Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Election/Restriction
Acknowledgement is made of Applicant’s election without traverse in the reply filed on 01/31/2025: 1) Group III, claims 273-286, drawn to a method of improving mitochondrial function ; 2) bardoxolone methyl (CDDO-Me; RTA 402) (page 58, line 25 of instant application) having following structure, as Nrf2 activator species and 3) mitochondrial dysfunction.
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It’s noted Applicant amended the preamble of method claims in Group III to “a method of improving mitochondrial function” and elects mitochondrial dysfunction without specifying SINGLE disclosed disease/disorder species as set forth in the Restriction requirement mailed on 10/31/2023. The term “mitochondrial dysfunction” is an umbrella term and there are vast variety of disease/disorder involving mitochondrial dysfunction through different pathways, e.g. neurological disease, cancer, cardiovascular disease, kidney disease, liver disease, metabolic disease, etc. Applicant is required to further elect one SINGLE disclosed disease/disorder species associated with mitochondrial dysfunction.
Claims 1, 3-5, 8, 10, 14, 16, 17, 19-22, 41 and 232 (Group I) and claim 173 (Group II) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim.
Claims 273-286 and new claims 287-292 are considered as read on the elected Nrf2 activator species bardoxolone methyl (CDDO-Me; RTA 402). It’s noted independent claim 273 does not recite compound of Formula II as the Nrf2 activator wherein Nrf2 activators are not necessarily a compound of Formula II. The Non-elected species of compound of Formula II and other Nrf2 activators are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected species.
Status of Claims
Claims 1, 3-5, 8, 10, 14, 16-17, 19-22, 41, 173, 232, 273- 276 and 278-292 are pending in the instant application.
Claims 1, 3-5, 8, 10, 14, 16-17, 19-22, 41, 173 and 232 are withdrawn as marked by the Applicant.
Claims 273- 276 and 278-292 are currently under examination.
Priority
This instant application 18/332,603 filed 06/09/2023 is a continuation of United States Application No.16/157,225 (now abandoned), filed October 11, 2018, which is a continuation of United States Application No. 14/466,495 (now abandoned), filed August 22, 2014, which claims the priority benefit of United States Provisional Application No. 61/869,527, filed August 23, 2013.
Information Disclosure Statement
The information disclosure statement filed 10/31/2023 is in compliance with the provisions of 37 CFR 1.97. It’s noted many references are submitted in parent US application No. 14/466,495 (now abandoned), filed August 22, 2014. The relevant reference listed in IDS are being considered by the Examiner . Reference written in foreign language is considered to the degree of English abstract or patent family of foreign patent by Examiner.
Claim Objections
Claim 286 are objected to because there are two “claim 286” in the claim set.
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Claims 280 and 282-285 are objected to because it’s not clear the time period when the patient's BNP or eGFR with recited value is measured, before or after being administered an Nrf2 activator.
Claim Rejections - 35 USC § 112
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 273- 276 and 278-292 are rejected under 35 U.S.C. 112(a), because the specification, while might be enabling for treating certain disease/disorder/conditions associated with endothelial dysfunction (e.g. diabetes, pulmonary arterial hypertension, etc.) with certain Nrf2 activator (e.g. bardoxolone methyl and its analog RTA dh404) in certain subject, does not reasonably provide enablement for any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims without undue experimentation. This is a scope of enablement rejection.
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). The determination that "undue experimentation" would have been needed to practice the claimed invention in full scope is not a single, simple factual determination.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. Keeping that in mind, the Wands factors are relevant to the instant application for the following reasons:
The Breadth of The Claims/ Nature of The Invention
Independent claim 273 and its dependent claims are amended to a method of improving mitochondrial function in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of an Nrf2 activator, wherein the patient has been identified as NOT having at least one of the following characteristics:(a) a history of left-sided myocardial disease;(b) an elevated B-type natriuretic peptide (BNP) level;(c) an elevated albumin/creatinine ratio (ACR); and(d) chronic kidney disease (CKD).
Instant claim 273- 285 do not recite any specific Nrf2 activator. Instant claim 286 and its dependent claims recite compound of Formula II genus, comprising vast varieties of moieties/ subgroups that have different chemical moieties and physical property, different pharmacological/biological activities, different toxicity profile, etc. Instant claim 273 and its dependent claims do not recite any disease or disorder or condition wherein the subject is in need of “improving mitochondrial function”. There are vast variety of disease/disorder involving mitochondrial dysfunction through different pathways, e.g. neurological disease, cancer, cardiovascular disease, kidney disease, liver disease, metabolic disease, etc.. As such, the scope of instant claims are extremely broad.
The State of the Prior Art and the Predictability or Lack Thereof in the Art
Independent claim 273 and its dependent claims only recite negative limitation of subject wherein the subject has been identified as NOT having at least one of the following characteristics:(a) a history of left-sided myocardial disease;(b) an elevated B-type natriuretic peptide (BNP) level;(c) an elevated albumin/creatinine ratio (ACR); and(d) chronic kidney disease (CKD). However, mitochondrial dysfunctions are identified in many common pathologies, e.g. neurodegeneration, cancer, cardiovascular diseases, metabolic syndrome, etc. The etiology, symptoms of mitochondrial dysfunction vary in different disease/ disorders and there are many factors contributed to the treatment outcome of disease/ disorders in different subjects. For example, Lin (2006) reviews mitochondrial dysfunction and oxidative stress in neurodegenerative disease. Lin disclosed many genetic biomarkers/pathway in neurodegenerative disease are associated with mitochondrial dysfunction (See Table 1-2, Figure 2), however knowledge of mitochondrial biology in different cell types is rudimentary because of cell selectivity and the complexity of mitochondrial ROS metabolism suggests that interventions by administration of one or a few antioxidants may be too simplistic (See page 794, left column).
Regarding the uncertainty of bardoxolone methyl (CDDO-Me) on mitochondrial function, Samudio (2006, Document C282 of Applicant’s IDS dated 10/31/2023 ) and its incorporated reference teach CDDO-Me display both antitumorigenic and anti-inflammatory activities, however, the precise anti-inflammatory and antitumorigenic mechanisms of action of CDDO and CDDO-Me remain elusive (See abstract, page 1183, left column). Samudio further teaches CDDO-Me is mitochondriotoxic that induces apoptosis and inhibits mitochondrial electron transport via perturbations in inner mitochondrial membrane integrity (See abstract, page 1183, right column; Discussion).
Further, activity by in-vitro experiment does not necessarily translate into efficacy in animals and/or humans. The in-vitro efficacy at certain dosage amount might lead to toxicologic effect in in-vivo and human study. As disclosed by instant specification (See instant publication US 2024/0115542 A1 [0059], [0066]-[0073]), BEACON study (Bardoxolone Methyl in patients with stage 4 chronic kidney disease (CKD) and type 2 diabetes ) was terminated in 2012 due to adverse events of heart failure, etc. associated with inhibition of endothelin-1 signaling in epithelial cells.
More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity (e.g., cancer prevention) is generally considered an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The Amount of Direction Present and Presence or Absence of Working Examples
The specification does not provide sufficient guidance for a skilled artisan to practice the claimed method of improving mitochondrial function that involves different pathways in vast variety of disease/disorders in its full scope.
Instant specification disclosed bardoxolone methyl improved markers of renal function, but Phase 3 clinical trial of BEACON of bardoxolone methyl in patients with stage 4 CKD and type 2 diabetes was terminated due to adverse events and mortality involved heart failure (See [0072]-[0073]). Based on analysis of BEACON study, instant specification further disclosed clinical design for method of treating pulmonary arterial hypertension, PAH with bardoxolone methyl wherein endothelial dysfunction is considered as contributing factor (See [0074]-[0145], Example 3). Instant specification disclosed activity of RTA 404 on animal model of PAH (See Example 2), but no other compounds of Formula II including the elected bardoxolone methyl was evaluated for treating pulmonary arterial hypertension patients with instantly recited negative limitation, e.g. NOT having the characteristics of myocardial disease, elevated BNP, etc. No efficacy data and/or safety data were disclosed for the patients having pulmonary arterial hypertension, but NOT having instantly recited negative characteristics. No working examples are directed to other vast variety of disease/disorder involving mitochondrial dysfunction/ endothelial dysfunction(e.g. neurological disease, etc.). Due to the high unpredictability as shown in BEACON study, one of ordinary skilled in the art would not know from the disclosure that any compound of Formula II could be used for treating vast variety of disease/disorder associated with mitochondrial dysfunction, in the absence of sufficient data /working example of other disease/disorder associated with mitochondrial dysfunction.
The level of one of ordinary skill in the art
The level of skill required to make and/or use the instant invention would likely require many years of professional experience conducting research in the art (e.g., medicine, pharmaceutical science, biology, biochemistry, medicinal chemistry, and/or organic chemistry, etc.) as well as an advanced educational degree (e.g., M.D. and/or Ph.D.) commensurate in level with the advanced techniques involved in the preparation and/or use of the instant invention.
The quantity of experimentation needed
Working examples in mammals and/or human subject would be needed to determine the therapeutically effective dose and administration route for different compound species and /or different disease/disorder respectively. The therapeutically effective amount may vary depending on many factors, such the subjects being treated ( mammals/human), the disease condition and intended result etc. Thus, the skilled artisan would have to undergo exhaustive studies to evaluate each condition that falls under the umbrella term of mitochondrial dysfunction (e.g. neurological disease, metabolic disease, etc.) with any compound of Formula II in order to be able to fully carry out the invention commensurate in scope with the claims.
Therefore, it would be a great burden for one of ordinary skill in the art to carry out undue experimentation to treat all mitochondrial dysfunction associated disease/disorder with any compound species of Formula II in full scope.
Conclusion
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562,27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here with respect to the method of improving mitochondrial function in a patient in need thereof with any compound species of Formula I in full scope, in view of the analysis above pursuant to In re Wands. In other words, one skilled in the art could not practice the claimed invention in full scope without undue experimentation.
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 273- 276 and 278-292 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.
Independent claim 273 and its dependent claims are amended to recite a method of improving mitochondrial function in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of an Nrf2 activator, wherein the patient has been identified as NOT having at least one of the following characteristics:(a) a history of left-sided myocardial disease;(b) an elevated B-type natriuretic peptide (BNP) level;(c) an elevated albumin/creatinine ratio (ACR); and(d) chronic kidney disease (CKD).
Instant claims do not recite any specific disease or disorder or condition wherein the subject is in need of “improving mitochondrial function”. Instant specification does not disclose disease or disorder or condition associated with mitochondrial dysfunction or subject in need of “improving mitochondrial function”. Instant specification disclosed “the present invention provides methods for treating and/or preventing endothelial dysfunction in patients who are diagnosed with or at risk for cardiovascular disease( including patients diagnosed with or at risk for pulmonary arterial hypertension, other forms of pulmonary hypertension, atherosclerosis, restenosis, hyperlipidemia, hypercholesterolemia, metabolic syndrome, or obesity) and other diseases or conditions using bardoxolone methyl and analogs thereof” (See [0012] [0071]). Although the negative limitation of patient population for a method of treating or preventing endothelial dysfunction is disclosed by instant specification (See [0032]-[0036]), the scope of a patient “in need of improving mitochondrial function” is indeterminate/uncertain with the negative limitation of a patient NOT having at least one of the recited characteristics.
Defining a disease(s) by its (their) underlying cause or mechanism without specifying the target subject renders the scope of the intended use/function indefinite since the claim language may read on diseases not yet known to be caused by or affected by such action or in ways not yet understood. Additionally, determining whether a given disease responds or not to such a mode of action involves much experimentation since a negative response from one patient does not mean the drug is not useful as no drug has 100% effectiveness. Instant limitation of a patient in need of improving mitochondrial function and a patient NOT having at least one of characteristics is confusing. It’s not clear what’s the correlation of patient NOT having history of left-sided myocardial disease or an elevated B-type natriuretic peptide (BNP) level or an elevated albumin/creatinine ratio (ACR) or chronic kidney disease (CKD), with the need of improving mitochondrial function. An ordinary skilled in the art would not know what’s the scope of subject in need of improving mitochondrial function with only negative limitation of patient population and to what extent the mitochondrial function is considered as “improved” as recited in instant claims. The lack of clarity of the subject in need of improving mitochondrial function renders the claims indefinite since the resulting claims do not clearly set forth the metes and bounds of the patent protection desired.
Further, there are two “claim 286” in the claim set.
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It’s not clear from which “claim 286” the dependent claims 287-292 depend from.
Claim Interpretation
Independent claim 273 and its dependent claims are amended to a method of improving mitochondrial function in a patient in need thereof, comprising administering to the patient a pharmaceutically effective amount of an Nrf2 activator, wherein the patient has been identified as NOT having at least one of the following characteristics:(a) a history of left-sided myocardial disease;(b) an elevated B-type natriuretic peptide (BNP) level;(c) an elevated albumin/creatinine ratio (ACR); and(d) chronic kidney disease (CKD).
Instant claims do not recite any specific disease or disorder or condition wherein the subject is in need of “improving mitochondrial function”. Instant specification does not disclose disease or disorder or condition associated with mitochondrial dysfunction or subject in need of “improving mitochondrial function”. Instant specification disclosed reactive oxygen species (ROS) and nitric oxide (NO) levels in human endothelial cells after treatment with bardoxolone methyl (RTA 402) (See Fig 3, [0053]) and speculate instant claimed compounds may be used to activate Nrf2 with positive effects on mitochondrial function (See [0194]). Instant specification disclosed “the present invention provides methods for treating and/or preventing endothelial dysfunction in patients who are diagnosed with or at risk for cardiovascular disease( (including patients diagnosed with or at risk for pulmonary arterial hypertension, other forms of pulmonary hypertension, atherosclerosis, restenosis, hyperlipidemia, hypercholesterolemia, metabolic syndrome, or obesity) and other diseases or conditions using bardoxolone methyl and analogs thereof” (See [0002], [0012] [0071]). Under broadest reasonable interpretation BRI in light of instant disclosure, instant claimed method for improving mitochondrial function is construed as treating and/or preventing disease/disorder involving oxidative stress/inflammation, comprising administering an effective amount of Nrf2 activator to patient in need of thereof, wherein the patients is diagnosed with or at risk for disease involving oxidative stress/inflammation, e.g. mitochondrial dysfunction or endothelial dysfunction or cardiovascular disease related disease/disorder, including obesity, diabetes, pulmonary hypertension, atherosclerosis, restenosis, hyperlipidemia, hypercholesterolemia, metabolic syndrome, etc.
Please note the amended preamble “improving mitochondrial function” is construed as expression of intended function/result of administering an effective amount of an Nrf2 activator which does not necessarily add patent weight . As stated in MPEP 2111.04 I: “the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)). The biological activity of Nrf2 activator, e.g. the elected bardoxolone methyl (CDDO-Me; RTA 402) is intrinsic property/direct result of administrating the Nrf2 activator that reduces oxidative stress associated with reactive oxygen species ROS and nitric oxide NO and/or inflammation. If bardoxolone methyl (CDDO-Me; RTA 402) and its CDDO analog is capable of treating patient/subject diagnosed with or at risk for disease/disorder involving oxidative stress associated with reactive oxygen species ROS and nitric oxide NO and/or inflammation, e.g. obesity, inflammation, diabetes, etc. it is construed as read on the intended function/result of improving mitochondrial function in the subjects even though the prior art is silent about the intended function.
Claim Rejections - 35 USC § 102/103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 273- 276 and 278-292 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Meyer et al. (US20110281955 A1, hereafter “Mayer’ 955”, corresponding to US 10105372B2, family member of WO2011130302A2, Applicant’s IDS dated 10/31/2023), evidenced by Casserly et al. (Design, Development and Therapy 2009:3 269–287, doi: 10.2147/dddt.s4805, Brain natriuretic peptide in pulmonary arterial hypertension).
Claim interpretation: Under broadest reasonable interpretation BRI in light of instant disclosure, instant claimed method is construed as a method for improving mitochondrial function, treating and/or preventing disease/disorder involving oxidative stress/inflammation, comprising administrating an effective amount of Nrf2 activator to patients in need thereof, wherein the patients are diagnosed with or at risk for mitochondrial dysfunction or endothelial dysfunction or cardiovascular disease, e.g. obesity, hypertension and other disease/disorder, etc..
Mayer’ 955 teaches a method for reducing weight, treating and preventing obesity in patient in need thereof, comprising administrating antioxidant/inflammation modulators AIMs, triterpenoids CDDO, compound of formula I or salt thereof , e.g. bardoxolone methyl(See abstract, [0003], [0008], [0011],[0062]-[0066], [0094], claims 135-151).
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Mayer’ 955 and its incorporated reference teach CDDO analogs (including CDDO-Me) are Antioxidant Inflammation Modulator (AIM) and activity/function thereof in diseases/disorder (e.g. obesity, diabetes, cardiovascular disease, etc.) associated with oxidative stress/inflammation through variety of pathway ( e. g. Keap 1/Nrf2/ARE pathway, IL-1, IFN-Y, etc. ) by increasing the production of antioxidant and reductive molecules (e.g., NOO1, HO-1, SOD1, and/or Y-GCS) and/or decreases oxidative stress and the production of pro-oxidant and pro-inflammatory molecules (e.g. iNOS, COX-2, and/or TNF-α.), etc. (See [0198]-[0205], [0206]-[0270]). Mayer’ 955 teaches Nrf2 activation promote weight loss in obesity associated with inflammatory state (See [0222] to [0227]). Mayer’955 also teaches induction of HO-1 has been shown to be beneficial in a variety of models of cardiovascular disease CV, thus CDDO analogs may be used in treating or preventing a variety of cardiovascular disorders including but not limited to atherosclerosis, hypertension, etc.(See [0238]). Please note the pathologies involving oxidative stress and/or inflammation (e.g. obesity, diabetes, cardiovascular disease (CVD) and related disease/ disorders etc. are considered as subjects in need of improving mitochondrial function that read on instant claims.
Mayer’ 955 explicitly teaches instantly elected Nrf2 activator, bardoxolone methyl (CDDO-Me; RTA 402) (See Examples 1-4, claim 1). Mayer’ 955 teaches bardoxolone methyl (BARD) promote weight loss, while simultaneously improving a variety of measures related to several obesity-related diseases, e.g. serum creatinine, estimated glomerular filtration rate, serum phosphorus, blood urea nitrogen, and uricemia), glycemic control (fasting glucose and hemoglobin Alc percentage), and cardiovascular disease (circulating endothelial cells) (See [0224], [0226], Examples 1-4).
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Regarding the negative limitation of population, Meyer’955 teaches variations of embodiments wherein the subject does not have elevated levels of at least one biomarker associated with diabetes, cardiovascular disease, renal disease, fatty liver disease or metabolic syndrome (See [0075]). Meyer’955 teaches variation of embodiments wherein the subject does not have chronic kidney disease (CKD) or exhibit any symptoms of CKD or has been identified as having CKD (See [0076], claim 1). Meyer’955 also teaches exclusion criteria in clinical trial of weight reduction, such as type 1 diabetes, nondiabetic kidney disease, hemoglobin A1c-10%, evidence of hepatic dysfunction, and recent cardiovascular disease in Example 3 (See [0301]). Please note Meyer’955 patient NOT having cardiovascular disease is considered as read on instant recited “ NOT having a history of left-sided myocardial disease”, which also reads on NOT having elevated B-type natriuretic peptide (BNP) level as recited in claims 279-280. Further, Mayer’ 955 teaches administrating bardoxolone methyl to healthy subjects (See [0227], Example 2 ) (which is also construed as read on the patients/subjects NOT having elevated B-type natriuretic peptide BNP). As disclosed by instant specification (See [0228]-[0230]): B-type natriuretic peptide (BNP) is a neurohormone synthesized in the ventricular myocardium and released into circulation in response to ventricular dilation and pressure overload wherein the plasma concentration of BNP is elevated among patients with congestive heart failure (CHF). A skilled artisan would have known to measure BNP level in the patient in need thereof.
Regarding the limitation of ACR , Meyer’955 teaches patient are randomized with several characteristics, e.g. urinary albumin to creatinine ratio (ACR) <= versus >300 mg/g), wherein ACR <30 mg/g, 30-300 mg/g (microalbuminuria), and ACR->300 mg/g were each represented by one-third of the patients (See [0302], [0306]). Please note ACR <30 mg/g or 30-300 mg/g (microalbuminuria) reads on instantly claimed at least one characteristics as NOT having elevated ACR as recited in claim 273. The patient NOT having elevated ACR and NOT having CKD are considered read on instant claim 274. The subject NOT having elevated ACR, NOT having CKD and NOT having elevated levels of at least one biomarker associated with cardiovascular disease are considered as NOT having at least three of the instantly recited characteristics of claim 275.
Regarding the limitation of eGFR recited in claims 283-285, Meyer’955 teaches variations of embodiments wherein administering the AIM results in an improvement in estimated glomerular filtration rate (eGFR) of the subject(See [0078]). Meyer’955 teaches patient with baseline eGFR at between 20 and 45 mL/min/1.73 m2, average 31 ml/min/1.73 m2 (See [0301], Table 3) which reads on claim 283. Meyer’955 teaches 89% patient eGFR rate increase 24% (See Table 4)(which would render claim 284-285 obvious).
Regarding the dosage and administration limitation of instant claims 287-292, Meyer’955 teaches various dose amount, e.g. daily dose from about 10 mg to about 200 mg, 0.1mg to about 30mg, about 25 mg, 75mg and 150mg , etc.(See [0089], [0278]). Meyer’955 teaches CDDO-Me administered to subjects for weight reduction in clinical trials, wherein patients are administered 25 mg, 75mg and 150mg (See Examples 3-4) (which reads on instant claims 287-290). Meyer’955 teaches single or multiple dosing schedule wherein subjects may be administered two doses daily or once a day (See [0287]). Meyer’955 teaches dosage form/formulation of CDDO compounds as hard or soft capsule or a tablet for oral administration (See [0069], [0088], [0277])( which reads on instant claim 291-292).
Meyer’955 collectively teach CDDO-Me / RTA 402 and its CDDO analogs as Nrf2 activator for method of reducing weight / treating and preventing disease/disorder involving oxidative stress and inflammation (e.g. overweight, obesity) and beneficial effects in measures related to several obesity-related diseases(e.g. glycemic control, cardiovascular disease, and renal function, etc.), in the same or similar patient in need thereof as instant recited.
Meyer’955 is silent of improving mitochondrial function in the subjects. However, products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances, " improving mitochondrial function in the subjects " would inevitably flow from the teachings of the prior art, since the same compound (e. g. CDDO-Me/RTA 402 and its CDDO analogs) is being administered to the same or similar subjects in need thereof. In other words, even though the prior art is silent about “ improving mitochondrial function in the subjects” , by practicing Meyer’955 ’s method administrating CDDO-Me/ RTA 402 to the same or similar subject in need thereof as instantly recited, one will also be improving mitochondrial function in the subjects even though the prior art was not aware of it. Thus, Meyer’955 anticipates instant claimed invention.
In the alternative, even if instantly intended result/use of improving mitochondrial function is different from prior art, the differences between what is disclosed in prior art and what is claimed are considered to be slight that the method taught by the cited reference is likely to possess the similar effects of instantly claimed method in view of the similar characteristics which they have been shown to share. Thus, instantly claimed method of improving mitochondrial function comprising administering CDDO analogs by activating Nrf2 pathway involving chronic inflammation and oxidative stress would have been obvious to those of ordinary skill in the art within the meaning of USC 103. A skilled artisan would have known to measure the biomarker associated with other inflammation/oxidative stress related disease/disorder for evaluation of treatment outcome in need thereof. For example, Casserly teaches the role of brain natriuretic peptide BNP in cardiovascular physiology, its use as a biomarker of right ventricular function and pulmonary arterial hypertension (See abstract, Introduction). Casserly teaches healthy individuals have plasma BNP concentrations around 1 fmol/ml (3.5 pg/ml), however plasma BNP levels in congestive heart failure patients can be 200- to 300-fold higher(See page 274 left column). Casserly also teaches variety of BNP in PAH patient and control groups, 294 ± 72 pg/mL versus 48 ± 14 pg/mL (See page 275, right column). 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. MPEP 2144.05. Accordingly, the claimed invention as a whole was at least prima facie obvious, if not anticipated by the cited reference, especially in the absence of sufficient, clear, and convincing evidence to the contrary.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 273- 276 and 278-292 are rejected under 35 U.S.C. 103 as being unpatentable over Meyer et al. (US20110281955 A1, “Mayer’ 955”, Applicant’s IDS dated 10/31/2023), in view of Kulkarni et al. (PLoS ONE, 8, 1-10; May 2013; C185 under NPL of Applicant’s IDS dated 10/31/2023), Price et al. (Chest, 141, 210-221; 2012, C262 under NPL of Applicant’s IDS dated 10/31/2023) and Casserly et al. (Design, Development and Therapy 2009:3 269–287, doi: 10.2147/dddt.s4805, Brain natriuretic peptide in pulmonary arterial hypertension).
The collective teachings of Mayer’ 955 are elaborated in preceding 102/103 rejection and applied as before. Meyer’955 collectively teach a method of treating disease/disorder involving oxidative stress and inflammation (e.g. obesity), comprising administering CDDO-Me / RTA 402 and its CDDO analogs as Nrf2 activator, to the patients that does not have CKD and cardiovascular disease, or does not have elevated levels of at least one biomarker associated with diabetes, cardiovascular disease, renal disease, fatty liver disease or metabolic syndrome, etc. Meyer’955 teaches combination of beneficial effects, e.g. weight loss and improvement in measures of several obesity-related diseases (e.g. glycemic control, and renal function, etc.).
Mayer’ 955 is silent about administering CDDO-Me and analog thereof in pulmonary hypertension and biomarker associated with the disease/disorder. However, Mayer’ 955 teaches oxidative stress and inflammation play an important role in variety of other disease /disorders (e.g. fibrotic lung diseases, atherosclerosis, hypertension) (See [0198]-[210], [238]), and treatment may comprise administering to a subject a therapeutically effective amount of a compound , administered preventively, in advance of a predictable state of oxidative stress or it may be administered therapeutically in settings involving established oxidative stress and inflammation for pathologies involving oxidative stress alone or oxidative stress exacerbated by inflammation(See [0211]).
Kulkarni teaches the elected CDDO-Me(bardoxolone methyl) is a novel triterpenoid with anti-fibrotic and anti-inflammatory properties that inhibits lung Inflammation and fibrosis (See whole article). Kulkarni teaches CDDO-Me strongly reduced cellular inflammation, pro-inflammatory and pro-fibrotic cytokines, e. g. TGFβ , KC and IL-6 by over 90%, thus CDDO-Me has broad anti-inflammatory effect against multiple cytokines involved in fibrosis (See abstract; page 8, right column). Kulkarni teaches CDDO-Me is a potent electrophile and activates multiple cellular pathways via multiple mechanisms, including the activation of Keap1-Nrf2 pathway and inhibition of the PI3K-Akt pathway wherein Nrf2 is a master regulator of the antioxidant response and inducing oxidative stress response (See page 9, left column, 2nd paragraph). Kulkarni teaches that CDDO-Me reduced markers of fibrosis and significantly improved overall lung function in mouse model which can ‘translates’ the observed antifibrotic and strong anti-inflammatory actions of CDDO-Me into clinically relevant measurements (Fig. 5) (See page 9, left column, first column). Kulkarni teaches CDDO-Me has high potential as a human therapy to arrest the cellular pathology underlying lung inflammation and that it can be rapidly translated to human subjects who are predisposed to lung injury, inflammation, and fibrosis (see page 9, right column, 2nd paragraph).
Please note Kulkarni method of inhibiting inflammation in lung fibrosis with CDDO-Me through the activation of Keap1-Nrf2 pathway is considered as read on instant claimed intended function of improving mitochondrial function by administrating CDDO-Me.
Price teaches increasing evidence that inflammation plays an important role in pulmonary arterial hypertension (i.e. PAH) and pathologic samples from patients with PAH reveal an accumulation of perivascular inflammatory cells and elevated circulating levels of certain cytokines and chemokines, and that certain inflammatory conditions such as connective tissue diseases are associated with increased incidence of PAH, and therefore treatment of the underlying inflammatory condition alleviates PAH (See abstract). Price teaches patients with PAH have elevated serum levels of the IL-6 cytokine (see page 212, Columns 1-2, bridging paragraph), and that elevated IL-6 levels in PAH patients correlates with severity of the disease and increased mortality (page 216-217; bridging paragraph).
Casserly teaches reactive oxygen species are produced in the lung tissue of patients with severe pulmonary hypertension as a consequence of tissue hypoxia148,149 or ischemia150 or through the activation of inflammatory cascades and increased production of inflammatory cytokines (See page 280, left column). Casserly teaches multiple factors contributing to pulmonary arterial hypertension: pathological lesions in IPAH include areas of marked intima remodeling and near complete obliteration by fibrous tissue, intravascular and perivascular inflammatory infiltrates contributing to the pulmonary vascular remodeling seen in some forms of PAH, etc. (See page 280, left column, 2nd column). Casserly teaches the role of brain natriuretic peptide BNP in cardiovascular physiology, its use as a biomarker of right ventricular function and pulmonary arterial hypertension (See abstract, Introduction). Casserly teaches monitoring of BNP provides important objective information regarding the ability of the right ventricular to compensate for increased after load as pulmonary vascular disease progresses (see page 282, right column, 1st column). Casserly teaches healthy individuals have plasma BNP concentrations around 1 fmol/ml (3.5 pg/ml), however plasma BNP levels in congestive heart failure patients can be 200- to 300-fold higher(See page 274 left column). Casserly also teaches various amount of BNP in PAH patient and control groups, e.g. 294 ± 72 pg/mL versus 48 ± 14 pg/mL (See page 275, right column).
It’s common practice to explore different therapeutic area for active drug. It would have been prima facie obvious to one of ordinary skilled in the art to further explore CDDO-Me and it’s analog thereof taught by Mayer’ 955 for treatment of other inflammation/oxidative stress associated disease/disease (e.g. pulmonary arterial hypertension) based on the combined beneficial teachings of Kulkarni, Price and Casserly. One would have been motivated to do so as Kulkarni teaches CDDO-Me reduced markers of fibrosis and significantly improved overall lung function in this mouse model which can ‘translates’ the observed antifibrotic and strong anti-inflammatory actions of CDDO-Me into clinically relevant measurements. Both Price and Casserly teach inflammation play an important role in pulmonary arterial hypertension PAH. All references are related to inflammation/oxidative stress that are contributing factor of mitochondrial dysfunction. One of ordinary skill in the art would reasonably expect that administration of CDDO-Me would inhibit pulmonary inflammation in patients with PAH and/or reduce the risk of developing PAH caused by inflammation/oxidative stress based on the combined teachings of prior art and general knowledge of inflammation/oxidative stress in disease/disorder. Please note CDDO-Me inhibiting pulmonary inflammation in patients with PAH would also be considered as read on instant claimed intended function of improving mitochondrial function by administrating CDDO-Me.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of inflammation/oxidative stress associated with mitochondrial dysfunction/ endothelial dysfunction in disease/disorder. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
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