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 .
Claims 1-11, submitted on 9 June 2023, represent all claims currently under consideration.
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.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The effective filing date is 10 December 2020.
Information Disclosure Statement
Two Information Disclosure Statements (IDSs), submitted on 29 August 2023 and 21 October 2025, are acknowledged and have been considered.
Claim Objections
Claim 1 is objected to because of the following informalities: The substituent “[(3-fluoro-1-bicyclo[1.1.1]pentanyl)methyl” is missing a “]” and should be properly named. Appropriate correction is required.
Claims 10 and 11 are objected to because of the following informalities: There is no definition provided for “HFrEF, HFmrEF, and HFpEF”. Each of these types of heart failure should be defined prior to their abbreviation being utilized. Appropriate correction is required.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 7 and 8 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claims do not fall within at least one of the four categories of patent eligible subject matter – namely, machine, manufacture, composition of matter, and process claims. Claims 7 and 8 are non-statutory because they are directed towards the use of a compound according to Claim 1. As such, the claims are not directed to a process, machine, manufacture, or composition of matter (See MPEP § 2173.05 (q)).
Claim Rejections - 35 USC § 112(a)
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.
Claims 5-8 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Factors to be considered in making the determination as to whether one skilled in the art would recognize that applicant was in possession of the claimed invention as a whole at the time of filing include: (a) Actual reduction to practice; (b) Disclosure of drawings of structural chemical formulas; (c) Sufficient identifying characteristics such as: (i) Complete structure, (ii) Partial structure, (iii) Physical and/or chemical properties or (iv) Functional characteristics when coupled with a known or disclosed correlation between function and structure; (d) Method of making the claimed invention; (e) Level of skill and
knowledge in the art and (f) Predictability in the art. While all of these factors are
considered, a sufficient number for a prima facie case are discussed below:
Claim 5 is directed to a compound according to claim 1 for use in the treatment and/or prophylaxis of disease, Claim 6 is directed to a compound according to claim for use in the treatment and/or prophylaxis of several conditions including neurodegenerative diseases and dementias, Claim 7 claims the use of a compound according to claim 1 for producing a medicament for use in the treatment and/or prophylaxis of disease, and Claim 8 is directed to the use of a compound according to claim 1 for producing a medicament for use in the treatment and/or prophylaxis of several diseases including sickle cell disease, neurodegenerative diseases, and dementias . Thus, this claims are directed to the treatment or prophylaxis of any disease with the compounds of Claim 1. The specification indicates that the compounds of the invention are useful for the treatment of cardiovascular and cardiac diseases, as well as neurodegenerative diseases. The specification further indicates that these compounds activate guanylate cyclase (Table 2, Page 291), and thus would be useful for the treatment of conditions and diseases associated with guanylate cyclase. However, the specification does not demonstrate that these compounds would be useful for the treatment of all diseases, and the current state of pharmacology does not lend support to a treatment that functions as a panacea for every disease. The artisan would have no predictability in practicing this invention as claimed because there is no indication that the compounds and/or formulations of the compounds of the invention are capable of treating or preventing every possible disease. Therefore, there is no support that Applicant was in possession of the entire invention as claimed at the time of filing.
Claims 5-8, and 10-11 are 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 the treatment of the several of the claimed conditions, does not reasonably provide enablement for the prevention of these conditions, specifically, the prevention of neurodegenerative diseases and dementias, nor does it provide enablement for the treatment of all neurodegenerative diseases and dementias. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. Consideration of the relevant factors sufficient to establish a prima facie case for lack of enablement is set forth below:
The nature of the invention and breadth of the claims:
The claims are directed to compositions and compounds of Claim 1 used in methods for the treatment and/or prophylaxis of diseases including heart failure, hypertension, chronic and diabetic kidney disease, pulmonary hypertension, systemic sclerosis, sickle cell disease, neurodegenerative diseases and dementias, and diabetic foot ulcer. The compounds of the invention are activators of soluble guanylate cyclase (sGC). Thus, the claims are directed towards methods of preventing neurodegenerative diseases and dementias by activation of soluble guanylate cyclase.
The state of the prior art and the predictability or unpredictability of the art:
Nelissen (Pharmacological Research, 197, 2023) provides a review of vascular cognitive impairment (VCI) and the involvement of soluble guanylate cyclase (sGC). VCI describes neurodegenerative disorders characterized by a vascular component. These conditions involve decreased cerebral blood flow, white matter lesions, endothelial dysfunction, and blood-brain barrier impairments. Oxidative stress and inflammation are two of the major underlying mechanisms. Nitric oxide (NO) stimulates soluble guanylate cyclase (sGC) to induce cGMP production. However, under pathological conditions, NO seems to be the basis of oxidative stress and inflammation, leading to a decrease in sGC activity and expression. sGC agonists have shown efficacy in cardiovascular diseases by restoring the physiological and protective functions of the NO-sGC-cGMP pathway, including the reduction of oxidative stress and inflammation, and improvement of vascular functioning (Abstract). Within VCI, there are four different subtypes: post stroke dementia, subcortical ischemic vascular dementia, multi-infarct dementia, and mixed dementia. The primary cause of VCI is cerebral small vessel disease, although large vessel disease is also prevalent. The pathobiology of VCI is even more variable, yet can be categorized into key processes: white matter lesions, reduced cerebral blood flow, hemorrhages, and infarcts. Stroke can also be a cause for the manifestation of VCI (Page 2). To adequately treat VCI, it is imperative to disrupt the vicious cycle of cerebrovascular pathology. The decrease in sGC activity caused by oxidative stress, eNOS uncoupling, and inflammation exacerbate pathological processes. Currently there are two distinct pharmacological approaches for targeting sGC to enhance its activity and increase cGMP production: stimulating the activity of Fe(II)sGC or by activating the activity of Fe(III)sGC and apo-sGC. Several sGC stimulators have been approved for use to treat cardiovascular disease, with ongoing investigations for the treatment of conditions such as kidney disease, sickle cell disease, and hypertension. However, sGC as a target for neuronal disorders and cerebrovascular disease has been limited likely due to the lack of brain penetrability of most sGC stimulators and activators (3. Direct targeting of sGC-cGMP signaling for the treatment of VCI). Based on the current knowledge regarding the overall beneficial effects of sGC direct agonists in cardiovascular disease and the functional importance of the NO-sGC-cGMP axis in the neurovascular unit and in neurons themselves, it is reasonable to suggest that sGC agonists seem promising therapeutic agents in VCI whose utility should be further investigated at both the preclinical and clinical level (Conclusions). Thus, activation of soluble guanylate cyclase would be expected to be able to treat cardiovascular conditions which are associated with nitric oxide, with the current state of the art currently investigating the treatment of specific dementias such as vascular dementia with vasodilators. However, not all forms of dementia or neurodegenerative diseases would be expected to be treatable by stimulation of soluble guanylate cyclase. For example, Huntington’s disease is a neurodegenerative condition caused by loss of neurons and astrogliosis due to mutations in the huntingtin gene, causing aggregation of this mutant protein within neurons, leading to toxicity and cell death. There is currently no known treatment for Huntington’s disease. Alcohol-related dementia is caused by chronic, excessive alcohol consumption and leads to dementia due to loss of thiamine and death of neurons. Treatment for this condition is accomplished by abstinence from alcohol. Lewy body dementia is caused by accumulation of accumulation of α-synuclein proteins within neurons, causing nerons to eventually die. There is no known treatment for this form of dementia, with current treatment paradigms designed to manage symptoms. Johns Hopkins Medicine (https://web.archive.org/web/20200925183953/https://www.hopkinsmedicine.org/health/conditions-and-diseases/dementia/dementia-prevention-reduce-your-risk) provides an overview of ways to reduce the risk of developing dementia, but there are no known methods which can entirely prevent the occurrence of dementia. Controlling high blood pressure, addressing diabetes, smoking cessation, achieving and maintaining a healthy weight, and becoming more physically active help to improve cerebrovascular help, and work to reduce the risk of developing dementia. However, there are genetic vulnerabilities which can result in dementia, as well as unknown environmental causes which can lead to the development of various forms of dementia, and those are not able to be prevented. Thus, the activation of guanylate cyclase would be expected to treat cardiovascular conditions and certain forms of dementia, such as vascular dementia, but there are no known methods which can prevent the development of dementias, nor would the activation of guanylate cyclase be expected to treat all forms of neurodegenerative disease as not all forms of neurodegenerative disease are associated with guanylate cyclase.
The relative skill of those in the art:
The artisan would likely have a medical degree and advanced training in the treatment of cerebrovascular disorders and diseases, but their training and knowledge would not be sufficient to overcome the lack of guidance and evidence in the current state of the art for the prevention of the development of dementia as dementia has genetic and environmental factors which contribute to its development, and sGC activation would not be expected to overcome these factors in the development of dementia.
The amount of direction or guidance presented and the presence or absence of working examples:
The specification indicates that the compounds of the invention are useful for the treatment of cardiovascular and cardiac diseases, as well as neurodegenerative diseases. The specification further indicates that these compounds activate guanylate cyclase (Table 2, Page 291), and thus would be useful for the treatment of conditions and diseases associated with guanylate cyclase. However, the specification does not provide any data demonstrating that the use of these compounds can prevent the development of conditions such as dementia, or other neurodegenerative conditions.
The quantity of experimentation necessary:
Given the current state of the art, as well as the lack of guidance provided within the specification, the artisan would be burdened with undue experimentation to practice the invention commensurate in the scope of the claims.
Claim Rejections - 35 USC § 112(b)
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 1-4 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 recite the limitation "or one of the salts thereof, solvates thereof or solvates of the salts thereof". There is insufficient antecedent basis for “the salts thereof” as this has not been defined in the claim previously. Claims 5-11 are similarly rejected as indefinite as dependent upon an indefinite claim without resolving the underlying issue of indefiniteness.
Claims 7 and 8 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 “use” limitations of Claims 7 and 8 render the metes and bounds of the claims undefined (rendering the claims indefinite) since there are no active gerund (“-ing”) ending verbs actually setting out each step required in a method claim. Additionally, there is genuine confusion as to whether the claims are intended as a method claim, given that “use” claims are non-statutory in nature (See 35 U.S.C § 101 rejection above) (See MPEP § 2173.05 (q)).
Claim 1 is 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. Claim 1 is indefinite because the definitions for variable R6 are unclear and are open for different interpretations. For example, one interpretation is that R6 can be a C1-C6 alkyl substituted by a group consisting of methoxy, trifluoromethoxy, nitril or amido; or R6 can be a C2-C6 halogenoalkyl substituted by 1 to 5 fluoro substituents. A second interpretation can be that R6 can be a C1-C6 alkyl substituted by a group consisting of methoxy, trifluoromethoxy, nitril, amido, C2-C6 halogenoalkyl substituted by 1 to 5 fluoro substituents, C3-C6 cycloalkyl, C3-C6 cycloalkyl-methyl, etc. The lack of “or” or “and” within each potential option creates a lack of clarity that leaves the claim open to interpretation. The Examiner suggests including “or” or “and” to end each groups substituents, and including a semi-colon “;” to delineate each specific group within the variable. Claims 2 and 3 are similarly rejected as they have similar issues which would be resolved by the inclusion of semi-colons between individual substituents for variable R6. Claims 4-11 are rejected as dependent upon an indefinite claim without resolving the underlying issue of indefiniteness.
Claim 2 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. Claim 2 is indefinite because there is no “or” or “and” within the Markush groupings for variables R1 and R2, rendering the claim indefinite.
Claims 6, 8, 10 and 11 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 claim a method for treatment and/or prophylaxis of heart failure… and diabetic foot ulcer. It is unclear if the human or animal in need thereof is suffering from all conditions at once, or if the method is for the treatment of only one of the conditions, selected from this group.
Claims 10 and 11 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 directed towards methods for the treatment and/or prophylaxis of conditions, including heart failure. It is unclear how these methods can be used to both prevent and treat conditions such as heart failure in the same patient, i.e., it is not possible to both prevent and treat something at the same time.
Claims 10 and 11 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 claim a method for the treatment and/or prophylaxis of heart failure (HFrEF, HFmrEF, and HFpEF). It is unclear if the information within the parentheticals is a necessary part of the invention, or if these are merely exemplary forms of heart failure which can be treated using the claimed methods as these three forms of heart failure are not the only types of heart failure which can occur.
Claims 6, 8, and 10 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 contain the limitation “chronic and diabetic kidney disease” and “neurodegenerative diseases and dementias” (emphasis added). It is unclear if the patient to be treated needs to have both chronic and diabetic kidney disease, or neurodegenerative disease and dementia, leading to a potential interpretation where both sets of conditions are required.
Claim 11 is 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 claim contains the limitation “chronic and diabetic kidney disease” (emphasis added). It is unclear if the patient to be treated needs to have both chronic and diabetic kidney disease leading to a potential interpretation where both sets of conditions are required.
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 1-3 and 5-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-11 of copending Application No. 18/256,647 (‘647) (Amended claims of 9 June 2023) in view of Meanwell (J. Med. Chem., 2018, 61, 5822-5880).
Claim 1 of ‘647 is directed to a compound of Formula (I)
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wherein R1 and R2 are hydrogen or halogen, R3 is chloro or trifluoromethyl, R4 is hydrogen or C1-C4 alkyl, R5 is C1-C6 alkyl, X1 and X2 are nitrogen or carbon. Claim 2 is directed to a compound according to claim 1 wherein R1 and R2 are hydrogen or fluorine, R3 is chloro or trifluoromethyl, R4 is hydrogen or methyl, R5 is isobutyl, and X1 and X2 are nitrogen or carbon. Claim 3 is directed to a compound according to claim 1 of formula
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. Claim 5 is directed to a compound according to claim 1 for use in the treatment and/or prophylaxis of diseases. Claim 6 claims a compound according to claim 1 for use in the treatment and/or prophylaxis of heart failure, hypertension, chronic and diabetic kidney disease, pulmonary hypertension, systemic sclerosis, sickle cell disease, neurodegenerative diseases and dementia, and diabetic foot ulcer. Claim 7 claims the use of a compound according to claim 1 for producing a medicament for use in the treatment and/or prophylaxis of disease. Claim 8 claims the use of a compound according to claim 1 for producing a medicament for use in the treatment and/or prophylaxis of heart failure, hypertension, chronic and diabetic kidney disease, pulmonary hypertension, systemic sclerosis, sickle cell disease, neurodegenerative diseases and dementias, and diabetic foot ulcer. Claim 9 claims a medicament comprising a compound according to claim 1 in combination with an inert, nontoxic pharmaceutically acceptable excipient. Claim 10 claims a method for the treatment and/or prophylaxis of heart failure, hypertension, chronic and diabetic kidney disease, pulmonary hypertension, systemic sclerosis, sickle cell disease, neurodegenerative diseases and dementia, and diabetic foot ulcer, comprising administering a therapeutically effective amount of the medicament of claim 9 to a human or animal in need thereof. Claim 11 is directed to a method for the treatment and/or prophylaxis of heart failure, hypertension, chronic and diabetic kidney disease, pulmonary hypertension, systemic sclerosis, sickle cell disease, and diabetic foot ulcer in humans and animals comprising administering a therapeutically effective amount of at least one compound according to claim 1.
The compounds of ‘647 and the examined application differ by the presence of halogenated or fluorinated alkyl groups at the variable R5 (analogous to variable R6 of the examined application) position.
Meanwell teaches the use of fluorine and fluorinated motifs in drug development and their use as bioisosteres. The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. Fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule (Abstract). The use of bioisosteres is a common principle in drug design. Introduction of fluorine can increase the overall lipophilicity of a molecule (Page 5823). The replacement of hydrogen with fluorine can lead to resistance towards oxidative metabolism, and fluorination has developed into a popular approach to address the poor pharmacokinetic performance of drug-like compounds in vitro and in vivo (Page 5824). Table 12 shows the physicochemical data of fluorinated derivatives of drug-like compounds, demonstrating that introduction of fluorine can modulate solubility and LogP of compounds. Further, addition of fluorine has been shown to enhance potency of certain drugs (Table 22, Page 5839).
‘647 and Meanwell are considered analogous to the claimed invention as all are involved in the development of drugs and therapeutic agents. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to modify the compounds of ‘647 through the fluorination of the alkyl chain present at the R5 position (analogous to variable R6 of the examined application) to arrive at the compounds and methods which are claimed. As Meanwell teaches, fluorination is a common technique utilized in the pharmaceutical arts used to enhance both the potency and metabolic stability of compounds, and the artisan would recognize this, and by fluorinating this alkyl chain, would predictably arrive at compounds which have similar properties as those of ‘647. The fluorination of the alkyl chain of the compounds of ‘647 is prima facie obvious use of a known technique to improve similar products in the same way (See MPEP § 2143 I (C)); the compounds of ‘647 are sGC activators similar to those of the examined application, and fluorination is a common technique is drug development to enhance potency and metabolic stability of compounds, and performing this would predictably result in an sGC with enhanced potency or metabolic stability.
This is a provisional nonstatutory double patenting rejection.
Claims 1-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of copending Application No. 18/256,650 (‘650) (Amended claims of 9 June 2023) in view of Meanwell (J. Med. Chem., 2018, 61, 5822-5880).
Claim 1 of ‘650 is directed to a compound of formula (I)
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wherein R1 represents hydrogen or halogen, R2 represents hydrogen or halogen, R3 represents chloro or trifluoromethyl, R4 represents hydrogen or C1-C4 alkyl, R5 represents a group of the formula
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, R6 represents C1-C6 alkyl, substituted by one or more substituent independently selected from trifluoromethoxy, nitril, amido, C2-C6 halogenoalkyl, substituted by 1 to 5 fluoro substituents, C3-C6 cycloalkyl, C3-C6 cycloalkyl-methyl, optionally substituted by 1 to 5 fluoro substituents or a trifluoromethyl group, C1-C6 alkylcarbonyl, optionally substituted by 1 to 3 fluoro substituents, C3-C6 cycloalkyl-carbonyl, optionally substituted with 1 to 3 fluoro substituents, oxetanyl, spiro[2.2]pentan-2-ylmethyl or [(3-fluoro-1-bicyclo[1.1.1.]pentanyl)methyl, R7 represents C1-C4 alkylcarbonyl, optionally substituted by C3-C6 cycloalkyl group, R8 represents C2-C4 halogenoalkyl substituted by 1 to 6 fluoro substituents, X1 and X2 represent nitrogen or carbon. Claim 2 is directed to a compound according to claim 1 wherein R1 and R2 are hydrogen or fluorine, R3 is chloro or trifluoromethyl, R4 is hydrogen or methyl, R5 represents a group
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, R6 is C1-C4 alkyl substituted by one or more substituent selected from trifluoromethoxy and nitril, C2-C6 halogenoalkyl substituted by 1 to 5 fluoro substituents, C3-C6 cycloalkyl-methyl optionally substituted by 1 to 2 fluoro substituents or a trifluoromethyl group, C1-C3 alkyl carbonyl optionally substituted by 1 to 3 fluoro substituents, C3-C6 cycloalkyl carbonyl, R7 is C1-C3 alkyl carbonyl optionally substituted by cyclopropyl, R8 is C2-C4 halogenoalkyl optionally substituted by 1 to 3 fluoro substituents, X1 and X2 are nitrogen or carbon. Claim 3 claims the compound according to claim 1 wherein R1 and R2 are hydrogen, R3 is chloro, R4 is hydrogen, R5 is a group of the formula
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R6 represents C1-C4 alkyl substituted by trifluoromethoxy or nitril, C2-C3 halogenoalkyl substituted by 1 to 5 fluoro substituents, C3-C4 cycloalkyl-methyl optionally substituted by 1 to 2 fluoro substituents or a trifluoromethyl group, C1-C3 alkylcarbonyl optionally substituted by 1 to 3 fluoro substituents, cyclopropyl carbonyl, R7 is C1-C3 alkyl carbonyl optionally substituted by cyclopropyl, and X1 and X2 are carbon. Claim 4 claims a process for preparing a compound according to formula (I) of claim 1 wherein in a first step [B] the compounds of the formula (III)
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in which R1, R2, and R3 are as previously defined, are reacted with compounds of the formula (IV)
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in which R4, R5, X1, and X2 are as defined previously, and in which R9 represents hydrogen, methyl, or both R9 form via the adjacent oxygen atoms a 4,4,5,5,-tetramethyl-1,3,2-dioxaborolane in the presence of a palladium source, a suitable ligand and base to provide compounds of the formula (II)
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and in a second step [A], compounds of formula (II) are reacted with a base to provide compounds of the formula (I), optionally transferred to a third step to form the corresponding salts of the formula (1a) in the presence of a suitable acid in a suitable solvent. Claim 5 claims a compound according to claim 1 for use in the treatment and/or prophylaxis of diseases. Claim 6 claims a compound according to claim 1 for use in the treatment and/or prophylaxis of heart failure, hypertension, chronic and diabetic kidney disease, pulmonary hypertension, systemic sclerosis, sickle cell disease, neurodegenerative diseases and dementia, and diabetic foot ulcer. Claim 7 claims the use of a compound according to claim 1 for producing a medicament for use in the treatment and/or prophylaxis of diseases. Claim 8 claims the use of a compound according to claim 1 for producing a medicament for use in the treatment and/or prophylaxis of heart failure, hypertension, chronic and diabetic kidney disease, pulmonary hypertension, systemic sclerosis, sickle cell disease, neurodegenerative diseases and dementias and diabetic foot ulcer. Claim 9 claims a medicament comprising the compound according to claim 1 in combination with an inert, nontoxic pharmaceutically suitable excipient. Claim 10 is directed to a method for the treatment and/or prophylaxis of heart failure, hypertension, chronic and diabetic kidney disease, pulmonary hypertension, systemic sclerosis, sickle cell disease, neurodegenerative diseases and dementias, and diabetic foot ulcer comprising administering a therapeutically effective amount of the medicament of claim 9 to a human or animal in need thereof. Claim 11 claims a method for the treatment and/or prophylaxis of heart failure, hypertension, chronic and diabetic kidney disease, pulmonary hypertension, systemic sclerosis, sickle cell disease, neurodegenerative diseases and dementias, and diabetic foot ulcer comprising administering a therapeutically effective amount of at least one compound according to Claim 1 to a human or animal in need thereof.
The compounds of ‘650 differ from those of the examined application by the presence of a difluoromethyl (CF2) group on the pyrazole ring rather than a trifluoromethyl (CF3) group of the examined application.
Meanwell, as previously described, teaches the use of fluorination in drug development as a means of increasing potency and enhancing the metabolic stability of therapeutic compounds.
‘650 and Meanwell are considered analogous to the claimed invention as all are involved in the development of drugs and therapeutic agents. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to modify the compounds of ‘650 through addition of a third fluorine to the CF2 moiety on the pyrazole ring to form a CF3 to arrive at the compounds and methods which are claimed. As Meanwell teaches, fluorination is a common technique utilized in the pharmaceutical arts used to enhance both the potency and metabolic stability of compounds, and the artisan would recognize this, and by adding a single fluorine to this moiety, would predictably arrive at compounds which have similar properties as those of ‘650. The fluorination of the moiety of ‘650 is prima facie obvious use of a known technique to improve similar products in the same way (See MPEP § 2143 I (C)); the compounds of ‘650 are sGC activators similar to those of the examined application, and fluorination is a common technique is drug development to enhance potency and metabolic stability of compounds, and performing this would predictably result in an sGC with enhanced potency or metabolic stability.
This is a provisional nonstatutory double patenting rejection.
Claims 1-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 7-11 and 13 of copending Application No. 17/667,410 (‘410) (Amended claims of 22 August 2025) in view of Meanwell (J. Med. Chem., 2018, 61, 5822-5880).
Claim 7 of ‘410 is directed to a process for preparing a compound of Formula (I), characterized in that a first step [D] compounds of formula (VIII)
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in which R1 and R2 are hydrogen or halogen, R2 represents hydrogen or halogen, and R3 represents chloro or trifluoromethyl, are reacted with compounds of formula (VII)
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in which R4 is hydrogen or C1-C4 alkyl, R5 represents C1-C6 alkyl, R9 represents hydrogen, methyl, or both R9 groups combine to form via the adjacent oxygen atoms a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan, X1 and X2 represent nitrogen or carbon, in the presence of a palladium source, a suitable ligand, and a base to provide compounds of formula (II)
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and in a second step [A] compounds of formula (II) are reacted with a base in a suitable solvent to provide compounds of formula (I)
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and optionally the compounds of formula (I) are transferred to a third step [A]* into the corresponding salts of formula (Ia) in the presence of a suitable acid in a suitable solvent. Claim 8 is directed to a compound of formula (I)
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in which R1 and R2 represents hydrogen or halogen, R3 represents chloro or trifluoromethyl, R4 represents hydrogen or C1-C4 alkyl, R5 represents C1-C6 alkyl, and X1 and X2 represent nitrogen or carbon, for use in the treatment and/or prophylaxis of disease. Claim 9 claims the compound of formula (I) as previously described for use in the treatment and/or prophlyaxis of herat failure, hypertension, chronic and diabetic kidney disease, pulmonary hypertension, systemic sclerosis, sickle cell disease, neurodegenerative diseases and dementias, or diabetic foot ulcer. Claim 10 claims a composition for use as a medication for the treamtent and/or prophylaxis of diease comprising a compound according to formula (I) as previously described. Claim 11 claims a composition for use as a medication for the treatment and/or prophylaxis of disease comprising a compound according to formula (I) as previously described, wherein the disease is selected from the group consisting of heart failure, hypertension, chronic and diabetic kidney disease, pulmonary hypertension, systemic sclerosis, sickle cell disease, neurodegenerative diseases and dementias, and diabetic foot ulcer. Claim 13 claims a medicament containing a compound of formula (I) as in claim 9 for use in the treatment and/or prophylaxis of heart failure, hypertension, chronic and diabetic kidney disease, pulmonary hypertension, systemic sclerosis, sickle cell disease, neurodegenerative disease and dementias, or diabetic foot ulcer.
The compounds of ‘410 and those of the examined application differ by the presence of CF2 on the pyrazole moiety rather than CF3, and the fluorination of the alkyl chains of variable R5 (analogous to variable R6 of the examined application).
Meanwell, as previously described, teaches the use of fluorination in drug development as a means of increasing potency and enhancing the metabolic stability of therapeutic compounds.
‘410 and Meanwell are considered analogous to the claimed invention as all are involved in the development of drugs and therapeutic agents. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to modify the compounds of ‘410 through addition of a third fluorine to the CF2 moiety on the pyrazole ring to form a CF3, and fluorination of the alkyl chain at the variable R5 position to arrive at the compounds and methods which are claimed. As Meanwell teaches, fluorination is a common technique utilized in the pharmaceutical arts used to enhance both the potency and metabolic stability of compounds, and the artisan would recognize this, and by adding a single fluorine to this moiety and fluorination of the alkyl chain at variable R5, would predictably arrive at compounds which have similar properties as those of ‘410. The fluorination of the compounds of ‘410 is prima facie obvious use of a known technique to improve similar products in the same way (See MPEP § 2143 I (C)); the compounds of ‘410 are sGC activators similar to those of the examined application, and fluorination is a common technique is drug development to enhance potency and metabolic stability of compounds, and performing this would predictably result in an sGC with enhanced potency or metabolic stability.
This is a provisional nonstatutory double patenting rejection.
Claims 1-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, and 7-10 of U.S. Patent No. 12,195,448 (‘448) in view of Meanwell (J. Med. Chem., 2018, 61, 5822-5880).
Claim 1 of ‘448 is directed to a compound of formula (I)
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wherein R1 and R2 are hydrogen or halogen, R3 is chloro or trifluoromethyl, R4 is hydrogen or C1-C4 alkyl, R5 is C1-C6 alkyl, and X1 and X2 are nitrogen or carbon. Claim 2 claims the compound of claim 1 wherein R1 and R2 are hydrogen or fluorine, R3 is chloro or trifluoromethyl, R4 is hydrogen or methyl, R5 is isobutyl, and X1 and X2 are carbon. Claim 3 claims the compound of claim 1 of the formula
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. Claim 7 claims a process for preparing a compound of formula (I) according to claim 1 comprising in a first step [D] reacting a compound of formula (VIII)
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with a compound of formula (VII)
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wherein R9 represents hydrogen, methyl or both R9 form via the adjacent oxygen atoms a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan in the presence of a pallidum source , a suitable ligand, and a base to provide a compound of the formula (II)
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and in a second step [A] reacting the compound of formula (II) with a base in a suitable solvent to provide a compound of the formula (I), and optionally transferring the compounds of formula (I) in a third step [A]* into the corresponding salts in the presence of a suitable acid in a suitable solvent. Claim 8 claims a method for treatment of a disease or condition comprising administering a therapeutically effective amount of the compound according to claim 1 to a human or animal in need thereof wherein the disease or condition is chronic kidney disease and diabetic kidney disease. Claim 9 claims a medicament comprising the compound according to claim 1 in combination with an inert nontoxic pharmaceutically acceptable excipient. Claim 10 claims a method for treatment of chronic kidney disease and diabetic kidney disease in humans and animals comprising administering a therapeutically effective amount of at least one compound according to claim 1 to a human or animal in need thereof.
The compounds of ‘448 and those of the examined application differ by the presence of CF2 on the pyrazole moiety rather than CF3, and the fluorination of the alkyl chains of variable R5 (analogous to variable R6 of the examined application).
Meanwell, as previously described, teaches the use of fluorination in drug development as a means of increasing potency and enhancing the metabolic stability of therapeutic compounds.
‘448 and Meanwell are considered analogous to the claimed invention as all are involved in the development of drugs and therapeutic agents. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to modify the compounds of ‘448 through addition of a third fluorine to the CF2 moiety on the pyrazole ring to form a CF3, and fluorination of the alkyl chain at the variable R5 position to arrive at the compounds and methods which are claimed. As Meanwell teaches, fluorination is a common technique utilized in the pharmaceutical arts used to enhance both the potency and metabolic stability of compounds, and the artisan would recognize this, and by adding a single fluorine to this moiety and fluorination of the alkyl chain at variable R5, would predictably arrive at compounds which have similar properties as those of ‘448. The fluorination of the compounds of ‘448 is prima facie obvious use of a known technique to improve similar products in the same way (See MPEP § 2143 I (C)); the compounds of ‘448 are sGC activators similar to those of the examined application, and fluorination is a common technique is drug development to enhance potency and metabolic stability of compounds, and performing this would predictably result in an sGC with enhanced potency or metabolic stability.
Claims 1-3 and 5-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 11 and 15 of copending Application No. 18/893,545 (‘545) (Amended claims of 2 January 2025) in view of Meanwell (J. Med. Chem., 2018, 61, 5822-5880).
Claim 1 of ‘545 claims the use of a compound of formula (I)
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wherein R1 and R2 are hydrogen or halogen, R3 is chloro or trifluoromethyl, R4 is hydrogen or C1-C4 alkyl, R5 is C1-C6 alkyl, and X1 and X2 are nitrogen or carbon, for producing a medicament for use in the treatment and/or prophylaxis of heart failure, hypertension, pulmonary hypertension, systemic sclerosis, sickle cell disease, and diabetic foot ulcer. Claim 15 claims a method for treating a patient suffering from at least one ailment selected from the group consisting of heart failure, hypertension, pulmonary hypertension, systemic sclerosis, sickle cell disease, and diabetic foot ulcer, comprising administering to the patient an effective amount of a compound of formula (I), as described previously.
The compounds of ‘545 and those of the examined application differ by the presence of CF2 on the pyrazole moiety rather than CF3, and the fluorination of the alkyl chains of variable R5 (analogous to variable R6 of the examined application).
Meanwell, as previously described, teaches the use of fluorination in drug development as a means of increasing potency and enhancing the metabolic stability of therapeutic compounds.
‘545 and Meanwell are considered analogous to the claimed invention as all are involved in the development of drugs and therapeutic agents. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to modify the compounds of ‘545 through addition of a third fluorine to the CF2 moiety on the pyrazole ring to form a CF3, and fluorination of the alkyl chain at the variable R5 position to arrive at the compounds and methods which are claimed. As Meanwell teaches, fluorination is a common technique utilized in the pharmaceutical arts used to enhance both the potency and metabolic stability of compounds, and the artisan would recognize this, and by adding a single fluorine to this moiety and fluorination of the alkyl chain at variable R5, would predictably arrive at compounds which have similar properties as those of ‘545. The fluorination of the compounds of ‘545 is prima fac