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 .
Claim Rejections - 35 USC § 102
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 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.
Claim(s) 1-8, 10, 12, 14, 16, 18-28, and 33-36 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhou, Bo, et al. "Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure." The Journal of clinical investigation 130.11 (2020): 6054-6063.
Zhou aimed to investigate the mechanistic link between mitochondrial dysfunction and inflammatory activation in peripheral blood mononuclear cells (PBMCs), and the potential anti-inflammatory effect of boosting the NAD level (Abstract). Zhou compared the PBMC mitochondrial respiration of 19 hospitalized patients with stage D HF with that of 19 healthy participants. Zhou then created an in vitro model of sterile inflammation by treating healthy PBMCs with mitochondrial damage–associated molecular patterns (MitoDAMPs) isolated from human heart tissue. Last, Zhou enrolled patients with stage D HF and sampled their blood before and after taking 5 to 9 days of oral nicotinamide riboside (NR), a NAD precursor. Zhou demonstrated that HF is associated with both reduced respiratory capacity and elevated proinflammatory cytokine gene expressions. In the in vitro model, MitoDAMP-treated PBMCs secreted IL-6 that impaired mitochondrial respiration by reducing complex I activity. Last, oral NR administration enhanced PBMC respiration and reduced proinflammatory cytokine gene expression in 4 subjects with HF.
Zhou teaches that a total of 19 patients with stage D HF and 19 healthy participants were recruited (e.g., identifying a human Stage D heart failure patient). See page 6055. Zhou teaches, for experiments associated with oral NR administration (Figure 5, C–F), 5 hospitalized patients with stage D HF undergoing advanced HF therapy evaluations were put on escalating doses of NR (250 mg twice a day for day 1,500 mg twice a day for day 2, and 1000 mg twice a day from day 3 on) for 5 to 9 days (e.g., orally administering to the human Stage D heart failure patient 2000 mg/day of NR, wherein the 2000 mg/day is split into two 1000 mg/day doses). See page 6059. Fasting blood samples were obtained for PBMC isolation at baseline and after NR administration (e.g., obtaining PBMCs from the human Stage D heart failure patient). Zhou teaches that OCR of freshly isolated PBMCs was assessed using a Seahorse XFe24 analyzer (e.g., measuring OCR of the obtained PBMCs). Zhou teaches that relative mRNA levels of NLRP3 and inflammatory cytokines of PBMCs from subjects with stage D HF before and after NR administration (e.g., measuring the expression level of IL6, IL1b, and IL18 by the obtained PBMCs). See page 6060.
PNG
media_image1.png
324
1182
media_image1.png
Greyscale
Zhou teaches that purified PBMCs from study participants were subjected to the standard Seahorse Mito Stress Test (Figure 1A and ref. 21). See page 6055. Mean PBMC basal respiration (oxygen consumption rate [OCR]) trended lower in subjects with HF than healthy subjects though not reaching statistical significance (Figure 1B). Consistent with previous reports that HFrEF is associated with a proinflammatory state, Zhou found that mRNA levels of NLRP3, a key component of the inflammasome in monocytes and macrophages, as well as proinflammatory cytokines (IL-1B, IL-18, TNF-α), were significantly higher in patients with stage D HFrEF as compared with healthy participants. IL-6 showed a similar trend but did not reaching statistical significance (Figure 1D).
PNG
media_image2.png
316
510
media_image2.png
Greyscale
Zhou teaches all of the instantly claimed elements. Thus, claims 1-8, 10, 12, 14, 16, 18-28, and 33-36 are anticipated.
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.
Claim(s) 9, 11, 13, 15, and 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhou, Bo, et al. "Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure." The Journal of clinical investigation 130.11 (2020): 6054-6063 as applied to claims 1-8, 10, 12, 14, 16, 18-28, and 33-36 above, and further in view of Haugen, Espen, et al. "Increased interleukin-6 but not tumour necrosis factor-alpha predicts mortality in the population of elderly heart failure patients." Experimental & Clinical Cardiology 13.1 (2008): 19 (Haugen) and Naito, Y., et al. "Increased circulating interleukin-18 in patients with congestive heart failure." Heart 88.3 (2002): 296-297 (Naito) in combination.
Zhou differs from the instantly claimed invention in that Zhou 1) does not explicitly teach a method wherein the PBMC's IL6 expression level is higher than 6 pg/mL; 2) does not explicitly teach a method wherein the PBMC's IL1b expression level is higher than 1.0 pg/mL; 3) does not explicitly teach a method wherein the PBMC's IL18 expression level is higher than 492 pg/mL; and/or 4) does not explicitly teach a method wherein the PBMC's TNFa expression level is higher than 1 pg/mL. However, these deficiencies would have been obvious in view of the teaching of Haugen and Naito in combination.
In the instant case, the references may be combined to show obviousness because Zhou, Haugen, and Naito are each drawn to proinflammatory cytokines associated with heart failure. They are from the same field of endeavor, and/or are reasonably pertinent to a method of treating a human patient identified with a preexisting inflammation marker profile comprising administering the patient a NAD precursor.
Haugen teaches increased levels of IL-6, IL-8, IL-10, IL-1b, TNF-α and EGF in heart failure patients compared with those in the control group (Table 2). See page 20.
PNG
media_image3.png
448
522
media_image3.png
Greyscale
Naito showed that serum IL-18 was raised in CHF patients, in whom elevations correlated with poorer cardiac functional class and higher TNFα concentrations (page 297). Naito teaches that
Serum concentrations of IL-18 in 34 patients with congestive heart failure and 24 subjects without congestive heart failure (non-CHF) as a function of severity of symptoms according to New York Heart Association (NYHA) functional class (class II, n = 17; class III, n = 14; class IV, n = 3). *p < 0.01 v non-CHF (Figure 1).
PNG
media_image4.png
258
372
media_image4.png
Greyscale
In determining the differences between the prior art and the claims, the question under 35 U.S.C. 103 is not whether the differences themselves would have been obvious, but whether the claimed invention as a whole would have been obvious. Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 218 USPQ 871 (Fed. Cir. 1983); Schenck v. Nortron Corp., 713 F.2d 782, 218 USPQ 698 (Fed. Cir. 1983).
It would have been prima facie obvious to employ the method of Zhou to treat a human patient, wherein the patient has been identified as having a PBMC's IL6 expression level higher than 6 pg/mL, a PBMC's IL1b expression level higher than 1.0 pg/mL, a PBMC's IL18 expression level higher than 492 pg/mL, and/or a PBMC's TNFa expression level higher than 1 pg/mL as such levels were recognized in the art as being associated with heart failure as evidenced by the teachings of Haugen and Naito in combination.
All of the instant limitations are taught by the combination of Zhou, Haugen, and Naito. A person of ordinary skill in the art would have had a reason to combine the teachings of Zhou, Haugen, and Naito. A person of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Zhou, Haugen, and Naito. Thus, claims 9, 11, 13, 15, and 17 would have been obvious based on the preponderance of the evidence.
Claim(s) 29-32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhou, Bo, et al. "Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure." The Journal of clinical investigation 130.11 (2020): 6054-6063 as applied to claims 1-8, 10, 12, 14, 16, 18-28, and 33-36 above, and further in view of GlaxoSmithKline Intellectual Property No 2 Ltd US 2017/0204131 A1 (GSK) and Suave et al. US 9,321,797 (Suave) in combination.
Zhou differs from the instantly claimed invention in that Zhou does not explicitly teach a method wherein the NAD precursor is an NR analog; however, this deficiency would have been obvious in view of the teachings of GSK and Suave in combination.
In the instant case, the references may be combined to show obviousness because Zhou, GSK, and Suave are each drawn to NAD precursors. They are from the same field of endeavor, and/or are reasonably pertinent to a method of treating a human patient identified with a preexisting inflammation marker profile comprising administering the patient a NAD precursor.
GSK provides nicotinamide riboside chloride preparations and methods for using the same in the prophylaxis or treatment of a clinical condition in a mammal, such as a human, for which a NAD precursor is indicated, which comprises administration of a therapeutically effective amount of beta-D-nicotinamide riboside chloride [0049]. In particular, the present invention provides such a method for the prophylaxis or treatment of a disease or disorder that would benefit from increased NAD levels such as insulin resistance, a metabolic syndrome, diabetes, obesity, or a mitochondrial disease or disorder. GSK describes the preparation and characterization of two distinct crystalline forms of nicotinamide riboside chloride [0010]. GSK further teaches a substantially isomerically pure 3-carbamoyl-1-((2R,3R,4S,5R)-3,4-dihydroxy-5 (hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (β-D-nicotinamide riboside (or 2R (β) nicotinamide riboside)) chloride crystal of greater than 90% chemical purity (w/w) [0015]. GSK taches that the compound and pharmaceutical formulations according to the invention may be used in combination with or include one or more other therapeutic agents, for example selected from other NAD precursors, such nicotinamide mononucleotide (NMN) [0056].
Suave teaches that the experiment suggests that different forms of nicotinate ribosides are available as metabolizable sources of niacin and that these chemical forms of niacin of novel composition have the effect of substantially increasing NAD+ concentrations in cells as determined by a quantitative MS assay (Example 10). Increases in NAD+ concentrations within cells can lead to clinical benefits. The minimal increase in NAD+ concentration in cells we observed was from 618 pmol per million cells (Table 3, and bar chart FIG. 9) in untreated cells to 1004 pmol per million cells in the case of treatment with 500 micromolar treatment of the compound O-ethyl nicotinate riboside. This represents a 62% increase over the control NAD+ content. Increasing the concentration of this compound to 800 micro molar led to an increase in NAD+ concentration of approximately three fold (Table 3). Similarly nicotinic acid riboside and the fully esterified compound tri-acetyl-ethylnicotinate riboside was able to increase NAD+ concentrations in cells by 60% and three-fold respectively (Table 3). These data demonstrate that these derivatives are metabolized by cells and increase NAD+ concentrations in cells in a substantive manner (60-300%).
PNG
media_image5.png
338
562
media_image5.png
Greyscale
In determining the differences between the prior art and the claims, the question under 35 U.S.C. 103 is not whether the differences themselves would have been obvious, but whether the claimed invention as a whole would have been obvious. Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 218 USPQ 871 (Fed. Cir. 1983); Schenck v. Nortron Corp., 713 F.2d 782, 218 USPQ 698 (Fed. Cir. 1983).
It would have been prima facie obvious to substitute NR employed in the method of Zhou with another NAD precursor such as NMN, crystalline 3-carbamoyl-1-((2R,3R,4S,5R)-3,4-dihydroxy-5 (hydroxymethyl)tetrahydrofuran-2-yl)pyridin-1-ium (β-D-nicotinamide riboside, or O-ethyl NR in view of their close chemical structures and shared function as being a NAD precursor. The simple substitution of one known element (e.g., NAD precursors) for another to obtain predictable results is prima facie obvious. The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.
All of the instant limitations are taught by the combination of Zhou, GSK, and Suave. A person of ordinary skill in the art would have had a reason to combine the teachings of Zhou, GSK, and Suave. A person of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Zhou, GSK, and Suave. Thus, claims 29-32 would have been obvious based on the preponderance of the evidence.
Claim(s) 37-43 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhou, Bo, et al. "Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure." The Journal of clinical investigation 130.11 (2020): 6054-6063; GlaxoSmithKline Intellectual Property No 2 Ltd US 2017/0204131 A1 (GSK); and Suave et al. US 9,321,797 (Suave) in combination as applied to claims 29-32 above, and further in view of.
Zhou, GSK, and Suave in combination differs from the instantly claimed invention in that the combination does not explicitly teach a composition comprising at least 1000 mg of a NAD precursor; however, this deficiency would have been prima facie obvious.
It would have been obvious to a composition comprising at least 1000 or 2000 mg of a NAD precursor as Zhou explicitly teaches the administration of 2000 mg of a NAD precursor (e.g., NR) to a subject in need thereof. Zhou is silent on whether the NR is administered in a single composition or divided; however, combination of 2000 mg of a NAD precursor into a single composition would have been prima facie obvious.
All of the instant limitations are taught by the combination of Zhou, GSK, and Suave. A person of ordinary skill in the art would have had a reason to combine the teachings of Zhou, GSK, and Suave. A person of ordinary skill in the art would have had a reasonable expectation of success in combining the teachings of Zhou, GSK, and Suave. Thus, claims 37-43 would have been obvious based on the preponderance of the evidence.
Conclusion
Claims 1-43 are pending. Claims 1-43 are rejected. No claims are allowed.
Contacts
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PATRICK T LEWIS whose telephone number is (571)272-0655. The examiner can normally be reached Monday to Friday, 10 AM to 4 PM EST (Maxi Flex).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Shaojia Jiang can be reached at (571) 272-0627. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/PATRICK T LEWIS/Primary Examiner, Art Unit 1691
/PL/