DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of the following species:
Compound 15 having the structure of:
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as the elected species of nitric donor beraprost derivative or a pharmaceutically acceptable salt thereof;
oral preparation as the elected preparation species;
granules as the elected formulation species; and
a filler as the elected carrier species
in the reply filed on July 16, 2026 is acknowledged.
Expansion of Election of Species Requirement
A reasonable and comprehensive search of the elected species conducted by the Examiner
discover a prior art by Batra et al. that teaches a lubricant as the pharmaceutically acceptable carrier; and discover a prior art by Ongini et al. that render obvious the compound 3 having the structure of:
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. In light of this discovery, the search is expanded to the subject matter of the pharmaceutically acceptable carrier to include a filler in addition to the elected species (“a filler”); and expanded to the subject matter of the nitric oxide donor beprost derivative
, such that it does not encompass the full scope of the claims.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on July 16, 2026, wherein claims 1-2 and 4-5 are canceled; claims 3 and 6-7 are amended; and claims 8-9 are unchanged.
Claims 3 and 6-9 are under examination in accordance with the elected species along with the expanded species set forth in the Expansion of Election of Species Requirement section above.
Priority
The instant application 18/668,422 filed on May 20, 2024 is a continuation of 371 of PCT/CN2023/072256 filed on January 16, 2023, which claims priority to, and the benefits of Foreign Provisional Application No. CN202111366683.9 filed on November 18, 2021.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on May 22, 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Please note that foreign references without an English translation but have an English translation of the abstract will only have the abstract considered by the Examiner.
Specification
The abstract of the disclosure is objected to because the abstract is repleted with the term “new” to describe the compounds (see e.g., line 1 and 6). It is suggested that the term “new” be deleted from the language of the abstract, because the abstract of the disclosure should avoid using phrases which can be implied. Once the determination of the novelty of a claimed invention has been established and the disclosure of the invention made public and/or patented, the claimed invention is no longer novel or new, since the scope of the invention no longer embraces what is considered “new”. Thus, the incorporation of the term “new” into the language of the abstract is not appropriate.
The disclosure is objected to because of the following informalities:
the specification is repleted with the term “new” (see e.g., page 3, line 4; page 6, line 25). It is suggested that the term “new” be deleted from the language of the disclosure. Once the determination of the novelty of a claimed invention has been established and the disclosure of the invention made public and/or patented, the claimed invention is no longer novel or new, since the scope of the invention no longer embraces what is considered “new”. Thus, the incorporation of the term “new” into the language of the specification is not appropriate.
The use of the terms “VYZULTA” and “Careload”, which are trade names or marks used in commerce, have been noted in this application. Each of these terms should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. While the Examiner has made every attempt to check the specification for trade name or mark compliance, Applicant is required to carefully check the entire specification for any and all issues regarding trade name or mark.
Appropriate correction is required.
Claim Objections
Claims 3 and 9 are objected to because of the following informalities:
Regarding claim 3, the claim recites the term “beprost” that is not being consistent with the term “beraprost” in claim 6, and that appears to be a typographical error.
Regarding claim 9,
the phrase “the oral formulation” should read –the oral preparation--, because said phrase is not being consistent throughout the claims. It is respectfully noted that claim 8, which claim 9 depends upon, recites “oral preparation” rather than “oral formulation” as claimed in claim 9; therefore, said phrase should stay consistent for the sake of clarity.
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 7-9 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.
The claims are generally narrative and indefinite, failing to conform with current U.S. practice. They appear to be a literal translation into English from a foreign document and are replete with grammatical and idiomatic errors.
Regarding claim 7,
the claim recites “a mixture of one or more of …” that is ambiguous as it can lead to various interpretations. First, “a mixture of one or more of …” is indefinite, because it is not clear if applicant is referring to (a) one selected carrier; (b) two or more of different carriers; or (c) multiple amounts of the same carrier. Second, the phrase “one or more of” encompasses the selection of only a single listed component (e.g., a single wetting agent), whereas “mixture” ordinarily denotes a combination of multiple components. Consequently, one of ordinary skill in the art cannot determine with reasonable certainty whether the claim encompasses (i) a pharmaceutically acceptable carrier consisting of only one selected listed component or (ii) a carrier containing multiple selected listed components. Accordingly, the metes and bounds of the claim are not reasonably certain.
The recitation of “…. an excipient, agent, a filler….” is ambiguous because it is not clear whether the “agent” constitutes an independent listed component of the claimed mixture or whether it was intended to modify the preceding or following term (e.g., “excipient”). Because the punctuation permits multiple reasonable interpretations of the claimed scope, one of ordinary skill in the art cannot determine the metes and bounds of the claim with reasonable certainty.
In order to advance prosecution, the examiner is examining claim 7 in view of the elected species to the extent that the pharmaceutically acceptable carrier is “a” filler, or “a” lubricant.
Regarding claim 8, the phrase of “is either of the topical, oral, and injectable preparations” is ambiguous and can leads to various interpretations. The term “either” is often used when referring to a pair of choices or items. Since the claimed list included three alternated options, it is not clear if applicant is intending to mean that the pharmaceutical composition is (a) a topical, oral or injectable preparation or (b) is intending to select the pharmaceutical composition from topical, oral and injectable preparations. In addition, the term “preparations” is in plural form rather than singular form, and it is also not clear if applicant is intending to mean that (i) the pharmaceutical composition is more than one different preparations selected from the list (e.g., topical and injectable preparations), or (ii) the pharmaceutical composition is more than one of the same preparation selected from the list (e.g., more than one topical preparations). Accordingly, the metes and bounds of the claim are not reasonably certain. In order to advance prosecution, the examiner is examining claim 8 in view of the elected species to the extent that the pharmaceutically acceptable carrier is oral preparation.
Regarding claim 9,
- the phrase “the oral formulation is any of the granules, capsules, and tablets” is ambiguous, because it is not clear how a singular oral formulation can be in the plural forms of granule, capsule, and tablet. It is also not clear if applicant is intending to mean that (i) the oral formulation is one of the many granules, capsules and tablets or (ii) the oral formulation is a mixture of more than one granules, capsules or tablets. To the extent that applicant is referring to the second scenario (ii), then the plural form fails to further limit the singular pharmaceutical composition set forth in claim 6 and 8. In addition, the phrase “is any of” is also ambiguous, because said phrase “is any of” means one, some, or all choices are selected. In other words, based on the current claim language, the oral formulation can be granules and tablets together; However, “a” pharmaceutical composition, which is a singular product, cannot be plural by itself, thus, one of ordinary skill in the art cannot determine the metes and bounds of the claim with reasonable certainty. In order to advance prosecution, the examiner is examining claim 9 to the extent that the pharmaceutical composition is one of the many oral granules.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 3 and 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over Batra et al. (WO 2020/086367 A1), in view of Satyam (US 2015/0328323 A1; cited in the IDS filed on May 22, 2024) and Ishihara et al. (US5,843,973).
Batra et al. teaches derivatives and prodrugs of existing drugs have the ability to improve the physicochemical properties of such drugs (see e.g., [0005]); and prodrugs of esuberaprost can be an esuberaprost derivative with one or more hydroxyl groups or the carboxylic acid group of the esuberaprost structure modified, but which can be converted in vivo into active esuberaprost following administration and subsequent diffusion into the blood (see e.g., [0074]). Batra et al. further teaches prodrugs of esuberaprost may be a compound the Formula (I), or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound:
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, wherein R3 represents NR7R8, OR9, or NHSO2R10 ; R9 represents H or C1-C6 alkyl, which may be optionally substituted with a terminal hydroxyl or carboxy group (see e.g., [0007]). Batra et al. further teaches esuberaprost, a single isomer of beraprost, has the following chemical formula:
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(see e.g., [0050]). Batra et al. further teaches the esuberaprost prodrugs may be used for one or more of the same purposes for which esuberaprost is known to be useful, such as for treating a condition, for which esuberaprost is known to be effective (see e.g., [0087]); and esuberaprost is currently being developed for the treatment of pulmonary arterial hypertension and vascular disease (see e.g., [0003]). Batra et al. further teaches beraprost is also currently under clinical trials for the treatment of pulmonary hypertension and vascular disease (excluding renal disease) in North America and Europe (see e.g., [0003]). Batra et al. further teaches esuberaprost prodrugs of the present technology may be provided in a form of a pharmaceutical composition, which may also comprise a pharmaceutically acceptable carrier; the composition may be in the form of, for example, granules; the composition may be formulated for a number of different administration routes, such as, for oral administration (see e.g., [0077]). Batra et al. further teaches for oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets may be acceptable as solid dosage forms (see e.g., [0079]); and these can be prepared, for example, by mixing one or more esuberaprost prodrugs, or pharmaceutically acceptable salts thereof, with at least one additive or excipient such as a starch or other additive (see e.g., [0079]); oral dosage forms may contain other ingredients to aid in administration, such as an inactive diluent, or lubricants (see e.g., [0079]).
Batra et al. does not teach the elected compound species.
Satyam further teaches nitric oxide (NO) plays an important role in numerous other physiological and pathophysiological conditions, e.g. blood pressure regulation, inflammation, infection and the onset and progression of malignant and cardiovascular diseases; though delivery of supplementary NO in the form of NO-donor drugs has long been an attractive therapeutic strategy in recent years, because of the beneficial biochemical and pharmacological properties of nitric oxide, the strategy of linking NO releasing moieties has been extended to a wide array of therapeutic agents selected from cardiovascular drugs (see e.g., [0008]). Satyam further teaches the aim of this strategy is to synthesize prodrugs that retain the pharmacological activity of the parent drug molecule coupled with the benefits of the biological actions of NO in reducing the adverse effects of the parent drug molecule (see e.g., [0008]). Satyam further teaches the carboxylic acid group is often present as an active functional group for derivatisation in several therapeutic agents (see e.g., [0003]); and NO-releasing derivatives and prodrugs of various therapeutic agent can be represented by the following generic or Markush structure (IA):
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(see e.g., [0011]-[0012]), wherein Dx represents a part of a drug or therapeutic agent containing at least one carboxylic acid group; Xz independently represents, inter alia, liner or branched alkylene C1-C20, substituted alkylene C1-C20, optionally substituted cycloalkylene C3-C7 or C5-C7, or [C(Ra)(Rb)]m, wherein m is preferably 2-5, Ra and Rb at each occurrence are independently, inter alia, a hydrogen, substituted or unsubstituted straight or branched alkyl C1-C20, or Ra and Rb taken together with the carbon atom to which they are attached form a cycloalkyl group, and so on among others (see e.g., [0012]-[0019]). Satyam further teaches said Markush encompassing compounds of formula (I)
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which primary constitutes (a) a drug or a therapeutic agent containing at least one carboxylic acid group i.e., DxCO2H that is covalently bonded to one side of the linker; (b) a linker [i.e., C(H)(Ry)]; and a nitrooxy (ONO2) group covalently bonded to the other side of the linker (see e.g., [0085]-[0090]); wherein Dx, the drug or therapeutic agent containing a carboxylic acid group capable of forming a covalent bio-cleavable ester linkage with a linker, is selected from the group comprising a cardiovascular agent (see e.g., [0155]); and the cardiovascular agent is a vasodilator agent selected from the group comprising of, inter alia, beraprost (see e.g., [0160]; [0163]). Satyam further teaches said compounds of formula (I) are nitric oxide releasing prodrugs of known carboxyl-containing drugs or therapeutic agents useful in the treatment of diseases or disorders that are characteristic of the drugs from which the prodrugs of the present invention are derived (see e.g., [0085]).
Ishihara et al. teaches a compound of example 14 (also referred to therein as “Exemplary compound 1-681”), N-(3-nitroxymethylcyclohexylmethyl)-(4R)-2-oxothiazolidin-4-yl-carboxamide (see e.g., Col. 105, line 23-36), in a series of nitrate derivatives; and said compound is a preferred thiazolidinone compound represented by the general formula (I):
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, or pharmacologically acceptable salts thereof (see e.g., Col. 9, line 18 to Col. 10, line 15; Table I, Compound No. 1-681); wherein R5 represents, inter alia, a 3-nitroxymethylcyclohexyl group (see e.g., claim 20); A represents a methylene group (see e.g., claim 27). Ishihara et al. further teaches the chemical structure of Exemplary compound 1-681 is represented by
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, wherein R1 is H; X1 is S; R2 is H; R3 is H; R4 is H; A is CH2; R5 is 3-(ONO2CH2)-Hxc (see e.g., Col. 9, line 18 to Col. 10, line 15; Table I, Compound No. 1-681); and the abbreviation of “Hxc” means cyclohexyl (see e.g., Col. 83, line 46). Ishihara et al. further teaches compounds of general formula (I) have an excellent collateral vessel dilating action and less side effects (see e.g., Col. 1, line 40-48).
In the present case, the difference between the esuberaprost of Batra et al. and the claimed invention is that the prior art compound is a single isomer of beraporast rather than racemic mixture (beraporast), and contains a hydrogen directly attached to the oxygen atom rather than the claimed 3 nitroxymethylcyclohexylmethyl group shown below (see shaded):
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.
In Summary, Batra et al. teaches derivatization of the carboxylic acid group of esuberaprost, a single isomer of beraprost, by attaching various promoieties, including substituted or usubstituted C1-C6 alkyl, to arrive at derivatives and prodrugs of existing drugs useful for the same purpose, such as treating pulmonary hypertension. Batra et al. teaches the purpose is to modify the physicochemical properties of existing drugs while retaining their therapeutic activity. Satyam teaches beraprost is a vasodilator agent containing at least one carboxylic acid group that can be linked with a nitric oxide (NO) releasing moieties (moieties containing -ONO2) to arrive at derivatives and prodrugs with the benefits of NO, including reducing the adverse effects of the parent drug molecule. Ishihara et al. teaches 3-nitroxymethylcyclohexylmethyl substituent is one of the known ONO2 moieties useful for cardiovascular therapeutic compounds, and said compounds have prolonged collateral vessel dilating action and less side effects. It is noted that pulmonary hypertension and angina pectoris are different diseases, but both involve the cardiovascular system and vasoactive drugs. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to derivatize the carboxylic acid group of beraprost, a racemic mixture containing esuberaprost, by replacing one of the Batra's known prodrug promoieties attached to the carboxyl group with the 3-nitroxymethylcyclohexylmethyl group of Ishihara et al. as the nitric oxide releasing moieties to arrive at the claimed invention. One would have been motivated to do so in order to obtain another beraprost prodrug or derivative expect to possess the known advantages associated with nitric oxide donor functionality while maintaining activity of the parent drug molecule. A person of ordinary skill in the art would have a reasonable expectation of success to arrive at the claimed invention, because Batra et al. demonstrates that the carboxyl group of esuberaprost, an isomer of beraprost, tolerates substitution with numerous promoieties to from therapeutically useful derivatives, and Satyam teaches the carboxylic acid group of beraprost can link with a nitric oxide (NO) releasing moieties using a linker, including the [C(Ra)(Rb)]m moiety, while Ishihara demonstrates that 3-nitroxymethylcyclohexylmethyl substituent is a stable nitric oxide donor group suitable for incorporation into cardiovascular therapeutic compounds. Accordingly, substituting one known prodrug substituent of Batra et al. with one known nitric oxide donor substituent (i.e., 3-nitroxymethylcyclohexylmethyl) would have presented the predictable substitution of one known functional group for another to obtain the expected properties associated with each.
Regarding the limitation of “[a] pharmaceutical composition comprising the nitric oxide donor beraprost derivative… and a pharmaceutically acceptable carrier” as claimed in claim 6, the limitation of “wherein the pharmaceutically acceptable carrier is…a lubricant” in claim 7, and the limitation of “wherein the pharmaceutical composition is either of the topical, oral, and injectable preparations” in claim 8, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to combine the derivative of beraprost set forth above with a pharmaceutically acceptable carrier, such as a lubricant, to arrive at a pharmaceutical composition suitable for oral administration, because Batra et al. teaches esuberaprost prodrugs, including diastereomers and enantiomers, may be provided in a form of a pharmaceutical composition suitable for various routes, such as oral administration, comprising a pharmaceutically acceptable carrier; and further teaches oral dosage forms may contain other ingredients to aid in administration, such as lubricants. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the derivative of beraprost can successfully be combine with a lubricant as the pharmaceutically acceptable carrier to arrive at a pharmaceutical composition suitable for oral administration.
Regarding “wherein the oral formulation is any of the granules” as claimed in claim 9, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to combine the derivative of beraprost set forth above with a pharmaceutically acceptable carrier to arrive at a pharmaceutical composition in the form of granule suitable for oral administration, because Batra et al. teaches esuberaprost prodrugs, including diastereomers and enantiomers, may be provided in a form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier; and further teaches said pharmaceutical composition may be in the solid dosage form of granules for oral administration. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the derivative of beraprost can successfully be combine with a pharmaceutically acceptable carrier to arrive at a pharmaceutical composition suitable for oral administration in the solid dosage form of granule.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 3 and 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over Batra et al. (WO 2020/086367 A1), in view of Satyam (US 2015/0328323 A1; cited in the IDS filed on May 22, 2024) and Ishihara et al. (US5,843,973) as applied to claims 3 and 6-9 above, and further in view of Batra et al. (US 10,246,430 B2; referred to herein as “Batra#2”).
To the extent that the claimed invention is drawn to the elected pharmaceutically acceptable carrier (i.e., “a filler”), then the following rejection applies.
The teachings of Batra et al., Satyam and Ishihara et al. are set forth above and applied as before.
Batra et al., Satyam and Ishihara et al. does not teach a filler; However, Batra et al. teaches at least one additive or excipient can be mixed with one or more esuberaprost prodrugs, or pharmaceutically acceptable salts thereof to prepare solid dosage forms, such as powders; and suitable additives or excipients may be, inter alia, lactose (see e.g., [0079]).
Batra#2 teaches a pharmaceutical formulation may comprise beraprost, and a pharmaceutically acceptable carrier or excipient (see e.g., Col. 50, line 64 to Col. 51, line 1). Batra#2 further teaches solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules; in such solid dosage forms, Beraprost, is mixed with at least one inert, pharmaceutical carrier and/or (a) fillers or extenders such as starches, sugars including lactose and glucose, mannitol, and silicic acid (see e.g., Col. 51, line 56-62).
it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to combine the derivative of beraprost set forth above with a pharmaceutically acceptable carrier, such as a lactose as the fillers, to arrive at a pharmaceutical composition suitable for oral administration, because Batra et al. teaches esuberaprost prodrugs, including diastereomers and enantiomers, can be mixed with lactose to arrive at solid dosage forms; and Batra#2 teaches lactose in the list of fillers. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the derivative of beraprost can successfully be combine with lactose as the pharmaceutically acceptable carrier and filler to arrive at a pharmaceutical composition.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 3 and 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over Batra et al. (WO 2020/086367 A1), in view of Satyam (US 2015/0328323 A1; cited in the IDS filed on May 22, 2024) and Ongini et al. (WO 2005/068421 A1).
Batra et al. teaches derivatives and prodrugs of existing drugs have the ability to improve the physicochemical properties of such drugs (see e.g., [0005]). Batra et al. further teaches beraprost is a synthetic benzoprostacyclin analogue of natural prostacyclin that is currently under clinical trials for the treatment of pulmonary hypertension and vascular disease (excluding renal disease) in North America and Europe; and esuberaprost is a reformulated single isomer of beraprost currently being developed for the treatment of pulmonary arterial hypertension and vascular disease (see e.g., [0003]). Batra et al. further teaches prodrugs of esuberaprost can be an esuberaprost derivative with one or more hydroxyl groups or the carboxylic acid group of the esuberaprost structure modified, but which can be converted in vivo into active esuberaprost following administration and subsequent diffusion into the blood (see e.g., [0074]). Batra et al. further teaches prodrugs of esuberaprost may be a compound the Formula (I), or a diastereomer, enantiomer or pharmaceutically acceptable salt of the compound:
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, wherein R3 represents NR7R8, OR9, or NHSO2R10 ; R9 represents H or C1-C6 alkyl, which may be optionally substituted with a terminal hydroxyl or carboxy group (see e.g., [0007]). Batra et al. further teaches esuberaprost, a single isomer of beraprost, has the following chemical formula:
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(see e.g., [0050]). Batra et al. further teaches the esuberaprost prodrugs may be used for one or more of the same purposes for which esuberaprost is known to be useful, such as for treating a condition, for which esuberaprost is known to be effective (see e.g., [0087]). Batra et al. further teaches esuberaprost prodrugs of the present technology may be provided in a form of a pharmaceutical composition, which may also comprise a pharmaceutically acceptable carrier; the composition may be in the form of, for example, granules; the composition may be formulated for a number of different administration routes, such as, for oral administration (see e.g., [0077]). Batra et al. further teaches for oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets may be acceptable as solid dosage forms (see e.g., [0079]); and these can be prepared, for example, by mixing one or more esuberaprost prodrugs, or pharmaceutically acceptable salts thereof, with at least one additive or excipient such as a starch or other additive (see e.g., [0079]); oral dosage forms may contain other ingredients to aid in administration, such as an inactive diluent, or lubricants (see e.g., [0079]).
Batra et al. does not teach the expanded compound species.
Satyam further teaches nitric oxide (NO) plays an important role in numerous other physiological and pathophysiological conditions, e.g. blood pressure regulation, inflammation, infection and the onset and progression of malignant and cardiovascular diseases; though delivery of supplementary NO in the form of NO-donor drugs has long been an attractive therapeutic strategy in recent years, because of the beneficial biochemical and pharmacological properties of nitric oxide, the strategy of linking NO releasing moieties has been extended to a wide array of therapeutic agents selected from cardiovascular drugs (see e.g., [0008]). Satyam further teaches the aim of this strategy is to synthesize prodrugs that retain the pharmacological activity of the parent drug molecule coupled with the benefits of the biological actions of NO in reducing the adverse effects of the parent drug molecule (see e.g., [0008]). Satyam further teaches the carboxylic acid group is often present as an active functional group for derivatisation in several therapeutic agents (see e.g., [0003]); and NO-releasing derivatives and prodrugs of various therapeutic agent can be represented by the following generic or Markush structure (IA):
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(see e.g., [0011]-[0012]), wherein Dx represents a part of a drug or therapeutic agent containing at least one carboxylic acid group; Xz independently represents, inter alia, liner or branched alkylene C1-C20, substituted alkylene C1-C20, optionally substituted cycloalkylene C3-C7 or C5-C7, or [C(Ra)(Rb)]m, wherein m is preferably 2-5, Ra and Rb at each occurrence are independently a hydrogen, or Ra and Rb taken together with the carbon atom to which they are attached form a cycloalkyl group, and so on among others (see e.g., [0012]-[0019]). Satyam further teaches said Markush encompassing compounds of formula (I)
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which primary constitutes (a) a drug or a therapeutic agent containing at least one carboxylic acid group i.e., DxCO2H that is covalently bonded to one side of the linker; (b) a linker [i.e., C(H)(Ry)]; and a nitrooxy (ONO2) group covalently bonded to the other side of the linker (see e.g., [0085]-[0090]); wherein Dx, the drug or therapeutic agent containing a carboxylic acid group capable of forming a covalent bio-cleavable ester linkage with a linker, is selected from the prostaglandin analog selected from the group comprising of, inter alia, beraprost, prostaglandin E1, and prostacyclin (see e.g., [0185]). Satyam further teaches said compounds of formula (I) are nitric oxide releasing prodrugs of known carboxyl-containing drugs or therapeutic agents useful in the treatment of diseases or disorders that are characteristic of the drugs from which the prodrugs of the present invention are derived (see e.g., [0085]).
Ongini et al. teaches a compound 1 having the structure of:
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(see e.g., claim 10), is an exemplary compound of general formula (I):
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, wherein the R is the prostaglandin residue of formula (II):
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, X is -O-, -S- or -NH-; Y is a bivalent radical having the following meaning, inter alia, a) a straight or branched C1-C20 alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of, inter alia, -ONO2 (see e.g., claim 1). Ongini et al. further teaches the invention relates to prostaglandin nitrooxyderivatives (see e.g., p. 1, line 5-9); and said derivatives not only to eliminate or at least reduce the side effects associated with these compounds, but also to possess an improved pharmacological activity (see e.g., p. 3, line 1-5). Ongini et al. further teaches prostaglandin nitrooxyderivatives are drugs useful for treating glaucoma and ocular hypertension (see e.g., p. 2, line 5-10); and dinitroglycerol esters of prostaglandins which may be used as vasodilators, antihypertensive cardiovascular agents or bronchodilators (see e.g., p. 2, line 26-28).
In the present case, the difference between the esuberaprost of Batra et al. and the claimed invention is that the prior art compound is a single isomer of beraporast rather than racemic mixture (beraporast), and contains a hydrogen directly attached to the oxygen atom rather than the claimed 4-
(nitrooxy)butyl group shown below (see shaded):
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In Summary, Batra et al. teaches derivatization of the carboxylic acid group of esuberaprost, a single isomer of beraprost, by attaching various promoieties, including substituted or usubstituted C1-C6 alkyl, to arrive at derivatives and prodrugs of existing drugs useful for the same purpose, such as treating pulmonary hypertension. Batra et al. teaches the purpose is to modify the physicochemical properties of existing drugs while retaining their therapeutic activity. Satyam teaches beraprost is a prostaglandin analog containing at least one carboxylic acid group that can be linked with a nitric oxide (NO) releasing moieties (moieties containing -ONO2) to arrive at derivatives and prodrugs with the benefits of NO, including reducing the adverse effects of the parent drug molecule; and liner or branched alkylene C1-C20 can be a linker between the carboxylic acid group and the nitrooxy group. Ongini et al. teaches 4-(nitrooxy)butyl substituent is one of the known ONO2 moieties useful for prostaglandin derivatives, and said compounds have improved pharmacological activity with less side effects. It is noted that prostaglandin derivatives and beraprost are both prostaglandin analog. It would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to derivatize the carboxylic acid group of beraprost, a racemic mixture containing esuberaprost, by replacing one of the Batra's known prodrug promoieties attached to the carboxyl group with the 4-(nitrooxy)butyl group of Ongini et al. as the nitric oxide releasing moieties to arrive at the claimed invention. One would have been motivated to do so in order to obtain another beraprost prodrug or derivative expect to possess the known advantages associated with nitric oxide donor functionality while maintaining activity of the parent drug molecule. A person of ordinary skill in the art would have a reasonable expectation of success to arrive at the claimed invention, because Batra et al. demonstrates that the carboxyl group of esuberaprost, an isomer of beraprost, tolerates substitution with numerous promoieties to from therapeutically useful derivatives, and Satyam teaches the carboxylic acid group of beraprost can link with a nitric oxide (NO) releasing moieties using a linker, including a liner alkylene C1-C20, while Ongini demonstrates 4-(nitrooxy)butyl substituent is a stable nitric oxide donor group suitable for incorporation into prostaglandin analog. Accordingly, substituting one known prodrug substituent of Batra et al. with one known nitric oxide donor substituent (i.e., 4-(nitrooxy)butyl) would have presented the predictable substitution of one known functional group for another to obtain the expected properties associated with each.
Regarding the limitation of “[a] pharmaceutical composition comprising the nitric oxide donor beraprost derivative… and a pharmaceutically acceptable carrier” as claimed in claim 6, the limitation of “wherein the pharmaceutically acceptable carrier is…a lubricant” in claim 7, and the limitation of “wherein the pharmaceutical composition is either of the topical, oral, and injectable preparations” in claim 8, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to combine the derivative of beraprost set forth above with a pharmaceutically acceptable carrier, such as a lubricant, to arrive at a pharmaceutical composition suitable for oral administration, because Batra et al. teaches esuberaprost prodrugs, including diastereomers and enantiomers, may be provided in a form of a pharmaceutical composition suitable for various routes, such as oral administration, comprising a pharmaceutically acceptable carrier; and further teaches oral dosage forms may contain other ingredients to aid in administration, such as lubricants. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the derivative of beraprost can successfully be combine with a lubricant as the pharmaceutically acceptable carrier to arrive at a pharmaceutical composition suitable for oral administration.
Regarding “wherein the oral formulation is any of the granules” as claimed in claim 9, it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to combine the derivative of beraprost set forth above with a pharmaceutically acceptable carrier to arrive at a pharmaceutical composition in the form of granule suitable for oral administration, because Batra et al. teaches esuberaprost prodrugs, including diastereomers and enantiomers, may be provided in a form of a pharmaceutical composition comprising a pharmaceutically acceptable carrier; and further teaches said pharmaceutical composition may be in the solid dosage form of granules for oral administration. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the derivative of beraprost can successfully be combine with a pharmaceutically acceptable carrier to arrive at a pharmaceutical composition suitable for oral administration in the solid dosage form of granule.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Claims 3 and 6-9 are rejected under 35 U.S.C. 103 as being unpatentable over Batra et al. (WO 2020/086367 A1), in view of Satyam (US 2015/0328323 A1; cited in the IDS filed on May 22, 2024) and Ongini et al. (WO 2005/068421 A1) as applied to claims 3 and 6-9 above, and further in view of Batra et al. (US 10,246,430 B2; referred to herein as “Batra#2”).
To the extent that the claimed invention is drawn to the elected pharmaceutically acceptable carrier (i.e., “a filler”), then the following rejection applies.
The teachings of Batra et al., Satyam and Ongini et al. are set forth above and applied as before.
Batra et al., Satyam and Ongini et al. does not teach a filler; However, Batra et al. teaches at least one additive or excipient can be mixed with one or more esuberaprost prodrugs, or pharmaceutically acceptable salts thereof to prepare solid dosage forms, such as powders; and suitable additives or excipients may be, inter alia, lactose (see e.g., [0079]).
Batra#2 teaches a pharmaceutical formulation may comprise beraprost, and a pharmaceutically acceptable carrier or excipient (see e.g., Col. 50, line 64 to Col. 51, line 1). Batra#2 further teaches solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules; in such solid dosage forms, Beraprost, is mixed with at least one inert, pharmaceutical carrier and/or (a) fillers or extenders such as starches, sugars including lactose and glucose, mannitol, and silicic acid (see e.g., Col. 51, line 56-62).
it would have been prima facie obvious to one of ordinary skill in the art at the time the application was filed to combine the derivative of beraprost set forth above with a pharmaceutically acceptable carrier, such as a lactose as the fillers, to arrive at a pharmaceutical composition suitable for oral administration, because Batra et al. teaches esuberaprost prodrugs, including diastereomers and enantiomers, can be mixed with lactose to arrive at solid dosage forms; and Batra#2 teaches lactose in the list of fillers. One would have reasonable expectation of success to arrive at the claimed invention, because one would have reasonably expected that the derivative of beraprost can successfully be combine with lactose as the pharmaceutically acceptable carrier and fillers to arrive at a pharmaceutical composition.
Therefore, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Conclusion
No claims are allowed.
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628
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