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.
Priority
The instant application is a 371 of PCT/US2023/011109 filed on 01/19/2023 and claims domestic benefit to US provisional application no. 63/300,950 filed on 01/19/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/19/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of the Claims
Claims 1-20 are pending and being examined on the merits herein.
Drawings
The drawings are objected to because:
FIG. 1-7 are duplicated, and one set should be deleted. FIG. 1-7 are also pixelated and have low resolution, making it difficult to read the text and data.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Paragraph 0051, page 12 line 20 contains the link “sec.gov/Archives/edgar/data/882796/000119312512311267/d383732dex991.htm”.
Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of ameliorating osteoarthritis, cartilage injury, gout, or age-associated disease, does not reasonably provide enablement for treatment in which the recited disease or disorder is completely inhibited. The specification does not enable 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.
To be enabling, the specification of the patent 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). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Formal, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) The breadth of the claims,
2) The nature of the invention,
3) The state of the prior art,
4) The level of one of ordinary skill,
5) The level of predictability in the art,
6) The amount of direction provided by the inventor,
7) The existence of working examples, and
8) The quantity of experimentation necessary
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention, the breadth of the claims, and relative skill level
The invention relates to a method of treatment for osteoarthritis (claims 1-7), gout (claims 8-13), and aging-associated disease (claims 14-20) comprising administering an effective amount of a PNP inhibitor and NRH.
The claims are broad in that they encompass a method of treatment of any aging-associated disease.
Applicant defines the term “treatment” as at least an amelioration of the symptoms associated with diseases in the patient, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g. symptom associated with the disease or condition being treated (paragraph 0054). Furthermore, Applicant defines “treatment” as also including situations where the disease, disorder, or pathological condition, or at least symptoms associated therewith, are completely inhibited (e.g. prevented from happening) or stopped (e.g. termination) such that the patient no longer suffers from the condition, or at least the symptoms that characterize the condition (paragraph 0054).
Therefore, in order to give the broadest reasonable interpretation to the claims, the recited term “treatment” is thus interpreted to mean the disease or disorder is completely inhibited such that the recited disease or condition is prevented from happening.
The relative skill of those in the art is high, that of an MD or PHD, someone with experience in the recited conditions/diseases.
The amount of direction or guidance provided and the presence or absence of working examples
Applicant discloses that the combination of NAD precursors such as NR or NRH with a PNP inhibitor (Ulodesine) exerted synergistic effect on inhibition of chondrocyte responses to IL-1β, a proinflammatory cytokine that is implicated to participate in osteoarthritis (OA) pathogenesis (paragraph 0062 page 16 in specification).
Applicant demonstrates in Figures 7A and 7B that NR or NRH at low dose (10 uM) showed little effect on IL-1B induced release. However, when combined with the PNP inhibitor ulodesine at 5 uM, there was significant inhibition (paragraph 0066). Applicant discloses that inhibition of PNP may significantly enhance the stability and availability of NR or NRH, therefore increasing their effectiveness. Applicant discloses that significant inhibition of IL-1B-induced NO release in chondrocytes by NR or NRH alone was only observed when treated at 200 uM (paragraph 0066). Applicant discloses that low doses of NR and NRH, when combined with a PNP inhibitor, when almost as effect as high dose of NR or NRH used alone (paragraph 0066). Applicant also demonstrates in Fig. 8 that the NR or NRH can inhibit MSU crystal-induced inflammation in a gout-like air pouch model in mice. Applicant discloses that given the potential of ulodesine in lowering uric acid, the combination of NR or NRH with PNP inhibitors present a novel therapeutic approach for gout (paragraph 0073)
While Applicant’s data and examples suggest that the recited compounds were effective in ameliorating the recited diseases or conditions, Applicant’s data does not show that a recited disease or disorder was completely inhibited.
Furthermore, the instant disclosure does not identify a method that could be used by one of ordinary skill in the art to determine that a subject would have predictably developed a recited disease or disorder without the claimed methods in order to establish that the disease or disorder was completely inhibited.
The state and predictability of the art
There are no art recognized methods that could be used to establish that a recited disease or disorder was completely inhibited using therapeutic treatment or to identify patients who would predictably develop a disease or disorder in order to predictably identify that complete inhibition was achieved using therapeutic approaches. Rather, the art indicates that identifying patients who would develop a recited disease or disorder was not predictable.
Franceschi (in PTO-892) discloses that ageing and age-related diseases (ARDs) and geriatric syndromes (GSs) are part of a continuum where precise boundaries do not exist and the two extremes are represented by centenarians, who largely avoided or postponed most ARDs/GSs and are characterized by decelerated aging, and patients who suffered one or more severe ARDs in their 60s, 70s, and 80s and show signs of accelerated aging, respectively (Abstract). Franceschi teaches that in between these two extremes, there is a continuum of intermediate trajectories representing a sort of gray area. Thus, clinically different, classical ARDs/GSs are, indeed, the result of peculiar combinations of alterations regarding the same, limited set of basic mechanisms shared with the aging process (Abstract). Franeschi teaches that whether an individual will follow a trajectory of accelerated or decelerated aging will depend on his/her genetic background interacting lifelong with environmental and lifestyle factors (Abstract). Fransechi further shows in Table 1 (page 3) that age-related pathology such as Alzheimer’s disease, cancer, osteoarthritis, Parkinson’s, rheumatoid arthritis, and others have several different mechanisms shared with the ageing process and a variety of different markers.
Furthermore, Fontana (in PTO-892) discloses that while aging is associated with the development of serious chronic diseases, including type 2 diabetes mellitus, cancer, heart, kidney and neurological diseases in mammals, associated does not equal causation (first paragraph left column page 1134). Fontana discloses that experimental data indicate that aging and age associated chronic diseases are not inextricably linked processes (first paragraph left column page 1134).
The teachings of Franceschi and Fontana establish that aging-associated diseases are not always developed due to the ageing process and are based on a complex combination of different factors such as the patient’s genetic background and environmental/lifestyle factors, which suggests it would not be predictable to identify individuals who would develop an age-associated disease or disorder.
The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of a predictable method to identify patients who would develop a recited disease or disorder without treatment, one of ordinary skilled in the art would not be able to predictably identify that a disease or disorder was completely inhibited by using the claimed agents. Furthermore, the quantity of experimentation would be undue because a method to identify a patient who would predictably get a disease or disorder in order to establish that the claimed method results in complete inhibition does not exist.
Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claims 14-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims recite “A method of treatment for aging-associated disease comprising administering to a subject in need thereof an effective amount of a purine nucleoside phosphorylase (PNP) inhibitor, and administering to the subject an effective amount of dihydronicotinamide riboside (NRH)”.
MPEP 2163 II.A.3.(a).ii. states that “[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention”, “The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus … Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus”, and “The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 "merely by clearly describing one embodiment of the thing claimed." … The issue is whether a person skilled in the art would understand inventor to have invented, and been in possession of, the invention as broadly claimed. In LizardTech, claims to a generic method of making a seamless discrete wavelet transformation (DWT) were held invalid under 35 U.S.C. 112, first paragraph, because the specification taught only one particular method for making a seamless DWT and there was no evidence that the specification contemplated a more generic method. Id.; see also Tronzo v. Biomet, 156 F.3d at 1159, 47 USPQ2d at 1833 (Fed. Cir. 1998)(holding that the disclosure of a species in a parent application did not provide adequate written description support for claims to a genus in a child application where the specification taught against other species”.
In this case, the disclosure does not provide sufficient description such that the ordinary skilled artisan would have understood the Applicant had possession of the recited method because the disclosure does not provide a structure-function relationship or a representative number of species for the recited “aging-associated disease” that the administered NRH and PNP inhibitor can be used for as treatment.
Applicant discloses that the combination of NAD precursors such as NR or NRH with a PNP inhibitor (Ulodesine) exerted synergistic effect on inhibition of chondrocyte responses to IL-1β, a proinflammatory cytokine that is implicated to participate in osteoarthritis (OA) pathogenesis (paragraph 0062 page 16 in specification).
Applicant demonstrates in Figures 7A and 7B that NR or NRH at low dose (10 uM) showed little effect on IL-1B induced release. However, when combined with the PNP inhibitor ulodesine at 5 uM, there was significant inhibition (paragraph 0066). Applicant discloses that inhibition of PNP may significantly enhance the stability and availability of NR or NRH, therefore increasing their effectiveness. Applicant discloses that significant inhibition of IL-1B-induced NO release in chondrocytes by NR or NRH alone was only observed when treated at 200 uM (paragraph 0066). Applicant discloses that low doses of NR and NRH, when combined with a PNP inhibitor, when almost as effect as high dose of NR or NRH used alone (paragraph 0066). Applicant has also demonstrated in Fig. 8 that the NR or NRH can inhibit MSU crystal-induced inflammation in a gout-like air pouch model in mice. Applicant discloses that given the potential of ulodesine in lowering uric acid, the combination of NR or NRH with PNP inhibitors present a novel therapeutic approach for gout (paragraph 0073)
Applicant discloses that NR effects have been and/or are being investigated in many clinical trials in aging and age-related diseases including cardiovascular disease, neural, and cognitive functions, metabolic disturbances, and muscular and kidney injuries (paragraph 0069). Applicant discloses that even though recent studies show that oral supplementation of NR is well-tolerated, safe, and boosted NAD+ metabolism in a dose-dependent manner, the clinical trial data showed that dietary NR supplementation has only mild benefits on blood pressure and exercise performance in elderly individuals and no significant impact on skeletal muscle mitochondria in obese and insulin-resistant men (paragraph 0069). Applicant discloses that since NR is readily metabolized by the PNP, the short stability of NR in circulation may limit its effectiveness in a clinical application (paragraph 0069). Applicant discloses that the combination of NRH and PNP inhibitor may overcome this limitation as NRH is more stable than NR, and the PNP inhibitor may increase efficiency of the NRH partly by preventing degradation of NR oxidized from NRH (paragraph 0070).
Applicant has only demonstrated or provided support in the disclosure for the use of the combined NRH and PNP inhibitor for treating osteoarthritis and/or gout as described above. Applicant has not provided further examples for other species of age-related diseases that can be treated by the combined NRH and PNP inhibitor administration. While Applicant does disclose the combination may increase the therapeutic effectiveness over NR alone, Applicant also discloses that NR supplementation may not have significant therapeutic effect for certain age-related conditions like cardiovascular disease as described above.
Furthermore, the state of the art does further establishes that NR supplementation is not predictable for treating any age-related diseases or disorders.
For example, Martens (Nature Communications, 2018 in PTO-892) discloses that while NMN and NR as NAD+ boosting compounds hold promise for enhancing cardiovascular health and physiological function with aging, the tolerability and effectiveness of chronic supplementation with NMN or NR have not been established in humans (last two paragraphs left column page 2). Martens further discloses that there is a lack of initial insight into the potential of NR for improving cardiovascular and other physiological functions with human aging (first paragraph right column page 2).
Furthermore, Elhassan (Cell Reports, 2019 in PTO-892) discloses that a hallmark feature of aging is the progressive loss of skeletal muscle mass and function that can progress to sarcopenia, which is associated with significant morbidity and mortality and substantial healthcare costs (first paragraph under “Introduction” section page 1717). Elhassan further discloses that while NR supplementation in mice has promise as a potential strategy to augment tissue-specific NAD+ homeostasis and improve physiological function, recent data in mice tracing NAD+ fluxes questioned whether oral NR has the ability to access muscle and thus, it is unknown whether oral NR can augment the human skeletal muscle NAD+ metabolome (second paragraph right column page 1717 through first paragraph left column page 1718).
The teachings of Martens and Elhassan establish that while increasing NAD+ via NAD+ boosting compounds such as NR may have potential therapeutic affects in improving age-related diseases/conditions, it is still unknown whether this supplementation is effective in humans and for treating any aging-associated conditions and/or diseases.
Therefore, it is not evident by the disclosure or the prior art, that the Applicant was in possession of the recited method of treating aging-associated disease comprising administering to a subject in need thereof an effective amount of a purine nucleoside phosphorylase (PNP) inhibitor, and administering to the subject an effective amount of dihydronicotinamide riboside (NRH). Furthermore, as described above, there is no disclosed and/or art recognized guidance of a structure-function relationship to determine what species of ageing-associated diseases can be treated using the recited combination, and Applicant has only demonstrated or provided support in the disclosure for the use of the combined NRH and PNP inhibitor for treating osteoarthritis and/or gout as described above.
Therefore, instant claims 1-6, 9-10, and 12-23 do not meet the written description requirement under 35 USC 112(a).
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.
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.
Claim(s) 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Pranesh et al. (US20200397807A1 in IDS filed 07/19/2024) in view of Nishida et al. (Bone & joint research, 2018 in PTO-892).
Pranesh teaches nicotinamide riboside (NR), the reduced form of NR (NRH), nicotinic acid riboside (NAR), the reduced form of NAR (NARH), derivatives thereof, compositions thereof and uses thereof (Abstract). As evidenced on lines 1-5 page 2 of the specification, the reduced form of NR is also known as dihydronicotinamide riboside (NRH).
Pranesh teaches that these compounds can increase cellular NAD+ levels and enhance mitochondrial and cellular function and cell viability (Abstract).
Pranesh teaches that reactive oxygen species (ROS) incite inflammation, in part by activating transcriptions factors such as NF-κB that increase the expression of pro-inflammatory cytokines, and that their compounds can reduce ROS levels by stimulating SIRT3 activity (paragraph 0236). Pranesh further teaches their compounds can increase the activity of NAD-dependent deacetylase sirtuin-1 (SIRT1), which inhibits NF-κB (paragraph 0236). Pranesh teaches that NF-κB is the main promoter of the transcription of genes encoding pro-inflammatory cytokines, and therefore their compounds are useful for treating inflammatory diseases such as neuroinflammation, Alzheimer’s disease, rheumatic diseases such as osteoarthritis and gout, and other listed inflammatory diseases/conditions (paragraph 0236).
Even though Pranesh suggests that their NRH compound can be used to treat inflammatory diseases such as osteoarthritis via increasing the activity of SIRT1, Nishida provides further guidance and demonstrates that osteoarthritis (OA) was attenuated in a rat OA model from the administration of a potent SIRT1 activator (SRT1720) (Abstract). Nishida teaches that delayed OA progression in the mice treated with SRT1720 was associated with increased SIRT1-positive chondrocytes (Abstract). Nishida also teaches that the expression of cartilage-degrading enzymes such as MMP-13 was significantly decreased in the mice treatment group. Nishida discloses that SIRT1 suppressed NF-κB signaling through deacetylation of the NF-κB p65 subunit and that NF-κB p65 positively regulated the expression of MMPs and ADAMTS-5 in chondrocytes. Therefore, Nishida discloses that the attenuation of OA development in the mice treated with SRT1720 may have occurred though decreases in cartilage-degrading enzymes via the modulation of the NF-κB pathway by SIRT1 (third paragraph left column page 260).
It would have been prima facie obvious before the effective filing date to have treated osteoarthritis using NRH as suggested in Pranesh and further supported by Nishida with a reasonable expectation of success because Pranesh provides guidance that their NRH compound can treat inflammatory disorders such as osteoarthritis by increasing the activity of NAD-dependent deacetylase SIRT-1 and inhibit NF- κB, which is the main promotor of transcription of genes encoding pro-inflammatory cytokines. Furthermore, Nishida demonstrates that OA was attenuated in a mice model through the same mechanism of increasing SIRT1.
Furthermore, the ordinary skilled artisan would have reasonably expected that the articular chondrocytes of this patient population would have increased NAD levels based on Pranesh disclosing that their NRH compound can increase cellular NAD+ levels.
Additionally, this mechanism would have flowed naturally from the combined teachings of Pranesh and Nishida described above because FIG. 2A-2G of the instant specification demonstrates that administering the NRH increased NAD levels in CD-38 expressing chondrocytes, which is increased in the knee cartilage of human OA patients (paragraph 0058 page 14), and the combined teachings described above provide guidance of administering the same NRH to the same human OA patient.
MPEP 2145 II states that “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter.m 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.").”
In regards to instant claims 3-4, an ordinary skilled artisan would have also reasonably expected that the treatment as disclosed by the combined teachings of Pranesh and Nishida described above would have also inhibited expression of matrix-degrading enzymes and progression of OA because Nishida demonstrates that increased SIRT1 activation led to decreased cartilage-degrading enzymes such as MMP-13 via the modulation of the NF-κB pathway by SIRT1 as well as delayed OA progression in the mice, and Pranesh discloses that their NRH compound can also increase the activity of SIRT1.
Furthermore, these mechanisms would have flowed naturally from the combined teachings of Pranesh and Nishida described above because FIG. 3A-3G of the instant specification demonstrates that administering the NRH decreased MMP3 and MMP13 in CD-38 expressing chondrocytes, which is increased in the knee cartilage of human OA patients (paragraph 0058 page 14), and the combined teachings described above provide guidance of administering the same NRH to the same human OA patient.
MPEP 2145 II states that “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter.m 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.").”
Claim(s) 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over Pranesh et al. (US20200397807A1 in IDS filed 07/19/2024) in view of Nishida et al. (Bone & joint research, 2018 in PTO-892), as applied to claim 1 above, and further in view of Neogi et al. (Joint Bone Spine, 2019 in PTO-892) and Gras (Drugs of the Future, 2014 in PTO-892).
The combined teachings of Pranesh and Nishida are as described above and teach the method of instant claim 1 as discussed above.
The combined references, however, do not teach administering a PNP inhibitor such as ulodesine.
Neogi teaches that hyperuricemia is a common condition, and in a subset of patients leads to gout, the most common inflammatory arthritis. Osteoarthritis (OA) is the most common form of arthritis overall, and gout and osteoarthritis frequently coexist in the same patient (Abstract).
Neogi teaches that the overlap between OA and gout—and more particularly, OA and hyperuricemia—suggests that a co-occurrence that had been recognized clinically may not be merely coincidental (first paragraph left column page 581). Neogi teaches that it has become clearer that at least some mechanisms recognized in each are probably shared by both conditions (also see Fig. 2 on page 579), suggesting the possibility of a reiterative relationship in which each condition may exacerbate the other
(first paragraph left column page 581). Neogi teaches that given OA structural disease is currently untreatable, whereas multiple drugs are available to manage hyperuricemia and gouty inflammation, the efficacy of urate-lowering therapies for OA becomes a testable hypothesis (first paragraph left column page 581).
Gras teaches that ulodesine is a new, orally active, highly potent inhibitor of purine nucleoside phosphorylase (PNP) for the treatment of hyperuricemia and gout (first paragraph left column page 1). Gras teaches that during three phase II trials in patients with gout who failed to reach serum uric acid levels lower than 6 mg/dL on allopurinol alone, ulodesine as add-on therapy showed sustained efficacy in reducing serum uric acid and plasma xanthine and hypoxanthine levels, and the product was safe and well tolerated (first paragraph left column page 1).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the OA treatment as disclosed by the combined teachings of Pranesh and Nishida described above by further including the ulodesine of Gras based on guidance from Neogi to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to include the ulodesine of Gras because Neogi teaches that gout and osteoarthritis frequently coexist in the same patient and may exacerbate either condition.
One of ordinary skill in the art would have a reasonable expectation of success because Neogi suggests that alternative urate-lowering therapies for managing hyperuricemia and gout may be effective for also treating OA, and Gras teaches that ulodsesine is PNP inhibitor that can treat hyperuricemia and gout by reducing serum uric acid
It is noted that the instant specification was analyzed for unexpected results.
As stated in MPEP 716.02(e), the showing of unexpected results must be compared to the closest prior art to be effective to rebut a prima facie case of obviousness.
In this case, the closest prior art is Pranesh, which suggests the treatment of OA by administering the NRH compound as discussed above.
Applicant discloses that the combination of NAD precursors such as NR or NRH with a PNP inhibitor (Ulodesine) exerted synergistic effect on inhibition of chondrocyte responses to IL-1β, a proinflammatory cytokine that is implicated to participate in osteoarthritis (OA) pathogenesis (paragraph 0062 page 16 in specification).
Applicant demonstrates in Figures 7A and 7B that NR or NRH at low dose (10 uM) showed little effect on IL-1B induced release. However, when combined with the PNP inhibitor ulodesine at 5 uM, there was significant inhibition (paragraph 0066). Applicant discloses that inhibition of PNP may significantly enhance the stability and availability of NR or NRH, therefore increasing their effectiveness. Applicant discloses that significant inhibition of IL-1B-induced NO release in chondrocytes by NR or NRH alone was only observed when treated at 200 uM (paragraph 0066). Applicant discloses that low doses of NR and NRH, when combined with a PNP inhibitor, when almost as effect as high dose of NR or NRH used alone (paragraph 0066).
While Applicant has demonstrated a synergistic effect between NRH and PNP inhibitor as described above, Applicant’s showing of unexpected results do not appear to commensurate in scope with the instant claims, which is required as stated in MPEP 716.02(d).
Furthermore, MPEP 716.02(d) I states that “The nonobviousness of a broader claimed range can be supported by evidence based on unexpected results from testing a narrower range if one of ordinary skill in the art would be able to determine a trend in the exemplified data which would allow the artisan to reasonably extend the probative value thereof. “.
In this case, Applicant’s unexpected synergistic results are based on the usage of a low dosage amount of NRH (5 uM) in combination with a PNP inhibitor at 5 uM, and the instant claims currently recite any effective amount for the two compounds. Furthermore, there is no additional disclosure or suggestions that Applicant’s data can be extrapolated such that any effective amount would also have the unexpected synergistic effect. It is noted that in FIG. 6A the combination of NR at 100 uM and Ulodesine at 5 uM exhibited less inhibition than the combination of NR at 10 uM and Ulodesine at 5 uM
Therefore, Applicant’s showing of unexpected results are not commensurate in scope with the instant claims and currently not sufficient to establish non-obviousness over the closest prior art (Pranesh).
Claim(s) 8-16 and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Pranesh et al. (US20200397807A1 in IDS filed 07/19/2024) in view of Chen et al. (Clin Rheumatol, 2016 in PTO-892) and Gras (Drugs of the Future, 2014 in PTO-892), and as evidenced by Saag et al. (Arthritis Res Ther, 2006 in PTO-892).
The teachings of Pranesh are as described above.
Furthermore, Pranesh teaches that their NRH compound can be combined with one or more additional therapeutic agents to treat a disease/disorder, and that the additional therapeutic agent can be administered prior to, concurrently, or subsequent to the administration of the NRH compound (paragraph 0270).
Even though Pranesh suggests that their NRH compound can be used to treat inflammatory diseases such as gout via increasing the activity of SIRT1, Chen provides guidance and demonstrates that the SIRT1-activator resveratrol suppressed hyperuricemia and gouty arthritis in a mouse model (Abstract and last paragraph left column page 1194). Chen teaches that overexpression or increase of SIRT-1 activity significantly suppresses cytokines production and reduces inflammation in different animal models, and that their results suggest prophylactic treatment of resveratrol might be a new therapeutic method to prevent the acute attacks in chronic gouty arthritis (second paragraph left column page 1194). Furthermore, as evidenced by Saag, gout prevalence increases in direct association with age (Abstract). Therefore, gout meets the limitation of an age-associated disease.
It would have been prima facie obvious before the effective filing date to have treated gout using NRH as suggested in Pranesh and further supported by Chen with a reasonable expectation of success because Pranesh provides guidance that their NRH compound can treat inflammatory disorders such as osteoarthritis by increasing the activity of NAD-dependent deacetylase SIRT-1 and inhibit NF-κB, which is the main promotor of transcription of genes encoding pro-inflammatory cytokines. Furthermore, Chen demonstrates that gout was suppressed in a mice model through the same mechanism of increasing SIRT1.
Even though Pranesh teaches combining their NRH compound with additional therapeutic agents, Pranesh does not teach further administering a PNP inhibitor such as ulodesine.
Gras teaches that ulodesine is a new, orally active, highly potent inhibitor of purine nucleoside phosphorylase (PNP) for the treatment of hyperuricemia and gout (first paragraph left column page 1). Gras teaches that during three phase II trials in patients with gout who failed to reach serum uric acid levels lower than 6 mg/dL on allopurinol alone, ulodesine as add-on therapy showed sustained efficacy in reducing serum uric acid and plasma xanthine and hypoxanthine levels, and the product was safe and well tolerated (first paragraph left column page 1).
It would have been prima facie obvious before the effective filing date to have combined the treatment method as disclosed by the combined teachings of Pranesh and Chen described above with the ulodesine treatment disclosed in Gras to arrive at the claimed invention.
One of ordinary skill in the art would have made this combination with a reasonable expectation of success because both the combined teachings of Pranesh and Chen described above and Gras teach that their respective compositions are useful for the same purpose of treating gout. See MPEP 2144.06 I.
In regards to instant claims 9 and 16, an ordinary skilled artisan would have been able to perform routine optimization to arrive at administering the PNP inhibitor compound before NRH administration based on Pranesh providing guidance of administering an additional therapeutic compound before, concurrent, or subsequent to the NRH administration. See MPEP 2144.05 II.
In regards to instant claims 13 and 20, an ordinary skilled artisan would have also reasonably expected that the treatment as disclosed by the combined teachings of Pranesh, Chen, and Gras described above would have also inhibited progression of gout because Chen demonstrates that gout was suppressed in a mice model through a SIRT1 activator, and Pranesh discloses that their NRH compound can also increase the activity of SIRT1.
Furthermore, the recited mechanisms of inhibiting expression of expression of matrix-degrading enzymes and progression of gout in instant claims 12-13 and 19-20 would have flowed naturally from the combined teachings of Pranesh, Chen, and Gras described above because FIG. 2A-2G and 3A-3G of the instant specification demonstrates that administering the NRH increased NAD levels and decreased MMP3 and MMP13 in CD-38 expressing chondrocytes, which is increased in gout patients (paragraph 0073 page 19), and the combined teachings described above provide guidance of administering the same NRH to the same human gout patient.
MPEP 2145 II states that “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter.m 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.").”
It is noted that the specification was analyzed for a showing of unexpected results for the combination of the NRH and PNP inhibitor for treating gout and aging-associated diseases but was found to not be in commensurate in the scope with the instant claims for the same reasons as discussed above.
Furthermore, it is noted that instant claim 8 recites a method of treating gout, and instant claim 14 recites a method of treating any aging-associated disease.
Applicant has demonstrated in Fig. 8 that the NR or NRH can inhibit MSU crystal-induced inflammation in a gout-like air pouch model in mice. Applicant discloses that given the potential of ulodesine in lowering uric acid, the combination of NR or NRH with PNP inhibitors present a novel therapeutic approach for gout (paragraph 0073)
While Applicant has provided sufficient disclosure that the unexpected synergistic effect between the two compounds may also be present in the treatment of gout, it cannot be determined that Applicant’s data and/or disclosure of an unexpected synergistic effect for the two compounds can be reasonably extrapolated across any aging-associated disease. Therefore, instant claims 14-20 are additionally not commensurate in scope with the instant claims.
Claim(s) 12 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Pranesh et al. (US20200397807A1 in IDS filed 07/19/2024) in view of Chen et al. (Clin Rheumatol, 2016 in PTO-892) and Gras (Drugs of the Future, 2014 in PTO-892), and as evidenced by Saag et al. (Arthritis Res Ther, 2006 in PTO-892), as applied to claims 8 and 14 above, and further in view of Nishida et al. (Bone & joint research, 2018 in PTO-892).
The combined teachings of Pranesh, Chen, and Gras are as described above and teach the method of instant claims 8 and 14, as evidenced by Saag, as discussed above.
The combined teachings, however, do not teach that the treatment inhibits expression of matrix-degrading enzymes.
The teachings of Nishida are as described above. Nishida discloses that SIRT1 suppressed NF-κB signaling through deacetylation of the NF-κB p65 subunit and that NF-κB p65 positively regulated the expression of MMPs and ADAMTS-5 in chondrocytes. Therefore, Nishida discloses that the attenuation of OA development in the mice treated with SRT1720 may have occurred though decreases in cartilage-degrading enzymes via the modulation of the NF-κB pathway by SIRT1 (third paragraph left column page 260).
It would have been prima facie obvious before the effective filing date of the claimed invention that the treatment as disclosed by the combined teachings of Pranesh, Chen, and Gras described above would have also inhibited matrix-degrading enzyme expression as suggested in Nishida to arrive at the claimed invention.
An ordinary skilled artisan would have this reasonable expectation because Nishida demonstrates that increased SIRT1 activation led to decreased cartilage-degrading enzymes such as MMP-13 in a related arthritic condition via the modulation of the NF-κB pathway by SIRT1, and Pranesh discloses that their NRH compound can also increase the activity of SIRT1 and inhibit NF-κB.
Claim(s) 17 is rejected under 35 U.S.C. 103 as being unpatentable over Pranesh et al. (US20200397807A1 in IDS filed 07/19/2024) in view of Chen et al. (Clin Rheumatol, 2016 in PTO-892) and Gras (Drugs of the Future, 2014 in PTO-892), and as evidenced by Saag et al. (Arthritis Res Ther, 2006 in PTO-892), as applied to claim 14 above, and further in view of Wakino et al. (Clinical Therapeutics, 2014 in PTO-892) and Borghi et al. (European Journal of Internal Medicine, 2020 in PTO-892).
The combined teachings of Pranesh, Chen, and Gras are as described above and teach the method of instant claim 14, as evidenced by Saag, as discussed above.
Furthermore, Pranesh teaches that in part by reducing inflammation, their NR compounds can be used to treat fibrotic conditions such as chronic kidney disease, cardiomyopathy, and others (paragraph 0239).
The combined teachings described above do not teach that the combination of the NRH and a PNP inhibitor can be used to treat a recited condition in instant claim 17.
Wakino teaches that renal protective effects of SIRT-1 was found in various models of renal disorders with metabolic impairment, such as diabetic nephropathy. Protective effects include the maintenance of glomerular barrier function, anti–fibrosis effects, anti–oxidative stress effects, and regulation of mitochondria function and energy metabolism (Abstract). Wakino teaches that decreased SIRT-1 expression in proximal tubular cells causes abnormal nicotine metabolism and reduces the supply of nicotinamide mononucleotide from renal tubules to glomeruli, and further concludes that activators of the sirtuin family of proteins may be important in the development of new therapeutic strategies for treating metabolic kidney diseases, including diabetic nephropathy (Abstract).
Borghi teaches that while uric acid is usually discussed in the context of gout, hyperuricaemia is also associated with hypertension, chronic kidney disease, hypertriglyceridaemia, obesity, atherosclerotic heart disease, metabolic syndrome, and type 2 diabetes (Abstract). Borghi teaches that treatment with uric acid-lowering therapies has also been found to improve outcomes in patients with hypertension and kidney disease and further concludes that uric acid is emerging as a potentially treatable risk factor for cardiometabolic diseases, and more clinical trials investigating the potential benefit of lowering serum uric acid are recommended in individuals with hyperuricaemia with and without deposition and concomitant hypertension, metabolic syndrome or chronic kidney disease (Abstract).
It would have been prima facie obvious before the effective filing date of the claimed to have modified the gout treatment method as disclosed by the combined teachings of Pranesh, Chen, and Gras described above to include treating other patient populations such as patients with kidney disease as suggested by Wakino, Pranesh, Borghi, and Gras to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Wakino discloses that SIRT-1 activation may be a therapeutic method to treat kidney disease, and Pranesh teaches that the NRH compound can be used to treat inflammatory conditions such as kidney disease by increasing SIRT1. Furthermore, Borghi provides guidance that uric acid-lowering therapies can also improve outcomes for patients with hypertension or kidney disease, and Gras establishes that ulodesine as add-on therapy in clinical trials showed sustained efficacy in reducing serum uric acid.
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 1-4 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 19/105,667 (‘667) in view of Pranesh et al. (US20200397807A1 in IDS filed 07/19/2024) and Nishida et al. (Bone & joint research, 2018 in PTO-892).
‘667 recites a method of treatment for osteoarthritis in a subject comprising administering to a subject in need an effective amount of a composition comprising nicotinamide-riboside (NR) and pterostilbene (PT) in a ratio of between about 4:1 and 1:1, or between about 3:1 and 1.5:1, or about 2:1 (claim 1). ‘667 recites that the administration inhibits progression of osteoarthritis (claim 5).
‘667, however, does not recite administering NRH.
The teachings of Pranesh and Nishida are as described above.
It would have been prima facie obvious before the effective filing date to have substituted the NR of ‘667 with the NRH as suggested in Pranesh and further supported by Nishida to arrive at the claimed invention.
One of ordinary skill in the art would have made this substitution with a reasonable expectation of success because Pranesh provides guidance that their NR and NRH compound can treat inflammatory disorders such as osteoarthritis by increasing the activity of NAD-dependent deacetylase SIRT-1 and inhibit NF- κB, which is the main promotor of transcription of genes encoding pro-inflammatory cytokines. Furthermore, Nishida demonstrates that OA was attenuated in a mice model through the same mechanism of increasing SIRT1.
Furthermore, the ordinary skilled artisan would have reasonably expected that the articular chondrocytes of this patient population would have increased NAD levels based on Pranesh disclosing that their NRH compound can increase cellular NAD+ levels.
Additionally, this mechanism would have flowed naturally from the combined references described above because FIG. 2A-2G of the instant specification demonstrates that administering the NRH increased NAD levels in CD-38 expressing chondrocytes, which is increased in the knee cartilage of human OA patients (paragraph 0058 page 14), and the combined references described above provide guidance of administering the same NRH to the same human OA patient.
MPEP 2145 II states that “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter.m 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.").”
In regards to instant claim 3-4, an ordinary skilled artisan would have also reasonably expected that the treatment as disclosed by the combined references described above would have also inhibited expression of matrix-degrading enzymes and progression of OA because Nishida demonstrates that increased SIRT1 activation led to decreased cartilage-degrading enzymes such as MMP-13 via the modulation of the NF-κB pathway by SIRT1 as well as delayed OA progression in the mice, and Pranesh discloses that their NRH compound can also increase the activity of SIRT1.
Furthermore, these mechanisms would have flowed naturally from the references described above because FIG. 3A-3G of the instant specification demonstrates that administering the NRH decreased MMP3 and MMP13 in CD-38 expressing chondrocytes, which is increased in the knee cartilage of human OA patients (paragraph 0058 page 14), and the combined references described above provide guidance of administering the same NRH to the same human OA patient.
MPEP 2145 II states that “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter.m 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.").”
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 5-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 19/105,667 (‘667) in view of Pranesh et al. (US20200397807A1 in IDS filed 07/19/2024), Nishida et al. (Bone & joint research, 2018 in PTO-892), Neogi et al. (Joint Bone Spine, 2019 in PTO-892), and Gras (Drugs of the Future, 2014 in PTO-892).
The combination of the claims of ‘667 and the teachings of Pranesh and Nishida are as described above and recite the method of instant claim 1 as discussed above.
The combined references, however, do not recite further administering a PNP inhibitor such as ulodesine.
The independent teachings of Neogi and Gras are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the OA treatment as disclosed by the combined references described above by further including the ulodesine of Gras based on guidance from Neogi to arrive at the claimed invention.
One of ordinary skill in the art would have been motivated to include the ulodesine of Gras because Neogi teaches that gout and osteoarthritis frequently coexist in the same patient and may exacerbate either condition.
One of ordinary skill in the art would have a reasonable expectation of success because Neogi suggests that alternative urate-lowering therapies for managing hyperuricemia and gout may be effective for also treating OA, and Gras teaches that ulodsesine is PNP inhibitor that can treat hyperuricemia and gout by reducing serum uric acid.
This is a provisional nonstatutory double patenting rejection.
Claims 8-16 and 18-20are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 19/105,667 (‘667) in view of Pranesh et al. (US20200397807A1 in IDS filed 07/19/2024), Chen et al. (Clin Rheumatol, 2016 in PTO-892), and Gras (Drugs of the Future, 2014 in PTO-892), and as evidenced by Saag et al. (Arthritis Res Ther, 2006 in PTO-892).
The claims of ‘667 are as described above.
The claims of ‘667 do not recite a method of treating gout by administering NRH and PNP inhibitor.
The independent teachings of Pranhes, Chen, Gras, and Saag are as described above.
It would have been prima facie obvious before the effective filing date to have substituted the NR of ‘667 with the NRH as suggested in Pranesh and further treat a patient with Gout as suggested in Pranesh and further supported by Nishida to arrive at the claimed invention.
One of ordinary skill in the art would have made this substitution with a reasonable expectation of success because Pranesh provides guidance that their NR and NRH compound can treat inflammatory disorders such as osteoarthritis by increasing the activity of NAD-dependent deacetylase SIRT-1 and inhibit NF- κB, which is the main promotor of transcription of genes encoding pro-inflammatory cytokines. Furthermore, Nishida demonstrates that OA was attenuated in a mice model through the same mechanism of increasing SIRT1.
One of ordinary skill in the art would made the modification of treating a gout patient with a reasonable expectation of success because Pranesh provides guidance that their NRH compound can treat inflammatory disorders such as osteoarthritis by increasing the activity of NAD-dependent deacetylase SIRT-1 and inhibit NF- κB, which is the main promotor of transcription of genes encoding pro-inflammatory cytokines, and Chen demonstrates that gout was suppressed in a mice model through the same mechanism of increasing SIRT1.
It would have been prima facie obvious before the effective filing date to have further combined the treatment method as disclosed by the combined references described above with the ulodesine treatment disclosed in Gras to arrive at the claimed invention.
One of ordinary skill in the art would have made this combination with a reasonable expectation of success because both the combined teachings of Pranesh and Chen described above and Gras teach that their respective compositions are useful for the same purpose of treating gout. See MPEP 2144.06 I.
In regards to instant claims 9 and 16, an ordinary skilled artisan would have been able to perform routine optimization to arrive at administering the PNP inhibitor compound before NRH administration based on Pranesh providing guidance of administering an additional therapeutic compound before, concurrent, or subsequent to the NRH administration. See MPEP 2144.05 II.
In regards to instant claims 13 and 20, an ordinary skilled artisan would have also reasonably expected that the treatment as disclosed by the combined references described above would have also inhibited progression of gout because Chen demonstrates that gout was suppressed in a mice model through a SIRT1 activator, and Pranesh discloses that the NRH compound can also increase the activity of SIRT1.
Furthermore, the recited mechanisms of inhibiting expression of expression of matrix-degrading enzymes and progression of gout in instant claims 12-13 and 19-20 would have flowed naturally from the combined references described above because FIG. 2A-2G and 3A-3G of the instant specification demonstrates that administering the NRH increased NAD levels and decreased MMP3 and MMP13 in CD-38 expressing chondrocytes, which is increased in gout patients (paragraph 0073 page 19), and the combined references described above provide guidance of administering the same NRH to the same human gout patient.
MPEP 2145 II states that “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter.m 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.").”
This is a provisional nonstatutory double patenting rejection.
Claims 8, 12, 14, and 19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 19/105,667 (‘667) in view of Pranesh et al. (US20200397807A1 in IDS filed 07/19/2024), Chen et al. (Clin Rheumatol, 2016 in PTO-892), Gras (Drugs of the Future, 2014 in PTO-892), and Nishida et al. (Bone & joint research, 2018 in PTO-892), and as evidenced by Saag et al. (Arthritis Res Ther, 2006 in PTO-892).
The combination of the claims of ‘667 and the teachings of Pranesh, Chen, and Gras are as described above and recite the method of instant claims 8 and 14, as evidenced by Saag, as disccused above.
The combined references, however, do not recite the treatment inhibits expression of matrix-degrading enzymes.
The teachings of Nishida are as described above.
It would have been prima facie obvious before the effective filing date of the claimed that the treatment as disclosed by the combined references described above would have also inhibited matrix-degrading enzyme expression as suggested in Nishida to arrive at the claimed invention.
An ordinary skilled artisan would have this reasonable expectation because Nishida demonstrates that increased SIRT1 activation led to decreased cartilage-degrading enzymes such as MMP-13 in a related arthritic condition via the modulation of the NF-κB pathway by SIRT1, and Pranesh discloses that the NRH compound can also increase the activity of SIRT1 and inhibit NF-κB.
This is a provisional nonstatutory double patenting rejection.
Claims 14 and 17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 19/105,667 (‘667) in view of Pranesh et al. (US20200397807A1 in IDS filed 07/19/2024), Chen et al. (Clin Rheumatol, 2016 in PTO-892), Gras (Drugs of the Future, 2014 in PTO-892), Wakino et al. (Clinical Therapeutics, 2014 in PTO-892), and Borghi et al. (European Journal of Internal Medicine, 2020 in PTO-892), and as evidenced by Saag et al. (Arthritis Res Ther, 2006 in PTO-892).
The combination of the claims of ‘667 and the teachings of Pranesh, Chen, and Gras are as described above and recite the method of instant claim 14, as evidenced by Saag, as disccused above.
The combined references, however, do not recite the aging-associated disease is a recited disease in instant claim 17.
The independent teachings of Wakino and Borghi are as described above.
It would have been prima facie obvious before the effective filing date of the claimed to have modified the gout treatment method as disclosed by the combined references described above to include treating other patient populations such as patients with kidney disease as suggested by Wakino, Pranesh, Borghi, and Gras to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Wakino discloses that SIRT-1 activation may be a therapeutic method to treat kidney disease, and Pranesh teaches that the NRH compound can be used to treat inflammatory conditions such as kidney disease by increasing SIRT1. Furthermore, Borghi provides guidance that uric acid-lowering therapies can also improve outcomes for patients with hypertension or kidney disease, and Gras establishes that ulodesine as add-on therapy in clinical trials showed sustained efficacy in reducing serum uric acid.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1-20 are rejected.
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
