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 .
Priority
The instant application claims priority to 371 National Stage Application PCT/US2022/021165, filed March 21st , 2022, under 35 U.S.C. 119(a)-(d), and claims benefit to provisional application 63163584, filed March 19th, 2021, under 35 U.S.C.119 (e). The priority date of March 19th, 2021 is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on September 14th, 2023, and January 19th, 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-14, in the reply filed on May 6th, 202 is acknowledged.
Applicant’s election without traverse of (1) the type of KOA being a peptide; (2) the KOA is both a peripherally restricted and a centrally acting KOA (3) the diuretic being a loop diuretic in the reply filed on May 6th, 2026 is acknowledged.
Claims 15-58 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 6th, 2026.
Claims 13-14 are also withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on May 6th, 2026.
Claims Status
The claims listing filed on May 9th, 2024 is pending. Claims 13-58 are withdrawn from further consideration for the reasons set forth in the restriction requirement, 37 CFR 1.142(b). Claims 1-12 are being examined on the merits in this office action.
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.
Claim 1-9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3, 5, and 9 of copending Application No. 17922727 (reference application) in view of Wilcox et al. (Wilcox, C. S., Testani, J. M., & Pitt, B. (2020). Pathophysiology of Diuretic Resistance and Its Implications for the Management of Chronic Heart Failure. Hypertension (Dallas, Tex. : 1979), 76(4), 1045–1054). Although the claims at issue are not identical, they are not patentably distinct from each other because it is obvious that a method for treating subjects afflicted with polycystic kidney disease has a patient population that overlaps with subjects with diuretic resistance.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 1, 17922727 recites a method of treating a subject afflicted with polycystic kidney disease (PKD), the method comprising administering to a subject a therapeutically effective amount of a kappa opioid receptor agonist (KOA) [claim 1]., 17922727 specifies that “administration of a kappa opioid receptor agonist (KOA) to animals or man causes an increase in urine output (diuresis) often associated with a decrease in urinary sodium/potassium excretion” and that “water and electrolyte imbalance, including fluid overload and hyponatremia, can occur in patients with PKD.” [0256]. 17922727 does not specifically teach that a decrease in urinary sodium/potassium excretion, water and electrolyte imbalance, fluid overload and hyponatremia are characteristics and mechanisms of diuretic resistance.
Wilcox et al. preface that diuretic resistance implies a failure to increase fluid and sodium (Na+) output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of a loop diuretic to a ceiling level [Abstract line 1]. Wilcox goes on to teach that one of the pathophysiological mechanisms of diuretic resistance is hyponatremia [Abstract line 8].
The patient population between the 17922727’s claim and the instant claim are not patentably distinct as a subject with PKD experiences fluid overload and hyponatremia and may also require a method to reverse diuretic resistance. Thus, it would have been obvious to one of ordinary skill in the art to use a method comprising administering to the subject an amount of a kappa opioid receptor agonist (KOA) sufficient to selectively increase urine output to reverse diuretic resistance because there is a reasonable expectation that a KOA would be successful at doing so.
Regarding claim 2, 17922727 specifies that “administration of a kappa opioid receptor agonist (KOA) to animals or man causes an increase in urine output (diuresis)” [0256]. Therefore, it would be obvious to one of ordinary skill to administer a KOA to a subject suffering from diuretic resistance, because it increases urine output in subjects with PKD.
Regarding claim 3, 17922727 states that “tolvaptan is the only drug that has shown efficacy in slowing down the progress of PKD, and its mechanism of action is to act in the collecting duct of the kidneys to block vasopressin type 2 (V2) receptors to cause water diuresis. KOAs also produce water diuresis but by a mechanism different than Tolvaptan. Therefore, without wishing to be bound by theory, KOA can be used for treatment of PKD” [0256]. 17922727 also states that
“[Tolvaptan] carries risk of severe hepatic toxicity, and patients treated with tolvaptan are suffering serious side effects, such as severe thirst and polyuria due to inhibition of V2 receptor in the distal nephrons. Research from our laboratory and others has demonstrated that administration of kappa opioid receptor agonists (KOAs) produce a water diuresis similar to tolvaptan, but by acting in the central nervous system to inhibit the release/secretion of vasopressin into the systemic circulation” and that in theory, “KOAs will be superior to tolvaptan in attenuating fluid filled cysts and fibrosis formation in PKD.” [0260]
This means a subject afflicted with polycystic kidney disease (PKD) who is resistant to the diuretic tolvaptan, may be better suited for a KOA. Therefore, the patient population is not patentably distinct as a it would have been obvious to give a subject afflicted with polycystic kidney disease (PKD) that has failed to achieve diuresis with diuretic therapy using tolvaptan, a KOA in a method to reverse diuretic resistance.
Regarding claim 4, 17922727 recites a method of treating a subject afflicted with polycystic kidney disease (PKD), the method comprising administering to a subject a therapeutically effective amount of a kappa opioid receptor agonist (KOA), where the kappa opioid receptor agonist comprises an organic small molecule [claims 1 and 3]. Therefore, it would have been obvious to claim a method to reverse diuretic resistance administering to the subject an amount of a kappa opioid receptor agonist (KOA), where the kappa opioid receptor agonist comprises an organic or synthetic small molecule or a peptide.
Regarding claim 5, 17922727 specifies that in embodiments, the KOA can be a peripherally restricted KOA and, in some embodiments, the KOA can act centrally [0193]. Therefore, it would have been obvious to claim a method to reverse diuretic resistance administering to the subject an amount of a kappa opioid receptor agonist (KOA), where the kappa opioid receptor agonist is a peripherally restricted KOA, a centrally acting KOA, or both, as that would have a reasonable expectation of success at reversing diuretic resistance.
Regarding claim 6, 17922727 specifies that “administration of a kappa opioid receptor agonist (KOA) to animals or man causes an increase in urine output (diuresis) often associated with a decrease in urinary sodium/potassium excretion. Therefore, it would have been obvious to a person of ordinary skill that a method to reverse diuretic resistance comprising administering to the subject an amount of a kappa opioid receptor agonist (KOA) would result in a decrease in the urinary excretion of sodium and potassium.
Regarding claim 7, 17922727 claims a method of treating a subject afflicted with polycystic kidney disease (PKD), the method comprising administering to a subject a therapeutically effective amount of a kappa opioid receptor agonist, where the KOA decreases circulating levels of vasopressin and the KOA is JT09, nalfurafine, CR665, or CR845 [claims 1-2 and 5]. Therefore, it would have been obvious to a person of ordinary skill that a method to reverse diuretic resistance comprising administering to the subject an amount of a kappa opioid receptor agonist (KOA), would have a reasonable expectation of success using organic small molecules or peptides JT09, nalfurafine, or CR665.
Regarding claim 8, 17922727 claims a method of treating a subject afflicted with polycystic kidney disease (PKD), the method comprising administering to a subject a therapeutically effective amount of a kappa opioid receptor agonist, where the KOA decreases circulating levels of vasopressin and the KOA is the same as instant structure (I), (II), (III), and (IV) [claims 1-2 and 9]. Therefore, it would have been obvious to a person of ordinary skill that a method to reverse diuretic resistance comprising administering to the subject an amount of a kappa opioid receptor agonist (KOA), would have a reasonable expectation of success using structures (I) to (IV).
Regarding claim 9, 17922727 specifies that supplementary active compounds can also be incorporated into the compositions [0226]. Therefore, it would have been obvious to a person in ordinary for the method to comprise of an additional active agent for a better expectation at being successful at reversing diuretic resistance.
Regarding claim 10, Wilcox et al teach that “diuretic therapy can upregulate Na+ transport in the proximal tube (PT) that limits Na+ delivery to the LH (loop of Henle) or upregulates Na+ transport in downstream nephron segments that limit natriuresis. These findings provide rationales for combining diuretics with actions on different nephron segments” [pg 5 section Diuretic Combinations]. Wilcox also shows strategies for the use of additional diuretics to counteract loop diuretic resistance in patients with heart failure by combining lop diuretics with major classes of diuretic drugs [Fig 5]. Therefore, it would have been obvious to an artisan of ordinary skill to combine the KOA, a major class of diuretics, with another diuretic, for the best expectation of overcoming and reversing diuretic resistance successfully.
Regarding claim 11, Wilcox shows strategies for the use of additional diuretics to counteract loop diuretic resistance in patients with heart failure by combining lop diuretics with major classes of diuretic drugs [Fig 5]. Therefore, it would have been obvious to an artisan of ordinary skill to combine the KOA, a major class of diuretics, with a loop diuretic, for the best expectation of overcoming and reversing diuretic resistance successfully.
Regarding claim 12, in the diuretic combinations Wilcox provides to overcome diuretic resistance, the loop diuretic used in the loop diuretic plus PT diuretic, loop diuretic plus early distal tubule diuretic, loop diuretic plus CD diuretic, loop diuretics plus PT and DT diuretic, and mineral corticosteroid receptor antagonist and aquaretic, furosemide was used. Therefore, it would have been obvious to an artisan of ordinary skill to use furosemide as the loop diuretic for the best expectation of success at reversing diuretic resistance.
Claim 1-9 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-3, 5, and 9 of copending Application No. 19527166 (reference application) in view of Wilcox et al. (Wilcox, C. S., Testani, J. M., & Pitt, B. (2020). Pathophysiology of Diuretic Resistance and Its Implications for the Management of Chronic Heart Failure. Hypertension (Dallas, Tex. : 1979), 76(4), 1045–1054). Although the claims at issue are not identical, they are not patentably distinct from each other because it is obvious that a method for treating subjects afflicted with polycystic kidney disease has a patient population that overlaps with subjects with diuretic resistance.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 1, 19527166 recites method of treating a subject afflicted with polycystic kidney disease (PKD), the method comprising administering to the subject a therapeutically effective amount of difelikefalin or a pharmaceutically acceptable salt thereof [claim 1]. 19527166 specifies that “water and electrolyte imbalance, including fluid overload and hyponatremia, can occur in patients with PKD.” [0006]. 19527166 does not specifically teach that a water and electrolyte imbalance, fluid overload and hyponatremia are characteristics and mechanisms of diuretic resistance.
Wilcox et al. preface that diuretic resistance implies a failure to increase fluid and sodium (Na+) output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of a loop diuretic to a ceiling level [Abstract line 1]. Wilcox goes on to teach that one of the pathophysiological mechanisms of diuretic resistance is hyponatremia [Abstract line 8].
The patient population between the 19527166’s claim and the instant claim are not patentably distinct as a subject with PKD may experience symptoms of diuretic resistance such as fluid overload and hyponatremia and thus, require a method to reverse diuretic resistance. It would have been obvious to one of ordinary skill in the art to use a method comprising administering to the subject an amount of a kappa opioid receptor agonist (KOA) sufficient to selectively increase urine output to reverse diuretic resistance because there is a reasonable expectation that a KOA such as difelikefalin would be successful at doing so.
Regarding claim 2, 19527166 specifies that “water and electrolyte imbalance, including fluid overload and hyponatremia, can occur in patients with PKD.” Therefore, it would be obvious to one of ordinary skill to administer a KOA to a subject suffering from diuretic resistance, because it helps offload fluid in subjects with PKD.
Regarding claim 3, 19527166 states that
“aspects of the invention are also drawn towards a method of decreasing an adverse effect of treatment with tolvaptan. For example, the adverse effect comprises polyuria, polydipsia, or both” [0014]. 19527166 also states that “tolvaptan, a V2 AVP (vasopressin) receptor antagonist which acts exclusively in the renal collecting ducts to block the water-retaining effects of AVP is used clinically to treat ADPKD. However, by inhibiting the central secretion/release of AVP into the blood, which would then attenuate/prevent actions of AVP throughout the body (e.g., within the brain, blood, systemic and renal blood vessels, and other sites in the kidneys other than only the collecting ducts), we hypothesized that difelikefalin would be superior to the V2 AVP receptor antagonist, tolvaptan, in slowing progression of early stage ADPKD and have fewer adverse effects.” [0073].
Therefore, the patient population of subjects afflicted with PKD can include patients who have experienced the adverse effects of tolvaptan and therefore failed to achieve diuresis and thus use the claimed method as a way of decreasing the adverse effects of treatment with tolvaptan, as difelikefalin may be superior. Therefore, the patient population is not patentably distinct as a it would have been obvious to give a subject afflicted with polycystic kidney disease (PKD) that has failed to achieve diuresis with diuretic therapy, a KOA in a method to reverse diuretic resistance.
Regarding claim 4, 19527166 claims a method of treating a subject afflicted with polycystic kidney disease (PKD), the method comprising administering to the subject a therapeutically effective amount of difelikefalin or a pharmaceutically acceptable salt [claims 1]. Difelikefalin is a small molecule peptide. Therefore, it would have been obvious to claim a method to reverse diuretic resistance administering to the subject an amount of a kappa opioid receptor agonist (KOA), where the kappa opioid receptor agonist comprises an organic or synthetic small molecule or a peptide.
Regarding claim 5, 19527166 specifies that pharmaceutical compositions can be in a form adapted for administration by a peripheral route or is suitable for oral administration or suitable for parenteral administration [0043]. Therefore, it would have been obvious to claim a method to reverse diuretic resistance administering to the subject an amount of a kappa opioid receptor agonist (KOA), where the kappa opioid receptor agonist is a peripherally restricted KOA, as that would have a reasonable expectation of success at reversing diuretic resistance.
Regarding claim 6, 19527166 specifies that “kappa opioid agonists including difelikefalin and nalfurafine are recognized to decrease the renal excretion of sodium and potassium” [0078]. Therefore, it would have been obvious to a person of ordinary skill that a method to reverse diuretic resistance comprising administering to the subject an amount of a kappa opioid receptor agonist (KOA) would result in a decrease in the urinary excretion of sodium and potassium.
Regarding claim 7, 19527166 claims a method of treating a subject afflicted with polycystic kidney disease (PKD), the method comprising administering to the subject a therapeutically effective amount of difelikefalin or a pharmaceutically acceptable salt thereof [claims 1]. Therefore, it would have been obvious to a person of ordinary skill that a method to reverse diuretic resistance comprising administering to the subject an amount of a kappa opioid receptor agonist (KOA), would have a reasonable expectation of success using difelikefalin.
Regarding claim 8, 19527166 claims a method of treating a subject afflicted with polycystic kidney disease (PKD), the method comprising administering to the subject a therapeutically effective amount of difelikefalin or a pharmaceutically acceptable salt thereof [claims 1]. Difelikefalin has the same structure as instant structure (IV) [0035]. Therefore, it would have been obvious to a person of ordinary skill that a method to reverse diuretic resistance comprising administering to the subject an amount of a kappa opioid receptor agonist (KOA), would have a reasonable expectation of success using structure (IV).
Regarding claim 9, 19527166 specifies pharmaceutical compositions disclosed herein can advantageously comprise between about 0.1% and 99% by weight of the compound or active agent based on the weight of the total composition including the carrier [0046]. Therefore, it would have been obvious to a person in ordinary for the method to comprise of an additional active agent for a better expectation at being successful at reversing diuretic resistance.
Regarding claim 10, Wilcox teaches that “diuretic therapy can upregulate Na+ transport in the proximal tube (PT) that limits Na+ delivery to the LH (loop of Henle) or upregulates Na+ transport in downstream nephron segments that limit natriuresis. These findings provide rationales for combining diuretics with actions on different nephron segments” [pg 5 section Diuretic Combinations]. Wilcox also shows strategies for the use of additional diuretics to counteract loop diuretic resistance in patients with heart failure by combining lop diuretics with major classes of diuretic drugs [Fig 5]. Therefore, it would have been obvious to an artisan of ordinary skill to combine the KOA, a major class of diuretics, with another diuretic, for the best expectation of overcoming and reversing diuretic resistance successfully.
Regarding claim 11, Wilcox shows strategies for the use of additional diuretics to counteract loop diuretic resistance in patients with heart failure by combining lop diuretics with major classes of diuretic drugs [Fig 5]. Therefore, it would have been obvious to an artisan of ordinary skill to combine the KOA, a major class of diuretics, with a loop diuretic, for the best expectation of overcoming and reversing diuretic resistance successfully.
Regarding claim 12, in the diuretic combinations Wilcox provides to overcome diuretic resistance, the loop diuretic used in the loop diuretic plus PT diuretic, loop diuretic plus early distal tubule diuretic, loop diuretic plus CD diuretic, loop diuretics plus PT and DT diuretic, and mineral corticosteroid receptor antagonist and aquaretic, furosemide was used. Therefore, it would have been obvious to an artisan of ordinary skill to use furosemide as the loop diuretic for the best expectation of success at reversing diuretic resistance.
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.
Applicant elected without traverse of (1) the type of KOA being a peptide; (2) the KOA is both a peripherally restricted and a centrally acting KOA (3) the diuretic being a loop diuretic in the reply filed on May 6th, 2026. The type of KOA being a small molecule and a peptide and the KOA being peripherally restricted and both peripherally restricted and centrally acting was found in the same prior art as the elected species so they were addressed. Claims 13-14 of Group I are withdrawn as the loop diuretic was found in the art.
Claims 1-4 and 6-12 are rejected under 35 U.S.C. 103 as being unpatentable over Wilson et al. (US20200085961A1) in view of Wilcox et al. (Wilcox, C. S., Testani, J. M., & Pitt, B. (2020). Pathophysiology of Diuretic Resistance and Its Implications for the Management of Chronic Heart Failure. Hypertension (Dallas, Tex. : 1979), 76(4), 1045–1054).
Wilson claims a formulation for the oral delivery of a kappa opioid receptor agonist, the formulation comprising a kappa opioid receptor agonist [Claim 1] Wilson et al. also teaches the method of treating or preventing a kappa opioid receptor-associated disease or condition in a mammal by administering an effective amount of the claimed formulation [0045] and that the kappa opioid receptor-associated disease can be hyponatremia [0112]. Wilson does not teach that hyponatremia is associated with diuretic resistance.
Wilcox prefaces that diuretic resistance implies a failure to increase fluid and sodium (Na+) output sufficiently to relieve volume overload, edema, or congestion, despite escalating doses of a loop diuretic to a ceiling level [Abstract line 1]. Wilcox goes on to teach that one of the pathophysiological mechanisms of diuretic resistance is hyponatremia [Abstract line 8].
Therefore, at the time before the effective filing date of the claimed invention, it would have been obvious to one of ordinary skill in the art to use the kappa opioid receptor agonist taught by Wilson in a method to reverse diuretic resistance where the KOA decreases or does not change urinary excretion of electrolytes because Wilson teaches a method of treating hyponatremia with a KOA formulation and Wilcox teaches that diuretic resistance is characterized by hyponatremia. Since, the failure to increase fluid and sodium output is an innate characteristic of diuretic resistance, there was a reasonable expectation of success prior to the effective filing date that a KOA decrease or not change the urinary excretion of electrolytes in a method to reverse diuretic resistance.
Regarding claim 2, a method of reversing diuretic resistance, found obvious in light of Wilcox, applies to a subject suffering from diuretic resistance, as the subject experiences hyponatremia during diuretic resistance and because Wilson has taught the claimed KOA formulation applies to a method of treating hyponatremia.
Regarding claim 3, Wilson teaches that hyponatremia can be due to intensive diuretic therapy with thiazides and/or loop diuretics and that the synthetic peptide amides of the invention exhibit a significant sodium-sparing and potassium-sparing aquaretic effect, which is beneficial in the treatment of edema-forming pathological conditions associated with hyponatremia and/or hypokalemia [0112]. This makes it obvious to one of ordinary skill that hyponatremia, a mechanism of diuretic resistance, can be due prior diuretic therapy and one would be reasonably successful administering KOA as it is beneficial in the treatment of edema-forming pathological conditions associated with hyponatremia, such as diuretic resistance.
Regarding claim 4, the kappa opioid receptor agonists Wilson goes on to claim are the small molecule peptide CR845 and the organic or synthetic small molecules asimadoline and nalfurafine [claim 2].
Regarding claim 6, Wilcox prefaces that diuretic resistance implies a failure to increase fluid and sodium (Na+) output sufficiently to relieve volume overload, edema, or congestion [Abstract line 1]. Wilson also teaches that the synthetic peptide amides of the invention exhibit a significant sodium-sparing and potassium-sparing aquaretic effect [0122]. Therefore, it would have been obvious to an artisan of ordinary skill that the KOA would spare or decrease the secretion of sodium and potassium
Regarding claim 7, the kappa opioid receptor agonist CR845 Wilson goes on to claim is also referred to in the literature as difelikefalin [0132] and in the same claim, Wilson also claims nalfurafine [claim 2].
Regarding claim 8, Wilson claims instant structures (II) and (IV) [claim 2].
Regarding claim 9, Wilsons formulation for oral delivery of a kappa opioid receptor agonist comprises of the kappa opioid receptor agonist and an absorption enhancer [claim 1]. By the broadest reasonable interpretation, the absorption enhancer is an additional active agent as it actively aids in the absorption of the agonist. Therefore, it would have been obvious to one of ordinary skill in the art to add an active agent, such as an absorption enhancer, to the method of reversing diuretic resistance for the best expectation of being successful.
Regarding claim 10 and 11, Wilcox teaches that “diuretic therapy can upregulate Na+ transport in the proximal tube (PT) that limits Na+ delivery to the LH (loop of Henle) or upregulates Na+ transport in downstream nephron segments that limit natriuresis. These findings provide rationales for combining diuretics with actions on different nephron segments” [pg 5 section Diuretic Combinations]. Wilcox also shows strategies for the use of additional diuretics to counteract loop diuretic resistance in patients with heart failure by combining lop diuretics with major classes of diuretic drugs [Fig 5]. Therefore, it would have been obvious to an artisan of ordinary skill to combine the KOA, a major class of diuretics, with a loop diuretic, for the best expectation of overcoming and reversing diuretic resistance successfully.
Regarding claim 12, in the diuretic combinations Wilcox provides to overcome diuretic resistance, the loop diuretic used in the loop diuretic plus PT diuretic, loop diuretic plus early distal tubule diuretic, loop diuretic plus CD diuretic, loop diuretics plus PT and DT diuretic, and mineral corticosteroid receptor antagonist and aquaretic, furosemide was used. Therefore, it would have been obvious to an artisan of ordinary skill to use furosemide as the loop diuretic for the best expectation of success at reversing diuretic resistance.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Wilson et al. (US20200085961A1) in view of Wilcox et al., as applied to claims 1-4 and 6-12 above, and further in view of Beck et al. (Beck, T. C., & Dix, T. A. (2019). Targeting peripheral κ-opioid receptors for the non-addictive treatment of pain. Future Drug Discovery, 1(2)).
Wilson et al. teaches using the small molecule peptide CR845 and the organic or synthetic small molecules asimadoline and nalfurafine as KOAs in a formulation [claim 2] used in a method of treating or preventing a kappa opioid receptor-associated disease [0045], where the kappa opioid receptor-associated disease can be hyponatremia [0112]. Wilcox teaches that hyponatremia is a mechanism of diuretic resistance. Both Wilson et al. and Wilcox et al. do not disclose whether the KOAs are peripherally-restricted, centrally-acting or both.
Beck et al. teaches that because KOAs also act on centrally located kappa opioid receptors, they promote untoward side effects, such as dysphoria, hallucinations, sedation and psychosis. This has motivated the development of pathway-biased KOAs or KOAs with limited CNS-penetration [pg 2 pgh 2 line 3]. One example, is CR665, which the applicant claims [instant claims 7 and 8] that demonstrates peripheral-selectivity of >500-fold, [pg 2 pgh 2 line 6]. Wilson’s and applicant’s claimed CR845 (difelikefalin) is also peripherally restricted [pg 2 pgh 2 line 10]. Beck et al. also found that claimed JT09 has a peripheral selectivity of >938-fold [pg 3 Table 1]. Therefore, it would have been obvious to one of ordinary skill in the art to use a KOA that is peripherally-restricted or both peripherally-restricted and centrally-acting, such as CR665, difelikefalin, and JT09, with a high peripheral selectivity, in a method to reverse diuretic resistance, so that the method of treatment is nonaddictive.
Summary
Claims 1-12 are provisionally rejected on the ground of nonstatutory double patenting. Claims 1-12 are rejected under 35 U.S.C. 103.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SACHI JAUHARI whose telephone number is (571)272-3769. The examiner can normally be reached Mon-Fri 9-4.
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/SACHI JAUHARI/Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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