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 .
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.
This office action is a response to applicant’s communication submitted December 20, 2023. This application claims benefit of provisional application 63/262,693 filed December 20, 2022.
Claims 1-21 are pending in this application.
Claim Interpretation
Claims 1 recites the phrases “a Na+/K+-ATPase inhibitor” and a “SGLT/ a Na+/K+-ATPase dual inhibitor”. The phrase “a Na+/K+-ATPase inhibitor” includes compounds that are SGLT/ a Na+/K+-ATPase dual inhibitors.
Regarding the phrase “analogs thereof”. The Examiner notes that the phrase is not particularly limiting based on the definition of the instant specification. On pages 6-7, applicants describe “the term "analog" refers to compounds having similar physical, chemical, biochemical, or pharmacological properties, which include structural analogs and/or functional analogs” (para. 0029). Moreover, the specification states that “The term "structural analog" or "chemical analog" refers to a compound having a structure similar to that of another compound, but differing with respect to one or more structural moieties” (pages 6-7, para. 0029) and “The term "functional analog" may include compounds that are not necessarily structural analogs with a similar chemical structure” (pages 6-7, para. 0029). Thus, wherein the compound has the same mechanism of action, it is considered to be an analog (i.e. an SGLT inhibitor).
Specification
The disclosure is objected to because of the following informalities:
The use of the term Trikafta®, Symdeko®, Kalydeco®, and Orkambi®, which is a trade name or a mark used in commerce, has been noted in this application (See USPTO trademark registry). The terms Symdeko®, Kalydeco®, and Orkambi® 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 (See instant specification pg. 18, para. 0081).
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.
Appropriate correction is required.
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 1-15, 18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1-15 and 18: Claims 1, 15, and 18 recite the phrase “subeffective”. The phrase renders the claim indefinite because it is contradictory. For example, if the amount is in a lower dose than normal, and is effective, wouldn’t it necessarily be an effective amount? According to the instant specification the phrase “subeffective amount” is defined as less than the effective concentration of each agent when administered alone, thereby allowing a reduction in the dose of one or more of the agents relative to the dose that would be needed if the agent was administered as a single agent (pg. 5, para. 0026). However, in the subsequent paragraph, the instant specification describes a subeffective amount being relative to the dose of the co-administered agent (pg. 5, para. 0024). It is unclear whether the subeffective amount is related to the activity of the compound alone, or is related to the dose of the co-administered agent. The term “subeffective” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Thus a person of ordinary skill in the art would be unable to ascertain the metes and bounds of the invention, thereby rendering claims 1, 15, and 18 indefinite. Claims 2-15 which depend from claim 1 are similarly rejected.
Claim Rejections - 35 USC § 112 (d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 6, 9, 10, 12, 14, 18, 19-20 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Regarding claims 6, 9, 10, 12, 19-20: Claim 6 which depends from claim 5 recites inter alia “wherein the SGLT/Na+/K+-ATPase dual inhibitor is selected from the group consisting of phlorizin….and analogs thereof.”. Claim 9 which depends from claim 8 recites inter alia, “wherein the SGLT1-selective inhibitor is selected from the group consisting of KGA-2727….and analogs thereof.”. Claim 10 which depends from claim 9 (also 8) recites inter alia, “wherein the SGLT1-selective inhibitor is mizagliflozin or analogs thereof.”. Claim 12 which depends from claim 11 recites inter alia, “wherein the non-selective SGLT inhibitor is phloretin or analogs thereof.” Claim 19 which depends from claim 17 recites inter alia, “wherein the SGLT/Na+/K+-ATPase dual inhibitor is selected from the group consisting of phlorizin….and analogs thereof.” Claim 20 which depends from claim 17 recites inter alia, “wherein the Na+/K+-ATPase dual inhibitor is selected from the group consisting of pyruvic acid….and analogs thereof.”
However, claims 5, 8, 11, and 17 are already drawn to SGLT/Na+/K+-ATPase dual inhibitor, SGLT1-selective inhibitor, non-selective SGLT inhibitor, and a SGLT/Na+/K+-ATPase dual inhibitor and Na+/K+-ATPase dual inhibitor respectively. As discussed above in the claim interpretation section above, the phrase “analogs” is not limiting and encompasses any chemical structure that possesses the respective inhibition property (i.e. SGLT1-selective inhibitor). Thus, claims 6, 9, 10, 12, 14, 18, 19-20 which recite the phrase “and analogs thereof” do not limit the claims drawn to the inhibitors generally, as all inhibitors possessing that property are encompassed by the phrase “analogs”.
Regarding claim 14: Claim 14 which depends from claim 11 recites inter alia, “….wherein the Na+/K+-ATPase inhibitor is selected from….pyruvic acid”. However, claim 11 already limits the inhibitor to a non-selective SGLT inhibitor. According to the specification, the inhibitors recited are not non-selective SGLT inhibitors (pg. 12, para. 0053). Thus claim 14 expands, rather than limits instant claim 11. The claim will be interpreted as if dependent from claim 13. The Examiner notes that if claim 14 were dependent on claim 13, the claim would have been rejected under 112(d) for the phrase “analogs thereof” as discussed above for failing to limit claim 13 which limits to a Na+/K+-ATPase inhibitor
Regarding claim 18: Claim 18 which depends from claim 17and recites, “wherein the effective amount of the Na+/K+-ATPase inhibitor is a subeffective amount”. However, claim 17 already recites an effective amount of Na+/K+-ATPase inhibitor. Changing from an effective amount to a subeffective amount contradicts the earlier claim and expands, rather than limits claim 17.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-2, 4-7, 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over Hirai (Molecular Therapy: Methods & Clinical Development, 2022, available online November 24, 2021, IDS filed January 15, 2025) in view of Xu (WO 2022/187658, cited on PTO-892).
Regarding claims 1-2, 4-7, 11, 13, and 15: Hirai teaches cystic fibrosis (CF) is a lethal autosomal-recessive inherited disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (abstract). Hirai teaches a study examining the effects of sodium-dependent glucose cotransporter 1/2 (SGLT1/2) inhibitor drugs phlorizin (PHL) and sotagliflozin (Sota) on the basis of our findings that SGLT1 expression is upregulated in CF HLOs and airway epithelial cells compared with their wild-type counterparts (abstract). According to the instant specification phlorizin is a SGLT1/Na+/K+-ATPASE dual inhibitor and is a non-selective SGLT inhibitor (pg. 7, para. 0031). Hirai also evaluated the forskolin (Fsk)-stimulated swellings of these HLOs in the presence of CFTR modulators (VX-770 and/or VX-809) and demonstrated that HLOs respond to CFTR modulators in a mutation-dependent manner (abstract). Hirai studied homozygous CFTR delF508 (dF/dF) mutation and heterozygous compound mutations of delF508 and G551D (dF/G551D) (pg. 12, col. 1, para. 2). According to the instant specification dF508 is a class II mutation (pg. 22, para. 00105). Hirai teaches PHL and Sota demonstrate GLTs as a potential new strategy to attenuate CF lung disease (pg. 14, col. 2, last para.). Hirai suggests SGLT1 inhibition may bring benefits beyond the lungs, because it is expressed in multiple other CF-affected organ systems (pg. 15, col. 1, para. 1). Hirai teaches the promoting effects by SGLT1/2 inhibition are comparable with that achieved by combinational treatment with VX-770 (ivacaftor) and VX-809 (lumacaftor) which was approved for treating dF/dF patients (i.e. CF with class II mutations, pg. 15, col. 1, para. 1). Because the promoting effect appears to be CFTR independent, SGLT1 inhibitor drugs such as Sota may serve as a candidate “bridge” drug to treat CF patients (e.g., those of class I mutations, col. 1, para. 1).
Although Hirai does not explicitly teach treating CF patients characterized by a class II mutation (dF/dF) with phlorizin or sotagliflozin and a combination of elexacaftor, tezacaftor, and ivacaftor, Hirai suggests although it is unlikely that Sota or PHL will exceed TRIKAFTA in benefiting dF/dF, it is reasonable to speculate that a combinational use of Sota and TRIKAFTA might bring synergistic effects (pg. 15, col. 1, para. 1). According to the instant specification TRIKAFTA is a combination of elexacaftor, tezacaftor, and ivacaftor (pg. 18, para. 0082).
Taken together, it would have been prima facie obvious to treat cystic fibrosis patients with dF/dF (i.e. class II) mutations with a combination of phlorizin or sotagliflozin and a combination of elexacaftor, tezacaftor, and ivacaftor (i.e. TRIKAFTA) as suggested by Hirai. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as Hirai demonstrates SGLT inhibitors, such as phlorizin or sotagliflozin, have therapeutic potential in alleviating cystic fibrosis via an alternate pathway to TRIKAFTA (i.e. independent of CFTR) and the combination of targeting alternate pathways may have a synergetic effect in order to more effectively treat the disease. Wherein phlorizin and sotagliflozin are SGLT inhibitors with therapeutic potential against cystic fibrosis, it is prima facie obvious to substitute equivalents known for the same purpose (See MPEP 2144.06 (II)).
Hirai does not teach wherein a subeffective amount of elexacaftor, tezacaftor, and ivacaftor is used.
However, Xu teaches TRIKAFTA, despite its remarkable benefits on the lung functions, increase the levels of key liver function enzymes ALT, AST and others. In fact, adverse effects on liver functions are major side effect concerns of this drug (pg. 2, lines 8-10).
Taken together, it would have been prima facie obvious to modify the method of Hirai such that a subeffective amount of elexacaftor, tezacaftor, and ivacaftor (i.e. TRIKAFTA) is utilized as suggested by Xu. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success given the synergistic relationship between SGLT inhibitors and TRIKAFTA in order to effectively treat cystic fibrosis while decreasing adverse effects on liver function.
Regarding claims 12 and 14: As discussed above in the claim interpretation section above, wherein a compound has the same mechanism of action, it is considered to be an analog (i.e. an SGLT inhibitor). Thus, wherein phlorizin is a SGLT1/Na+/K+-ATPASE dual inhibitor and is a non-selective SGLT inhibitor, it is considered to be a functional analog of phloretin as recited by instant claim 12, as well as the compounds recited by instant claim 14.
Claims 12 are rejected under 35 U.S.C. 103 as being unpatentable over Hirai (Molecular Therapy: Methods & Clinical Development, 2022, available online November 24, 2021, IDS filed January 15, 2025) and Xu (WO 2022/187658, cited on PTO-892) as applied to claims 1-2, 4-7, 11-15 in view of Nakhate (Nutrients, 2022, published September 2, 2022, cited on PTO-892).
Regarding claim 12: Even if assuming for the sake of argument the phrase “analogs thereof” was interpreted in such a way as to exclude phlorizin, claim 12 would still have been rendered obvious in view of Nakhate. As discussed above, the prior art render obvious the method of claim 7 wherein the non-selective SGLT inhibitor is phlorizin.
The prior art does not teach wherein the non-selective SGLT inhibitor is phloretin.
However, Nakhate teaches phloretin and phlorizin are both a SGLT1 inhibitor (pg. 8, para. 3). because of its better bioavailability and lower toxicity, phlorizin—a phloretin glycoside—is frequently utilized as a substitute for phloretin in numerous commercial products (pg. 2, para. 2). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments (See MPEP 2123 (II)).
Taken together, it would have been prima facie obvious to modify the method such that phlorizin is replaced with phloretin as taught by Nakhate. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as phloretin and phlorizin are known substitutes capable of inhibiting SGLT and it is prima facie obvious to substitute equivalents known for the same purpose (See MPEP 2144.06 (II)).
Claims 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Hirai (Molecular Therapy: Methods & Clinical Development, 2022, available online November 24, 2021, IDS filed January 15, 2025) and Xu (WO 2022/187658, cited on PTO-892) as applied to claims 1-2, 4-7, 11-15 in view of Dominguez Rieg (Diabetes Obes. Metab., 2019, IDS filed January 15, 2025).
As discussed above, the prior art render obvious the method of claim 7.
They do not explicitly teach administration of a SGLT1-selective inhibitor, such as mizagliflozin.
However, Dominguez Rieg teaches mizagliflozin and LX2761 are selective SGLT1 inhibitors (pg. 5, para. 4). Lack of SGLT1 inhibition leads to glucose galactose malabsorption and consequential osmotic diarrhea, dehydration, and metabolic acidosis (pg. 8, para. 2). The selective SGLT1 inhibitor mizagliflozin and the dual SGLT1/2 inhibitor sotagliflozin can be taken orally at doses that measurably inhibit intestinal glucose uptake but do not cause severe gastrointestinal side effects (pg. 8, para. 2). SGLT1 inhibition offers the possibility to enhance the effects of SGLT2 inhibitors (pg. 8).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art to modify the composition to include a selective SGLT1 inhibitor, such as mizagliflozin, as taught by Dominguez Rieg. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success in order prevent severe gastrointestinal side effects that occur in the presence of a dual SGLT1/2 inhibitor, such as phlorizin or sotagliflozin.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Hirai (Molecular Therapy: Methods & Clinical Development, 2022, available online November 24, 2021, IDS filed January 15, 2025) and Xu (WO 2022/187658, cited on PTO-892) as applied to claims 1-2, 4-7, 11-15 above in view of Dessen (WO 2016/151051, cited on PTO-892).
Regarding claim 14: Even if assuming for the sake of argument the phrase “analogs thereof” was interpreted in such a way as to exclude phlorizin, claim 14 would still have been rendered obvious in view of Dessen.
As discussed above, the prior art render obvious the method of claim 13.
They do not a teach a method wherein the Na+/K+-ATPase inhibitor is chlorpropamide.
However, Dessen teaches that in patients with cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, lung complications are typically managed through antibiotic, antifungal, anti-inflammatory and bronchodilator treatment regimes, the nutrient malabsorption caused by pancreatic complications can be treated with digestive enzyme supplements and cystic fibrosis-related diabetes may be treated by a combination of oral antidiabetic drugs (e.g. the sulfonylureas, biguanides and thiazolidinediones) and insulin (pg. 6, lines 4-9). Chlorpropamide is listed as a suitable antidiabetic drug (pg. 66, lines 21-22).
Taken together, it would have been prima facie obvious to further modify the composition by including Na+/K+-ATPase inhibitor chlorpropamide as taught by Dessen. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success in order to manage cystic fibrosis-related diabetes in a subject.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Hirai (Molecular Therapy: Methods & Clinical Development, 2022, available online November 24, 2021, IDS filed January 15, 2025) and Xu (WO 2022/187658, cited on PTO-892) as applied to claims 1-2, 4-7, 11-15 above in view of Chen (WO 2021/046325, cited on PTO-892) and Yeh (J. Physiol, 2020, cited on PTO-892).
Regarding claim 3: As discussed above, the prior art render obvious a method of treating class II cystic fibrosis.
They do not teach treatment of CF characterized by a class I mutation, such as W1282X.
However, Chen teaches a method of treating symptoms related to cystic fibrosis (CF), comprising administering to a subject a composition comprising one or more pharmaceutical agents which function as inhibitors of SGLT activity (abstract). Phlorizin is listed as pharmaceutical agents capable of inhibiting SGLT activity (pg. 9, lines 5-6, claim 3). Chen teaches SGLT1 expression is upregulated in bronchial epithelial cells and proximal lung organoids in humans with cystic fibrosis (substitute sheet 12, figure 13). Chen teaches the method is not limited to treating a particular form or mutation related to CF (pg. 6, line 19). Mutations in the CFTR gene lead to abnormal water and electrolyte transport through apical cell membranes in the lungs (pg. 1, lines 22-24). In some embodiments, the mutation is any mutation related to a class IB CTFR mutation, such as Gly542X (G542X) and Trp1282X (W1282X) mutations (pg. 4, lines 21-22). Chen teaches class I mutations of the CFTR gene lead to complete absence of CFTR protein synthesis (pg. 1, lines 25-26). In some embodiments, the mutation is a mutation related to a class 2 CTFR mutation, such as Phe508del (i.e. F508del, pg. 4, lines 22-23) Chen teaches class II mutations of the CFTR gene result in arrested maturation and intracellular localization defect (pg. 1, lines 26-27). Additionally, Yeh teaches that CFTR mutations yielding functional C-terminus truncated protein (such as W1282X) may be treated with the application of potentiators (VX770) and correctors (VX-809 and VX661) in order to enhance the function and expression of the protein (pg. 537, col. 1, para. 3).
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to modify the method by treating cystic fibrosis patients with a W1282X mutation as taught by Chen and Yeh. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as combination therapies for the treatment of cystic fibrosis is a known technique in the art, and the art recognizes the therapeutic potential of utilizing a CFTR potentiator or modulator to enhance function and expression of CFTR bearing W1282X (class I) mutations.
Claim 17-21 are rejected under 35 U.S.C. 103 as being unpatentable over Hirai (Molecular Therapy: Methods & Clinical Development, 2022, available online November 24, 2021, IDS filed January 15, 2025), Xu (WO 2022/187658, cited on PTO-892), Chen (WO 2021/046325, cited on PTO-892) and Yeh (J. Physiol, 2020, cited on PTO-892) as applied to claims 1-7, 11-15 above in view of Dessen (WO 2016/151051, cited on PTO-892).
Regarding claims 17-21: As discussed above, the prior art render obvious a method of treating class I cystic fibrosis with a W1282X mutation.
They do not a teach a method wherein the method includes a subeffective amount of an Na+/K+-ATPase inhibitor, such as chlorpropamide.
However, Dessen teaches that in patients with cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, lung complications are typically managed through antibiotic, antifungal, anti-inflammatory and bronchodilator treatment regimes, the nutrient malabsorption caused by pancreatic complications can be treated with digestive enzyme supplements and cystic fibrosis-related diabetes may be treated by a combination of oral antidiabetic drugs (e.g. the sulfonylureas, biguanides and thiazolidinediones) and insulin (pg. 6, lines 4-9). Chlorpropamide is listed as a suitable antidiabetic drug (pg. 66, lines 21-22).
Taken together, it would have been prima facie obvious to further modify the composition by including Na+/K+-ATPase inhibitor chlorpropamide as taught by Dessen. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success in order to manage cystic fibrosis-related diabetes in a subject. Although the prior art does not explicitly state using a subeffective amount of chlorpropamide, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation (See MPEP 2144.05 (II)).
Claim 16 is rejected under 35 U.S.C. 103 as being unpatentable over Hirai (Molecular Therapy: Methods & Clinical Development, 2022, available online November 24, 2021, IDS filed January 15, 2025), Xu (WO 2022/187658, cited on PTO-892), Chen (WO 2021/046325, cited on PTO-892), Yeh (J. Physiol, 2020, cited on PTO-892), and Dessen (WO 2016/151051, cited on PTO-892) as applied to claims 1-7, 11, 13-15, and 17-21 above in view of Emphycorp (NCT00308243, ClinicalTrials.gov, 2011, cited on PTO-892).
Regarding claim 16: As discussed above, the prior art render obvious the methods of claims 1-7, 11, 13-15, and 17-21. Dessen teaches that in patients with cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction, lung complications are typically managed through antibiotic, antifungal, anti-inflammatory and bronchodilator treatment regimes.
They do not teach treatment comprising administering pyruvic acid or an analog thereof.
However, Emphycorp teaches the administration of sodium pyruvate in 0.9% sodium chloride to patients with CF (i.e. analog of pyruvic acid, pg. 1, para. 1). Emphycorp teaches sodium pyruvate will reduce lung damage in patients with Cystic Fibrosis (CF) by its ability to reduce levels of toxic reactive oxygen and nitrogen compounds associated with the chronic inflammatory component of the disease (pg. 1, para. 1). Emphycorp teaches The CFTR gene mutation results in altered cell transport properties, which affect both chloride and glutathione secretion (pg. 2, para. 1). Chronic inflammation, associated with activated neutrophils and macrophages, is a common feature of CF. Highly reactive toxic oxygen (superoxide anion, free hydroxyl radical, hydrogen peroxide) and nitrogen species (nitric oxide, peroxynitrites) are abundant in the chronic inflammatory response in CF and appear to play a prominent role in the pathogenesis of this disease (pg. 2, para. 1). Sodium pyruvate has been shown to act as an anti-inflammatory agent that can reduce the number of infiltrating neutrophils and levels of oxygen radicals at wound sites, thereby limiting the production of pro-inflammatory mediators (pg. 2, para. 2).
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to modify the method by administering sodium pyruvate for the treatment of cystic fibrosis characterized by a class I mutation as taught by Emphycorp. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as combination therapies for the treatment of cystic fibrosis is a known technique in the art, for the purpose of treating the inflammatory components of the disease.
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, 5-15, 17-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/047,504 (US 20230181610, IDS, filed January 15, 2025) in view of Chen (WO 2021/046325, cited on PTO-892) and Yeh (J. Physiol, 2020, cited on PTO-892).
Regarding claims 1-3, 5-15, and 17-21: The copending claims teach a method for treating cystic fibrosis (CF) characterized by a class I nonsense mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition comprising an effective amount of an inhibitor selected from the group consisting of a sodium glucose co-transporter 1 (SGLTI)-selective inhibitor, a Na⁺/K - ATPase inhibitor, an SGLTI/Na/K-ATPase dual inhibitor, and combinations thereof, wherein the subject has two class I nonsense mutation CFTR alleles (copending claim 1). The copending claims teach wherein the SGLT1/Na+/K+-ATPase dual inhibitor is phlorizin (copending claim 3). As discussed above in the claim interpretation section above, wherein a compound has the same mechanism of action, it is considered to be an analog (i.e. an SGLT inhibitor). Thus, wherein phlorizin is a SGLT1/Na+/K+-ATPASE dual inhibitor and is a non-selective SGLT inhibitor, it is considered to be a functional analog of phloretin as recited by instant claim 12. The copending claims teach wherein the SGLT1-selective inhibitor is mizagliflozin (copending claim 7). The copending claims teach wherein the Na+/K+-ATPase inhibitor is ouabain or chlorpropamide (copending claim 10). The copending claims teach wherein the class I nonsense mutation is a G542X mutation (claim 19). The copending claims teach wherein the class I nonsense mutation is a W1282X mutation (copending claim 20). The copending claims teach further comprising administering an effective amount of a CFTR modulator, CFTR amplifier, and combinations thereof (copending claim 12). According to the copending specification, a CFTR modulator are potentiators and correctors (pg. 19, para. 0077).
The copending claims do not teach a subeffective amount of elexacaftor, tezacaftor, and ivacaftor.
However, Yeh teaches that CFTR mutations yielding functional C-terminus truncated protein (such as W1282X) may be treated with the application of potentiators (VX770) and correctors (VX-809 and VX661) in order to enhance the function and expression of the protein (pg. 537, col. 1, para. 3). Yeh discloses VX-809 is Lumacaftor, VX-661 is Tezacaftor, and VX-770 is Ivacaftor (pg. 519, col. 1, para. 1).
Taken together it would have been prima facie obvious to a person of ordinary skill in the art to modify the method of the copending claims such that elexacaftor, tezacaftor, and ivacaftor are administered. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as they are known CFTR potentiators and correctors (i.e. Modulators) that are known in the art to be beneficial in the treatment of Class I mutations. Although the prior art does not explicitly state using a subeffective amount of chlorpropamide, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation (See MPEP 2144.05 (II)).
Claim 4 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/047,504 (US 20230181610, IDS, filed January 15, 2025) and Yeh (J. Physiol, 2020, cited on PTO-892) as applied to claims 1-3, 5-15, 17-21 above in view of Chen (WO 2021/046325, cited on PTO-892).
Regarding claim 4: The copending claims teach the method of claim 1.
They do not teach treating CF characterized by a class II mutation.
However, Chen teaches a method of treating symptoms related to cystic fibrosis (CF), comprising administering to a subject a composition comprising one or more pharmaceutical agents which function as inhibitors of SGLT activity (abstract). Phlorizin is listed as pharmaceutical agents capable of inhibiting SGLT activity (pg. 9, lines 5-6, claim 3). Chen teaches SGLT1 expression is upregulated in bronchial epithelial cells and proximal lung organoids in humans with cystic fibrosis (substitute sheet 12, figure 13). Chen teaches the method is not limited to treating a particular form or mutation related to CF (pg. 6, line 19). Mutations in the CFTR gene lead to abnormal water and electrolyte transport through apical cell membranes in the lungs (pg. 1, lines 22-24). In some embodiments, the mutation is any mutation related to a class IB CTFR mutation, such as Gly542X (G542X) and Trp1282X (W1282X) mutations (pg. 4, lines 21-22). Chen teaches class I mutations of the CFTR gene lead to complete absence of CFTR protein synthesis (pg. 1, lines 25-26). In some embodiments, the mutation is a mutation related to a class 2 CTFR mutation, such as Phe508del (i.e. F508del, pg. 4, lines 22-23) Chen teaches class II mutations of the CFTR gene result in arrested maturation and intracellular localization defect (pg. 1, lines 26-27).
Taken together it would have been prima facie obvious to apply the method of the copending claims to the treatment of Class II mutations as suggested by Chen. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as phlorizin is known in the art to be able to treat class II CF mutations.
Claim 12 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/047,504 (US 20230181610, IDS, filed January 15, 2025) and Yeh (J. Physiol, 2020, cited on PTO-892) as applied to claims 1-3, 5-15, 17-21 above in view of Nakhate (Nutrients, 2022, published September 2, 2022, cited on PTO-892).
Regarding claim 12: Even if assuming for the sake of argument the phrase “analogs thereof” was interpreted in such a way as to exclude phlorizin, claim 12 would still have been rendered obvious in view of Nakhate. As discussed above, the prior art render obvious the method of claim 7 wherein the non-selective SGLT inhibitor is phlorizin.
The prior art does not teach wherein the non-selective SGLT inhibitor is phloretin.
However, Nakhate teaches phloretin and phlorizin are both a SGLT1 inhibitor (pg. 8, para. 3). because of its better bioavailability and lower toxicity, phlorizin—a phloretin glycoside—is frequently utilized as a substitute for phloretin in numerous commercial products (pg. 2, para. 2). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments (See MPEP 2123 (II)).
Taken together, it would have been prima facie obvious to modify the method such that phlorizin is replaced with phloretin as taught by Nakhate. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as phloretin and phlorizin are known substitutes capable of inhibiting SGLT and it is prima facie obvious to substitute equivalents known for the same purpose (See MPEP 2144.06 (II)).
Claim 16 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/047,504 (US 20230181610, IDS, filed January 15, 2025) and Yeh (J. Physiol, 2020, cited on PTO-892) as applied to claims 1-3, 5-15, 17-21 above in view of Emphycorp (NCT00308243, ClinicalTrials.gov, 2011, cited on PTO-892).
Regarding claim 16: Regarding claim 16: As discussed above, the prior art render obvious the methods of claims 1-3, 5-15, and 17-21.
They do not teach treatment comprising administering pyruvic acid or an analog thereof.
However, Emphycorp teaches the administration of sodium pyruvate in 0.9% sodium chloride to patients with CF (i.e. analog of pyruvic acid, pg. 1, para. 1). Emphycorp teaches sodium pyruvate will reduce lung damage in patients with Cystic Fibrosis (CF) by its ability to reduce levels of toxic reactive oxygen and nitrogen compounds associated with the chronic inflammatory component of the disease (pg. 1, para. 1). Emphycorp teaches The CFTR gene mutation results in altered cell transport properties, which affect both chloride and glutathione secretion (pg. 2, para. 1). Chronic inflammation, associated with activated neutrophils and macrophages, is a common feature of CF. Highly reactive toxic oxygen (superoxide anion, free hydroxyl radical, hydrogen peroxide) and nitrogen species (nitric oxide, peroxynitrites) are abundant in the chronic inflammatory response in CF and appear to play a prominent role in the pathogenesis of this disease (pg. 2, para. 1). Sodium pyruvate has been shown to act as an anti-inflammatory agent that can reduce the number of infiltrating neutrophils and levels of oxygen radicals at wound sites, thereby limiting the production of pro-inflammatory mediators (pg. 2, para. 2).
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to modify the method by administering sodium pyruvate for the treatment of cystic fibrosis characterized by a class I mutation as taught by Emphycorp. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as combination therapies for the treatment of cystic fibrosis is a known technique in the art, for the purpose of treating the inflammatory components of the disease.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims area allowed in this action.
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/SAMUEL L GALSTER/Examiner, Art Unit 1693
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