DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present application, filed January 23, 2023, is a national stage application of PCT/EP2021/071785, filed August 4, 2021, and claims priority to PCT/EP2020/071903, filed August 4, 2020.
Status of the Application
Applicant’s preliminary amendment, received July 6, 2023, is acknowledged. Claims 15-18 and 23-38 are pending and examined on the merits herein.
Drawings
The drawings are objected to because Figures 1 and 2 do not include labels on the horizontal or vertical axes, and thus it is not clear, for example, what each bar in the plots shown in Figures 1 and 2 represents.
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.
Claim Interpretation
As presently drafted, claim 17 requires doses of components B) and C) of 12-100 mmol/kg/day, which are considerably higher than the doses recited in claim 16 and suggested by the prior art as described in the rejections below.
Regarding the doses in claim 17, the specification states: “If the doses are not adjusted to the weight of the patient, the method of treatment may for example comprise administration, such as oral administration, of: A) in a dose of 100-600 mmol/day, such as 150-450 mmol/day, such as 170- 350 mmol/day; optionally B) in a dose of 12-100 mmol/kg/day, such as 16-75 mmol/day, such as 20-50 mmol/ day; optionally C) in a dose of 12-100 mmol/kg/day, such as 16-75 mmol/day, such as 20-50 mmol/ day; D) in a dose of 3-20 mmol/day, such as 4-15 mmol/day, such as 5-12 mmol/day (p. 16, lines 18-25).
Claim 17 is herein interpreted as drafted, wherein B) and C) require dosages of 12-100 mmol/kg/day. However, if this is a typographical error and claim 17 is intended to recite dosages of 12-100 mmol/day, consistent with A) and D) of claim 17 and the context of the specification recited above, then claim 17 and dependent claims 35-38 would be rejected as described below.
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 15, 18, and 23-25 are rejected under 35 U.S.C. 103 as being unpatentable over Wu (Publication No. CN 107982280 A; cited in PTO-892) in view of Mardinoglu (Mardinoglu, A.; et al. Nutrients 2019, vol. 11, 1578; cited in IDS received January 23, 2023) and Li (Li, J.; et al. Cellular Reprogramming 2019, vol. 21, pp. 152-161; cited in PTO-892), as evidenced by PubChem (PubChem entry for nicotinic acid; cited in PTO-892).
Wu was published in a language other than English. Both the original document and an English language machine translation are included with this Office action and cited in the PTO-892. Citations below refer to the English language machine translation document.
Mardinoglu was published July 12, 2019 and thus eligible as prior art under 35 U.S.C. 102(a)(1). In addition, this publication date is greater than 1 year prior to the filing date of the foreign priority application, and thus rejections relying on Mardinoglu may not be overcome by invoking exceptions under 35 U.S.C. 102(b)(1)(A) or 102(b)(1)(B).
Wu teaches a nutritional composition for delaying aging, comprising nucleotides,
lysine, methionine, phenylalanine, threonine, tryptophan, arginine, histidine, glycine, aspartic
acid, leucine, isoleucine, valine, serine, glutamine, glutamic acid, proline, tyrosine, cysteine, γ-
aminobutyric acid, taurine, orotic acid, soybean lecithin, egg yolk lecithin, cephalin, α-
linolenic acid, γ-linolenic acid, inositol, hydroxytyrosol, vitamin A, vitamin B1, vitamin B2,
vitamin B3, vitamin B4, vitamin C, vitamin D, vitamin E, niacin, folic acid, iron, zinc, manganese, copper, selenium, chromium, potassium, calcium, magnesium, choline, L-carnitine, pentose, sodium carbonate, and freeze-dried powder of three-day-old chicken embryos (English translation, document pp. 6-7, [0001], lines 1-9). Wu teaches this composition promotes the proliferation of neural stem cells, increases the number of autophagosomes, and enhances the activity of telomerase in bone marrow mesenchymal stem cells (English translation, document p. 7, lines 2-4).
As evidenced by the PubChem entry for niacin (cited in PTO-892), niacin is another name for nicotinic acid (p. 1, Synonyms section).
Wu further teaches compositions with preferred amounts of each composition component. As one example, Wu teaches and claims the nutritional composition with mass fractions including serine (200-600), cysteine (200-1200), L-carnitine (0.3-0.6), and niacin (20-30NE) (English translation, document pp. 111-112, claim 1).
Wu further teaches and claims the nutritional composition with mass fractions that are serine (200), cysteine (200), L-carnitine (0.3), and niacin (20NE) (English translation, document pp. 112-113, claim 2).
Wu teaches the composition was administered by gavage (English translation, document p. 46, [0138], lines 5-7), which is taken as oral administration as recited in claim 18.
Wu does not teach administering nicotinamide as part of their composition, or administering their composition for the purposes of specifically treating Alzheimer's disease or Parkinson's disease, each as required by independent claim 15.
Mardinoglu teaches the use of metabolic cofactors in treatment of non-alcoholic fatty liver disease (p. 1, Title). Relating to the administration of nicotinic acid, Mardinoglu teaches NAD is an endogenous substance that is involved in several important cell functions such as signal transduction, DNA repair, and post-translational protein modifications. Mardinoglu teaches that NAD-consuming activities and cell division necessitate ongoing NAD synthesis, either through a de novo pathway that originates with tryptophan or via salvage pathways from three NAD+ precursor vitamins, NR, nicotinamide, and nicotinic acid (p. 10, section 2.2, lines 1-5). In addition, Mardinoglu teaches that flushing is the most sensitive side effect of nicotinic acid supplementation, and after ingestion of supplemental nicotinamide, no cases of flushing or glucose intolerance have been reported (p. 10, Section 2.2.2, third paragraph, lines 1-2).
Li teaches Alzheimer’s disease (AD) is a neurological degenerative disease with clinical symptoms that include memory impairment. Li teaches that research on hippocampal neurogenesis of central nervous system (CNS) disorders, such as AD, stroke, and traumatic brain injury, found that the endogenous neural stem cells (NSCs) may play regenerative and reparative roles (p. 152, left column, lines 1-3 and 8-13).
Li teaches the abnormal deposition of amyloid-β peptide, a major component of senile plaques, has been reported to be the major cause of neuronal cell death and cognitive impairment in Alzheimer’s disease (AD). Li teaches that adult neurogenesis is linked to the amelioration of impaired neurons and cognitive impairment (p. 152, Abstract, lines 1-3).
Li teaches that studies with transplanted NSCs were limited by low survival rate and neuronal differentiation rate to develop therapeutic strategies, and thus the study of promoting the NSC environment and stimulating NSC neurogenesis is an active area of research for developing therapies that depend on NSCs for treating neurological diseases (p. 152, right column, first paragraph, lines 1-7).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to substitute niacin (or nicotinic acid) in the composition taught by Wu with nicotinamide. One of ordinary skill in the art would have been motivated to substitute niacin (or nicotinic acid) in the composition taught by Wu with nicotinamide because Mardinoglu teaches that NAD-consuming activities and cell division necessitate ongoing NAD synthesis, either through a de novo pathway that originates with tryptophan or via salvage pathways from NAD+ precursor vitamins that includes nicotinamide and nicotinic acid, and because Mardinoglu teaches administration of nicotinamide avoids the flushing side effect associated with administration of nicotinic acid. Accordingly, one of ordinary skill in the art would have considered administering nicotinamide in place of nicotinic acid, because nicotinamide is also used for NAD synthesis and may avoid unwanted side effects associated with nicotinic acid.
Regarding administration of the composition of Wu to a subject for the purposes of treating Alzheimer’s or Parkinson’s disease, it would have been prima facie obvious to one of ordinary skill in the art to administer the anti-aging composition disclosed by Wu for the purposes of treating Alzheimer’s disease. One of ordinary skill in the art would have been motivated to administer the anti-aging composition disclosed by Wu for the purposes of treating Alzheimer’s disease because Wu teaches their composition promotes the proliferation of neural stem cells, and because Li teaches endogenous neural stem cells (NSCs) may play regenerative and reparative roles and be useful for treating neurodegenerative diseases such as Alzheimer’s disease. Accordingly, one of ordinary skill in the art would have recognized that compositions capable of promoting the proliferation of neural stem cells, such as the composition disclosed by Wu, may be useful for regenerative and reparative roles in neurodegenerative diseases such as Alzheimer’s disease.
Regarding the molar ratio of A) to B) of between 16:1 and 1.5:1, Wu teaches an embodiment with equal mass fractions of serine and cysteine (200 parts each), which provides a molar ratio of approximately 1:1.15 when accounting for their molecular weights. However, Wu further suggests ranges for each of these components, including a range of 200-600 parts for serine. Accordingly, one ordinary skill in the art would have considered other masses of serine and cysteine for this composition, including for example, a mass ratio of serine:cysteine of 600:200, which provides a molar ratio of approximately 2.6:1, because such a ratio falls within the mass amounts suggested by Wu.
Therefore the invention taken as a whole is prima facie obvious.
Claims 15, 16, 18, and 23-35 are rejected under 35 U.S.C. 103 as being unpatentable over Mardinoglu (Mardinoglu, A.; et al. Nutrients 2019, vol. 11, 1578; cited in IDS received January 23, 2023) in view of Jha (Jha, S. K.; et al. Biochimica et Biophysica Acta 2017, vol. 1863, pp. 1132-1146; cited in PTO-892) and Scandibio (Publication no. WO 2018117954; cited in PTO-892).
Mardinoglu teaches the potential use of metabolic cofactors in treatment of NAFLD (p. 1, title). Mardinoglu teaches the dosage and usage of metabolic cofactors including l-carnitine, nicotinamide riboside (NR), l-serine, and N-acetyl-l-cysteine (NAC) in human clinical studies to improve the altered biological functions associated with different human diseases (p. 1, Abstract, lines 8-11). Mardinoglu further discusses the potential use of these metabolic cofactors in treatment of NAFLD and other metabolic diseases, including neurodegenerative and cardiovascular diseases, in which pathogenesis is linked to mitochondrial dysfunction (p. 1, Abstract, lines 10-12).
Finally, Mardinoglu teaches or suggests a clinical trial involving supplementation of the metabolic cofactors serine, nicotinamide riboside, carnitine, and N-acetyl cysteine in patients that have Parkinson’s Disease and Alzheimer’s Disease (p. 6, Table 1, final entry).
Therefore, in view of Mardinoglu, one of ordinary skill in the art would have recognized that the metabolic cofactors serine, nicotinamide riboside, carnitine, and N-acetyl cysteine may be administered for treating NAFLD and other diseases linked to mitochondrial dysfunction, including neurodegenerative diseases.
Mardinoglu does not expressly teach administering serine, carnitine, and N-acetyl cysteine, and nicotinamide to a subject for the purposes of treating Alzheimer’s disease or Parkinson’s disease, as recited in independent claim 15. In addition, Mardinoglu does not teach administering serine, carnitine, and N-acetyl cysteine, and nicotinamide in the required dosages for the purposes of treating Alzheimer’s disease or Parkinson’s disease, as recited in independent claims 16 and 17.
Jha teaches that increasing evidence suggests a link between metabolic syndrome (MetS), such as diabetes, obesity, and non-alcoholic fatty liver disease, in the progression of Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases (NDDs) (p. 1132, Abstract, lines 1-3). Jha teaches that Aβ oligomer enhances neuronal Ca2+ release and neural NO where increased NO level in the brain through post translational modification modulates the level of insulin production. Jha also teaches that irrespective of origin, brain insulin resistance triggers a cascade of the neurodegeneration phenomenon which can be aggravated by free reactive oxygen species burden, ER stress, metabolic dysfunction, neuroinflammation, reduced cell survival and altered lipid metabolism. Moreover, several studies confirmed that MetS and diabetic sharing common mechanisms in the progression of AD and NDDs where mitochondrial dynamics play a critical role (p. 1132, Abstract, lines 3-9) (emphasis added).
In addition, Jha teaches that the linkup mechanism between mitochondrial dysfunction and disease phenomenon of both MetS and NDDs is quite intriguing, therefore, it is pertinent for the researchers to identify and implement therapeutic interventions for targeting MetS and NDDs (p. 1132, Abstract, lines 13-15).
Scandibio teaches a composition comprising components A)-D), wherein A) may be serine, B) is N-acetyl cysteine, cysteine and/ or cystine, C) may be carnitine, and D) may be nicotinamide (p. 47, claim 1). Scandibio further claims A) is serine (p. 47, claim 5), B) is N-acetyl cysteine (p. 47, claim 6), and C) is L-carnitine (p. 47, claim 7).
Scandibio claims the molar ratio of A) to B) is between 12:1 and 1.5:1, preferably between 10:1 and 3:1 (p. 47, claim 2), the molar ratio of A) to C) is preferably between 50:1 and 8:1, and more preferably between 30:1 and 13:1 (p. 47, claim 3), and the molar ratio of A) to D) is preferably between 90:1 and 10:1, and more preferably between 50:1 and 20:1 (p. 47, claim 4).
Scandibio claims the composition is used for a therapeutic model of treatment in a subject, and wherein the therapeutic method of treatment is a medical condition selected from the group consisting of non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), type 2 diabetes, obesity, insulin resistance and dyslipidemia (p. 48, claims 14-15).
Scandibio claims their therapeutic method comprises oral administration of: A) in a dose of 0.48-24 mmol/kg/day, such as 0.48-4.8 mmol/kg/ day, 1.8-4.8 mmol/kg/day, or 2.9-4.6 mmol/kg/day (p. 48, claim 16), B) in a dose of 0.31-3.05 mmol/kg/day, such as 0.31-1.84 mmol/kg/day or 0.43-1.23 mmol/kg/day; optionally C) in a dose of 0.031-1.24 mmol/kg/day, such as 0.031-0.620 mmol/kg/day; and D) in a dose of 0.020-0.39 mmol/kg/day, such as 0.039-0.31 mmol/kg/day, such as 0.059-0.24 mmol/kg/day (pp. 48-49, claim 16).
Scandibio claims the composition of claim 1 as a solid, such as a powder (p. 48, claim 12). Scandibio further teaches their composition is for use in a therapeutic method of treatment in a subject (p. 18, lines 7-10), and wherein said therapeutic method comprises oral administration of said composition (p. 18, claims 22-23).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to administer a composition comprising L-serine, N-acetyl cysteine, L-carnitine, and nicotinamide to a subject for the purposes of treating Alzheimer's disease or Parkinson's disease. One of ordinary skill in the art would have been motivated to administer a composition comprising L-serine, N-acetyl cysteine, L-carnitine, and nicotinamide to a subject for the purposes of treating Alzheimer's disease or Parkinson's disease because Mardinoglu teaches the combination of metabolic cofactors for treating NAFLD, suggests that this treatment may also be effective for treating neurodegenerative diseases because pathogenesis is linked to mitochondrial dysfunction, and because Jha specifically links Alzheimer’s disease to both mitochondrial dysfunction metabolic syndrome, which includes NAFLD, and suggests that given the mechanism between mitochondrial dysfunction and disease in both metabolic syndrome and neurodegenerative diseases, it would be pertinent to implement therapeutic interventions for targeting MetS and NDDs.
Regarding the selection of nicotinamide as component D), because Mardinoglu teaches both NR and nicotinamide as NAD+ precursor vitamins and Scandibio recites each of NR and nicotinamide as options for component D), one of ordinary skill in the art would have contemplated nicotinamide as component D), because each are precursors for NAD+ and recited as options for component D) in the invention of Scandibio.
Regarding the specific dosages recited in claims 16 and 28-35 and the ratios of components recited in claims 25-27, these dosages and concentrations are taught by Scandibio in the composition and method of their invention. Accordingly, because the method of treating Parkinson’s Disease and Alzheimer’s Disease using this method is obvious over Mardinoglu in view of Jha and Scandibio, one of ordinary skill in the art would have contemplated the dosages and compositions, including the molar ratios of components in the method of Scandibio, when applying this method for the purposes of treating Alzheimer's disease or Parkinson's disease in a patient.
MPEP 2144.05(I) states: In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). MPEP 2144.05(II) at A states: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). In this instance, because Scandibio discloses dose ranges that encompass or overlap with the claimed doses of A), B), C), and D), one of ordinary skill in the art would have identified the optimal dose for treating Alzheimer’s disease by routine experimentation.
Therefore the invention taken as a whole is prima facie obvious.
Regarding claims 17 and 36-38, these limitations are not obvious over Mardinoglu in view of Jha and Scandibio, because claim 17 requires dosages of components B) and C) of 12-100 mmol/kg/day, which is a considerably higher dose than suggested by any of Mardinoglu, Jha, and Scandibio. For example, N-acetylcysteine (MW of 169.19 g/mol) administered at a dose of 12 mmol/kg/day would correspond with a dose of approximately 2g/kg/day, and L-carnitine (161.2 g/mol) administered at a dose of 12 mmol/kg/day would correspond with a dose of approximately 1.9 g/kg/day.
Therefore, based on the prior art cited above, one of ordinary skill in the art would not have reasonably administered this does of B) and C) to a subject for the purposes of treating Alzheimer's disease or Parkinson's disease in a patient.
The examiner further notes that dependent claim 38 would appear to require a relatively small subject (i.e., 1.33-6.25 kg at a dose of 12 mmol/kg/day), and would require component A) administered at a dose of 16-75 mmol/kg/day (based on a dose of 100 mmol/day).
However, if claim 17 were intended to recite doses of 12-100 mmol/day for B) and C), then these claims would be included in the above rejection over Mardinoglu in view of Jha and Scandibio, with the doses taught by Scandibio administered to, for example, an adult human between 50 and 100 kg in weight.
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 15, 16, 18, and 23-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, 6-8, and 10-11 of U.S. Patent No. 11,141,396 (reference patent, hereinafter ‘396) in view of Mardinoglu (Mardinoglu, A.; et al. Nutrients 2019, vol. 11, 1578; cited in IDS received January 23, 2023), Jha (Jha, S. K.; et al. Biochimica et Biophysica Acta 2017, vol. 1863, pp. 1132-1146; cited in PTO-892) and Scandibio (Publication no. WO 2018117954; cited in PTO-892).
Both the present application and ‘396 are assigned to ScandiBio Therapeutics AB and include Adil Mardinoglu, Jan Borén, and Mathias Uhlén as inventors.
Claim 1 of ‘396 claims a composition comprising: A) serine; B) N-acetyl cysteine; C) L-carnitine; and D) nicotinamide riboside, and/or nicotinamide, wherein the molar ratio of A) to D) is between 50:1 and 3:1 and the molar ratio of A) to B) is between 16:1 and 1.5:1.
Claim 3 of ‘396 claims the composition is a solid, claim 4 of ‘396 claims the composition is a solid powder.
Claim 6 of ‘396 claims a method of treating a medical condition in a subject, comprising administering the composition of claim 1 to the subject. Claim 7 claims the composition is administered orally, claim 8 claims the method comprises oral administration of: A) in a dose of 0.48-24 mmol/kg/day; B) in a dose of 0.31-3.05 mmol/kg/day; C) in a dose of 0.031-1.24 mmol/kg/day; and D) in a dose of 0.020-0.39 mmol/kg/day, claim 10 claims A) is administered in a dose of 1.8-4.8 mmol/kg/day, and claim 11 claims D) is administered in a dose of 0.039-0.31 mmol/kg/day.
The claims of ‘396 do not claim a method of treating treatment of a subject suffering from Alzheimer's disease or Parkinson's disease by administering components A)-D) as recited in independent claims 15 and 16.
Mardinoglu, Jha, and Scandibio teach as described in the above rejection under 35 U.S.C. 103.
It would therefore have been prima facie obvious to practice the method claimed by ‘396 for the purposes of treating Alzheimer’s disease or Parkinson’s disease in a subject, because ‘396 claims a method of treating a medical condition by administering the composition of comprising A)-D) as required by independent claims 15 and 16, and because Mardinoglu and Jha render obvious the use of treatments for mitochondrial dysfunction for treating both metabolic diseases, such as NAFLD, and neurodegenerative diseases, such as Alzheimer’s disease, that involves administering the metabolic cofactors of A)-D) as claimed by ‘396. Accordingly, one of ordinary skill in the art would have contemplated practicing the method claimed by ‘396 for the purposes of treating a neurodegenerative disease such as Alzheimer’s disease.
Regarding the molar ratios of A) to B) and A) to D) recited in claims 25 and 27, these ratios are satisfied by the ratios required by claim 1 of ‘396. Regarding the molar ratios of A) to C) recited in claim 26, because claim 8 of ‘396 recites A) in a dose of 0.48-24 mmol/kg/day and C) in a dose of 0.031-1.24 mmol/kg/day, one would have contemplated doses of, for example, 0.48 mmol/kg/day of A) and 0.031 mmol/kg/day of C), which would be a molar ratio of 15:1, and would satisfy the requirements of claim 26.
Regarding the doses of A) and D) recited in claims 28-29 and 30-31, these doses are satisfied by claims 10 and 11 of ‘396. Regarding the broad range of doses of B) and C) recited in claims 32 and 34, these are satisfied by claim 8 of ‘396. Regarding the narrower range of doses of B) and C) recited in claims 33 and 35, because these fall within the ranges claimed by ‘396, one of ordinary skill in the art would have considered these doses when practicing the method claimed by ‘396 for the purposes of treating Alzheimer’s disease Parkinson’s disease in a subject. See MPEP 2144.05 at I: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976).”
Regarding claims 17 and 36-38, these limitations are not obvious over the claims of ‘396. Mardinoglu, Jha, and Scandibio, because claim 17 requires dosages of components B) and C) of 12-100 mmol/kg/day, which is a much higher dose than suggested by any of the claims of ‘396, Mardinoglu, Jha, and Scandibio. For example, N-acetylcysteine (MW of 169.19 g/mol) administered at a dose of 12 mmol/kg/day would correspond with a dose of approximately 2g/kg/day, and L-carnitine (161.2 g/mol) administered at a dose of 12 mmol/kg/day would correspond with a dose of approximately 1.9 g/kg/day. Therefore, based on the prior art cited above, one of ordinary skill in the art would not have reasonably administered these doses of B) and C) to a subject for the purposes of treating Alzheimer's disease or Parkinson's disease in a patient.
However, if claim 17 were intended to recite doses of 12-100 mmol/day for B) and C), then these claims would be included in the above rejection as unpatentable over the claims of ‘396 in view of Mardinoglu, Jha, and Scandibio, because such limitations would be met by administering the composition in suggested doses to an adult weighing, for example, 50-100 kg.
Claims 15, 16, 18, and 23-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-5, 7-13, and 18-19 of U.S. Patent No. 11,813,236 (reference patent, hereinafter ‘236) in view of Mardinoglu (Mardinoglu, A.; et al. Nutrients 2019, vol. 11, 1578; cited in IDS received January 23, 2023), Jha (Jha, S. K.; et al. Biochimica et Biophysica Acta 2017, vol. 1863, pp. 1132-1146; cited in PTO-892) and Scandibio (Publication no. WO 2018117954; cited in PTO-892).
Both the present application and ‘396 are assigned to ScandiBio Therapeutics AB and include Adil Mardinoglu, Jan Borén, and Mathias Uhlén as inventors.
Claim 1 of ‘236 claims a composition comprising: A) serine, betaine, and/or glycine; B) N-acetyl cysteine and/or cysteine; C) L-carnitine; and D) nicotinamide riboside, and/or nicotinamide, wherein the molar ratio of A) to D) is between 50:1 and 3:1 and the molar ratio of A) to B) is between 16:1 and 1.5:1.
Claim 4 of ‘236 claims the composition is a solid, and claim 5 claims the composition is a solid powder.
Claim 7 of ‘236 claims a method of treating a medical condition in a subject, comprising administering the composition of claim 1 to the subject. Claim 8 claims the composition is administered orally, and claim 9 claims the method comprises oral administration of: A) in a dose of 0.48-24 mmol/kg/day; B) in a dose of 0.31-3.05 mmol/kg/day; C) in a dose of 0.031-1.24 mmol/kg/day; and D) in a dose of 0.020-0.39 mmol/kg/day when D) is nicotinamide riboside and 0.0196-1.96 mmol/kg/day when D) is nicotinamide. Claim 10 of ‘236 claims A) is administered in a dose of 0.48-4.8 mmol/kg/day, claim 11 of ‘236 claims A) is administered in a dose of 1.8-4.8 mmol/kg/day, and claim 12 claims D) is administered in a dose of 0.039-0.31 mmol/kg/day.
Claim 13 of ‘236 claims the medical condition is selected from the group consisting of non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), type 2 diabetes, obesity, insulin resistance, and dyslipidemia.
Claim 18 of ‘234 depends from claim 1 and requires the composition comprises: A) serine; B) N-acetyl cysteine; C) L-carnitine; and D) nicotinamide.
Claim 19 of ‘234 depends from claim 1 and requires the composition comprises:
A) serine; B) cysteine; C) L-carnitine; and D) nicotinamide.
The claims of ‘236 do not claim a method of treating treatment of a subject suffering from Alzheimer's disease or Parkinson's disease by administering components A)-D) as recited in independent claims 15 and 16.
Mardinoglu, Jha, and Scandibio teach as described in the above rejection under 35 U.S.C. 103.
It would therefore have been prima facie obvious to practice the method claimed by ‘236 for the purposes of treating Alzheimer’s disease or Parkinson’s disease in a subject, because ‘236 claims a method of treating NAFLD by administering the composition of comprising A)-D) as required by independent claims 15 and 16, and because Mardinoglu and Jha render obvious the use of treatments for mitochondrial dysfunction for treating both metabolic diseases such as NAFLD and neurodegenerative diseases such as Alzheimer’s disease, one of ordinary skill in the art would have contemplated practicing the method of treating NAFLD disclosed by ‘236 for the purposes of treating a neurodegenerative disease such as Alzheimer’s disease.
Regarding the molar ratios of A) to B) and A) to D) recited in claims 25 and 27, these ratios are satisfied by the ratios required by claim 1 of ‘236. Regarding the molar ratios of A) to C) recited in claim 26, because claim 9 of ‘236 recites A) in a dose of 0.48-24 mmol/kg/day and C) in a dose of 0.031-1.24 mmol/kg/day, one would have contemplated dosages of, for example, 0.48 mmol/kg/day of A) and 0.031 mmol/kg/day of C), which would be a molar ratio of 15:1, and would satisfy the requirements of claim 26.
Regarding the doses of A) and D) recited in claims 28-29 and 30-31, these doses are satisfied by claims 11 and 12 of ‘236. Regarding the broader range of doses of B) and C) recited in claims 32 and 34, these are satisfied by claim 9 of ‘236. Regarding the narrower range of doses of B) and C) recited in claims 33 and 35, because these ranges fall within the ranges claimed by ‘396, one of ordinary skill in the art would have considered these doses when practicing the method claimed by ‘236 for the purposes of treating Alzheimer’s disease of Parkinson’s disease in a subject. See MPEP 2144.05 at I.
Regarding claims 17 and 36-38, these limitations are not obvious over the claims of ‘236, Mardinoglu, Jha, and Scandibio, because claim 17 requires doses of components B) and C) of 12-100 mmol/kg/day, which is a much higher dose than suggested by any of the claims of ‘236, Mardinoglu, Jha, and Scandibio. For example, N-acetylcysteine (MW of 169.19 g/mol) administered at a dose of 12 mmol/kg/day would correspond with a dose of approximately 2g/kg/day, and L-carnitine (161.2 g/mol) administered at a dose of 12 mmol/kg/day would correspond with a dose of approximately 1.9 g/kg/day. Therefore, based on the prior art cited above, one of ordinary skill in the art would not have reasonably administered these doses of B) and C) to a subject for the purposes of treating Alzheimer's disease or Parkinson's disease in a patient.
However, if claim 17 were intended to recite doses of 12-100 mmol/day for B) and C), then these claims would be included in the above rejection as unpatentable over the claims of ‘396 in view of Mardinoglu, Jha, and Scandibio, because such limitations would be met by administering the composition in suggested doses to an adult weighing, for example, 50-100 kg.
Claims 15, 16, 18, and 23-35 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16 and 18-27 of copending U.S. Patent application 18/252843 (reference patent, hereinafter ‘843) in view of Nam (Nam, G. E.; et al. Movement Disorders 2019, vol. 34, pp. 1184-1191; cited in PTO-892) and Scandibio (Publication no. WO 2018117954; cited in PTO-892).
Both the present application and ‘843 are assigned to ScandiBio Therapeutics AB and include Adil Mardinoglu, Jan Borén, and Mathias Uhlén as inventors.
The amended claims for ‘843 received May 12, 2023 are cited in this provisional nonstatutory double patenting rejection.
Claim 16 of ‘843 claims a method of treating or preventing hyperuricaemia, gout and/or renal impairment in a subject, comprising administering components A)-D).
Claim 18 of ‘843 claims A), B), C) and D) are contained in a composition that is administered to the subject.
Claim 19 of ‘843 requires the molar ratio of A) to B) is between 20:1 and 1:4, claim 20 requires the molar ratio of A) to C) is between 100:1 and 2:1, and claim 21 requires the molar ratio of A) to D) is between 150:1 and 3:1.
Claim 22 of ‘843 requires A) is serine, glycine or betaine, claim 23 requires B) is N-acetyl cysteine or cysteine, claim 24 requires C) is carnitine, and claim 25 requires D) is nicotinamide riboside or nicotinamide.
Claim 26 of ‘843 claims orally administering the substances.
Claim 27 of ‘843 claims the method comprises administering: A) in a dose of 0.48-24 mmol/kg/day; B) in a dose of 0.31-3.05 mmol/kg/day; C) in a dose of 0.100-2.50 mmol/kg/day; and D) in a dose of 0.015-0.39 mmol/kg/day.
Claim 35 of ‘843 depends from claim 27 and claims the method comprises administering: A) in a dose of 1.8-4.8 mmol/kg/day; B) in a dose of 0.40-1.23 mmol/kg/day; C) in a dose of 0.230-1.00 mmol/kg/day; and D) in a dose of 0.040-0.20 mmol/kg/day.
The claims of ‘843 do not claim a method of treating Alzheimer’s disease or Parkinson’s disease, as recited in independent claims 15 and 16.
Nam teaches that chronic kidney disease (CKD) is known to be more prevalent in the older population, and this age group may be more vulnerable to metabolic and hormonal disturbances related to renal dysfunction. In addition, Nam teaches that urinary protein is a strong marker for impaired kidney function and renal damage, and that although CKD and proteinuria are well known to be related to cardiovascular risk, they have been indicated to also be associated with non-cardiovascular complications, cognitive dysfunction, and poor physical functioning in older adults (p. 1185, left column, second paragraph, lines 1-10)
Nam teaches a study in which approximately 3.5 million individuals greater than 65 years of age who had undergone health checkups between 2009 and 2012 were followed until 2015 (p. 1184, Abstract, Methods section, lines 1-6). Nam teaches that during follow up health checkups, approximately 30,000 individuals developed Parkinson’s disease. Nam teaches that lower estimated glomerular filtration rate and a higher degree of proteinuria on a dipstick test were associated with higher incidence probability of PD, wherein chronic renal dysfunction graded by estimated glomerular filtration rate (mL/min/1.73 m2) was associated with increased risk of PD after adjusting for potential confounding variables (p. 1184, Abstract, Results section, lines 1-10).
Nam concludes that chronic renal dysfunction may be an independent risk factor for the development of Parkinson’s disease (p. 1184, Abstract, Conclusion section, lines 1-4).
Scandibio teaches as described in the above rejection under 35 U.S.C. 103.
It would therefore have been prima facie obvious to practice the method claimed by ‘843 for the purposes of treating Parkinson’s disease in a subject because ‘843 claims a method of treating renal impairment by administering the composition of comprising A)-D) as required by independent claims 15 and 16, and because Nam teaches that impaired renal function, such as that associated with chronic kidney disease, is associated with the onset of Parkinson’s disease. Accordingly, one of ordinary skill in the art would have recognized that a method for treating renal impairment may reasonably treat symptoms associated with Parkinson’s disease in subjects with renal impairment and Parkinson’s disease.
Regarding the selection of serine as A) and nicotinamide as D), because these are claimed by ‘843 as options for components A) and D), one of ordinary skill in the art would have considered them when practicing the method claimed by ‘843.
Regarding the molar ratios of A) to B), A) to C), and A) to D) recited in claims 25-27, these ratios are obvious over the ratios of claims 19-21 of ‘843, because the claims of ‘843 claim ranges of molar ratios that encompass or overlap the presently claimed molar ratios. See MPEP 2144.05 at I.
Regarding the doses of A), B), C), and D) recited in claims 28-35, these doses are satisfied by the doses required by claim 35 of ‘843.
Regarding the powderous mixture of claim 24, because Scandibio teaches a composition comprising the same components may be formulated as a powder, one of ordinary skill in the art would have considered a powder formulation of the composition claimed in the method of ‘843.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not been patented.
Regarding claims 17 and 36-38, these limitations are not obvious over the claims of ‘843, Nam, and Scandibio, because claim 17 requires doses of components B) and C) of 12-100 mmol/kg/day, which is a much higher dose than suggested by any of the claims of ‘843, Nam, and Scandibio. For example, N-acetylcysteine (MW of 169.19 g/mol) administered at a dose of 12 mmol/kg/day would correspond with a dose of approximately 2g/kg/day, and L-carnitine (161.2 g/mol) administered at a dose of 12 mmol/kg/day would correspond with a dose of approximately 1.9 g/kg/day. Therefore, based on the prior art cited above, one of ordinary skill in the art would not have reasonably administered these doses of B) and C) to a subject for the purposes of treating Alzheimer's disease or Parkinson's disease in a patient.
However, if claim 17 were intended to recite doses of 12-100 mmol/day for B) and C), then these claims would be included in the above rejection as unpatentable over the claims of ‘843 in view of Nam, and Scandibio, because such limitations would be satisfied by claims 28 and 36 of ‘843.
Allowable Subject Matter
Claims 17 and 36-38 are allowed.
Independent claim 17 claims a method of treating of a subject suffering from
Alzheimer's disease or Parkinson's disease comprising administering administration to a subject in need thereof of: A) serine in a dose of 100-600 mmol/day; B) N-acetyl cysteine, cysteine and/or cystine in a dose of 12-100 mmol/kg/day; C) carnitine in a dose of 12-100 mmol/kg/day; and D) nicotinamide in a dose of 3-20 mmol/day.
As stated above, these doses of B) and C) are considerably higher than the doses of B) and C) suggested by the prior art. The closest prior art to claim 17 is considered Scandibio (Publication no. WO 2018117954; cited in PTO-892), who suggests the same B) and C) administered in a dose of 0.31-3.05 mmol/kg/day and in a dose of 0.031-1.24 mmol/kg/day (pp. 48-49, claim 16). Scandibio does not teach or motivate increasing the suggested dose by at least 4-fold for B) and at least 10-fold for C).
In addition, Gut (Publication no. WO 2020/064946 A2; cited in IDS received January 23, 2023) teaches administration of N-acetylcysteine in a range of 6-6000 mg/day for a 60 kg subject (p. 21, [0101]) for treating conditions associated with oxidative stress (cover page, Abstract, lines 102). A 6000 kg dose of N-acetylcysteine (with molecular weight of 163.19 g/mol) would correspond with a dose of 36.8 mmols, or 0.61 mmol/kg/day. Gut does not provide motivation to increase the dose of NAC approximately 20-fold as required by claim 17.
Moreover, Mardinoglu teaches recommended daily doses of carnitine is 1 to 3 g, with higher doses (e.g., 6 g/day) used in some instances (p. 9, Section 2.1.1). A 3 g/day dose of carnitine (with molecular weight of 161.2 g/mol) would be a dose of 18.6 mmol. Assuming this dose were administered to an adult human (e.g., a 50 kg human), as taught by the clinical trials cited by Mardinoglu (p. 5, Table 1), it would be a dose of well under 1 mmol/kg/day, and Mardinoglu does not provide to increase this dose to at least 12 mmol/kg/day, as required by claim 17.
Accordingly, claims 17 and 36-38 would require doses of components B) and C) well outside of the ranges taught by the prior art, such that one of ordinary skill in the art would not reasonably consider said doses in view of the prior art described above.
Conclusion
Claims 15-16, 18, and 23-35 are rejected.
Claims 17 and 36-38 are allowed.
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/B.M.B./Examiner, Art Unit 1693
/ANDREA OLSON/Primary Examiner, Art Unit 1693