhancing oral bioavailability and providing a rapid onset of action,
-Williams teaches that lipophilic salts are used for circumventing crystal polymorphism issues, increasing aqueous solubility for oral or parenteral drug delivery, for dual function salts combining anion and cation actives in one complex for combined, unique, or enhanced pharmacological/pharmacodynamics or biopharmaceutical effects, enhanced permeation across hydrophobic barriers, and/or for enhanced API loading in lipid-based formulations (pgs. 2-3).
As such, an ordinary skilled artisan would have been motivated to make such
a modification, to predictably arrive at a salt form of (2R,3S)-2-(3-(4,5-dichloro-1H-benzo[d]imidazole-1-yl)propyl)piperidin-3-ol with similar therapeutic or physicochemical effects, such as increased solubility in lipophilic formulations and increased bioavailability.
Conclusion
No claims are allowed.
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/LAUREN WELLS/Examiner, Art Unit 1622
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