Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
The office acknowledges Applicants’ filing of the amended claims dated 10/11/2023. Claims 3, 6, 8, 10, 12, 17, 19, 23-24, and 26-28 have been amended. Claims 2, 4-5, 7, 9, 16, 18, 25, and 29 have been cancelled. Claims 1, 3, 6, 8, 10-15, 17, 19-24, 26-28 are pending and are examined based on the merits herein.
Application Priority
This application filed 10/11/2023 is a Continuation of PCT/IL2022/050392, filed 04/13/2022, PCT/IL2022/050392 Claims Priority from Provisional Application 63174180, filed 04/13/2021.
Information Disclosure Statement
The information disclosure statement(s) (IDS) filed on 1/3/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS is being considered by the Examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 3, 8, 10, 21, 24, 28 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
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Claim 3 includes limitations of ‘caused by a bacterial or viral infection of said lung’; caused by an influenza infection of said lung; ‘caused by an influenza H1N1, H3N2 or H5N1 infection of said lung’. It is noted that influenza is a type of viral infection and H1N1, H3N2 or H5N1 are subtypes of influenza.
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Appropriate correction is required.
Claim 8 recites the limitation of ‘wherein said bacterial or viral infection produces pneumonia in said lung, is not a coronavirus infection or both’. It is clear that the infection is not a coronavirus infection however it is not clear what ‘or both’ means. Is it not two viral or bacterial or viral and bacterial infections together? Clarification is required. For examination purposes the claim has been examined based on the interpretation that bacterial or viral infection produces pneumonia in said lung.
Claim 10 recites the limitation of ‘wherein said disease is selected’ in lines 1-2. However claim 1 is to treating lipotoxicity and not to any disease. In other words no other disease is treated other than lipotoxicity in claim 1. There is insufficient antecedent basis for this limitation in the claim.
Claim 21 is to ‘PPARA agonist selected from a fibrate, pirinxic acid and conjugated linoleic acid and derivatives thereof’.
The term "derivative" is a relative term which renders the claims indefinite. In particular, "derivative" does not particularly point out the degree or type of derivation that a given compound may have in relation to the parent compound and still be considered a "derivative". According to Hackh's chemical dictionary, "derivative" is defined as a compound, usually organic obtained from another compound by a simple chemical process or an organic compound containing a structural radical similar to that from which it is derived (Hackh's chemical dictionary, 1972). The term ‘derivative’ includes salts, isomers, analogs, metabolites, prodrugs, crystals, polymorphs, solvates, hydrates etc. The claim does not set forth any metes and bounds for the terms and presents uncertainty with respect to the scope of the claims.
The primary purpose of this requirement of definiteness of claim language is to ensure that the scope of the claims is clear so the public is informed of the boundaries of what constitutes infringement of the patent. A secondary purpose is to provide a clear measure of what applicants regard as the invention so that it can be determined whether the claimed invention meets all the criteria for patentability and whether the specification meets the criteria of 35 U.S.C. 112, first paragraph with respect to the claimed invention.", (see MPEP § 2173).
Claim 24 is directed to ‘The method of claim 23, wherein said fibrate is fenofibrate or is not gemfibrozil’. It is not clear what ‘or is not gemfibrozil’. Is it the fibrate limited to fenofibrate? Clarification is required. For the sake of compact prosecution the claim has been examined based on that the fibrate is limited to fenofibrate and not gemfibrozil.
Claim 28 recites a limitation of ‘reduced symptoms’. It not clear what symptoms are reduced? The claim recites limitations reduced inflammation, reduced viral load etc. Is it symptoms other than these are reduced? In such case, the claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 6, 8, 10-15, 17, 19-20, 26-28 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 MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated:
"To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir.1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966." Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents" of the University of California v. Eli Lilly & Co. the court stated:
"A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus ...") Regents of the University of Califorrnia v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP states that for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618.
The Guidelines for Examination of Patent Applications Under 35 USC 112, "Written Description" Requirement (Federal Register, Vol. 66, No. 4, pg. ll05, column 3), in accordance with MPEP § 2163, specifically state that for each claim drawn to a genus the written description requirement may be satisfied through sufficient description of a representative number of species by a) actual reduction to practice; b) reduction to drawings or structural chemical formulas; c) disclosure of relevant, identifying characteristics (i.e. structure) by functional characteristics coupled with a known or disclosed correlation between function and structure. The analysis of whether the specification complies with the written description requirement calls for the examiner to compare the scope of the claim with the scope of the description to determine whether applicant has demonstrated possession of the claimed invention (Federal Register, Vol. 66, No. 4, p. ll05, 3rd column, 3rd paragraph). Below is such comparison.
Scope of claims: The scope is very broad in regards to the metabolic regulatory drug and its combinations for use in lipotoxicity.
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Scope of disclosure and reduction to practice:
As per the specification [004],
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As per instant claim 2, lipotoxicity in a lung is at least one of: (a) characterized by a reduction in carnitine palmitoyltransferase 1 A (CPTl1A) in lung tissue from said subject; b. caused by a bacterial or viral infection of said lung; c. caused by an influenza infection of said lung; d. caused by an influenza H1N1, H3N2 or H5N1 infection of said lung.
The specification in pages 4-6, examples 1-4 (p 32-34) and figures has support for PPARa activity inhibited by three strains of the influenza virus (H1N1, H3N2 and H5N1), microscopic analysis of lipid accumulation in lung cells induced by 10 pM of PPARy agonist rosiglitazone and 100 pM oleic acid with or without 20 pM fenofibrate.
The instant specification provides a select list of metabolic drugs, total of 33 selected from glycolysis inhibitors, PPARA agonists, AMPK activators and statins and its dose amount [096], Table 1. However the metabolic regulatory drug is not limited to the ones listed. There are hundreds of glycolysis inhibitors, PPARA agonists, AMPK activators and statins in addition to the list of other metabolic regulatory drugs.
The instant specification teach that according to some embodiments, the metabolic regulatory drug is a PPAR agonist [0027]. In some embodiments, the metabolic disease is a metabolic disease treatable by a metabolic regulatory drug. In some embodiments, the metabolic disease is a metabolic disease treatable by PPARA agonists [070].
Lin teach that peroxisome proliferator-activated receptor a (PPARa) is a ligand-activated transcription factor that is involved in lipid metabolism of various tissues. Different metabolites of fatty acids and agonists like fibrates activate PPARa for its transactivate or repressive function. PPARa is known to affect diverse human diseases. Some PPARa-specific agonists, such as Wy14643 and fenofibrate, have been applied in metabolic syndrome treatment, which might own potential in wider application. (Abstract). Several chemical agonists have also been developed, at least 30 kinds of PPARa agonists or antagonists according to MCE (https://www.medchem express.cn/). Fibrates, including gemfibrozil, fenofibrate, and ciprofibrate, are clinically used in the treatment of primary hypertriglyceridemia. However, it is noted that fibrates are weak PPARa agonists and their selectivity should be concerned, especially fibrates which might also activate PPARƔ and δ and even other proteins like NRF2. In some studies, fenofibrate is found to interact with over 80 proteins. Moreover, the potency of synthetic PPARa agonists may differ between human and mouse receptors, such as EC50 = 18,000 nM of fenofibrate in mouse but 30,000 in human (46). Wy14643 is another typical agonist of PPARa reversing insulin resistance and hepatic steatosis and it also has the disadvantage of fibrates (See p 03, col. 2, last para bridging p 4, col. 1, para 1), (Frontiers in Endocrinology, 2022, p 1-13).
PPARα Natural and Synthetic Ligands and Their Physiological Roles is provided in Table 4 of Bougarne et al. (Endocrine Reviews, Volume 39, Issue 5, October 2018, Pages 760–802). The reference in detail discuss the molecular actions of PPARα in lipid metabolism and inflammation. The first-generation PPARα agonists, the fibrates, have however been hampered by drug–drug interaction issues (Abstract).
Rubenstrunk teach that because of their wide range of actions on glucose homeostasis, lipid metabolism and vascular inflammation, peroxisome proliferator-activated receptors (PPARs) are promising targets for the development of new drugs for the treatment of metabolic disorders such as diabetes, dyslipidemia and atherosclerosis. In clinical practice, PPARα agonists, such as the already available fibrates, improve dyslipidemia, while PPARγ agonists, such as thiazolidinediones, improve insulin resistance and diabetes. However, despite the proven benefits of targeting PPARs, safety concerns have recently led to late stage development failures of various PPAR agonists including novel specific PPARγ agonists and dual PPARα/γ agonists. These safety concerns include potential carcinogenicity in rodents, signs of myopathy and rhabdomyolysis, increase in plasma creatinine and homocysteine, weight gain, fluid retention, peripheral edema and potential increased risk of cardiac failure. Although the discontinued compounds shared common side effects, the reason for discontinuation was always compound specific and the toxicological or adverse effects
which have motivated the discontinuation could be either due to the activation of PPARγ, PPARα or both (class effect) or due to a PPAR unrelated effect. Thus, the risk evaluation of each adverse effect should be viewed on a case by case basis considering both the PPAR profile of the drug, its absorption/distribution profile, the nature of the side effect and the putative PPAR-related mechanism of action (See Abstract). The reference also lists chemical structures of few PPAR-α ligands in page 1067 (Biochimica et Biophysica Acta 1771 (2007) 1065–1081).
In summary, the scope of the metabolic regulatory drugs to be used in the method is very large. Further claim 1 recites the limitation of ‘therapeutic composition comprising at least one metabolic regulatory drug’. Hence it can be a combination of multiple metabolic regulatory drugs in the composition that can be administered.
Representative number of Examples:
The data provided is limited to one specific metabolic drug fenofibrate and its effects in regards to lipid accumulation in lung. Also provided is a select list of metabolic regulatory drugs. A combination of metabolic regulatory drug composition has not been formulated or administered in the method as claimed.
The structure is the metabolic drug and the function is the treatment of lipotoxicity in a lung of subject in need thereof. The term ‘metabolic regulatory drug’ encompasses hundred of compounds, e.g. MAPK inhibitors, Glycolysis inhibitors, PPARα agonists, statins among few. It is not understood what specific structures of the metabolic drugs will lead to treating lipotoxicity in lung as claimed. The chemical, physical and pharmacological properties of the compounds is influenced based on the structural differences. A correlation between structure and function in achieving the property of wherein administration of the therapeutic composition of metabolic regulatory drug results in the treatment of lipotoxicity in lung. Even with few select PPARα agonists listed in instant claim 23, the chemical structures vary (See p 1067 of Rubenstrunk, Biochimica et Biophysica Acta 1771 (2007) 1065–1081).
There is substantial variation within the genus of metabolic drugs and one must describe a sufficient variety of species to reflect the variation within the genus. In some studies, fenofibrate is found to interact with over 80 proteins (See Lin above). Adverse effects are associated with metabolic regulatory drugs as taught by the prior art (see above) and further the instant method claims treating lipotoxicity arising from various bacterial, viral infections of the lung. Claim 1 recites the limitation of ‘therapeutic composition comprising at least one metabolic regulatory drug’. Hence it can be a combination of multiple metabolic regulatory drugs in the composition that can be administered. One skilled in the artisan cannot predict the interactions arising between the combinations and with the receptors they act on (for e.g. PPARα).
Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, "the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved". See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Due to the unpredictable nature of the effects of the large number of metabolic drugs and further in combination to treat lipotoxicity, one of ordinary skill in the art cannot predict from the data provided in the specification for one active agent, fenofibrate or from the prior art that a therapeutic composition comprising at least one of the all the hundreds of possible metabolic regulatory drugs will treat lipotoxicity.
Ehrlich teach that in contrast to fenofibrate which reduced the SARS-Cov2 viral load, another PPARα agonist, rosiglitazone didn’t affect the metabolic pathway or viral load, possibly due to the already active state of PPARα (IDS: Cell Press, July 2020, p 1-27). This clearly demonstrates the unpredictability and the variability in the pharmacological and biological effects of well-known PPARα agonists.
A skilled artisan would not be able to extrapolate from the data provided for fenofibrate to all metabolic regulatory drug compositions or the combination composition of the drugs as in the instant method for treating lipotoxicity.
Applicants have failed to provide guidance or data or evidence as to how the skilled artisan would be able to extrapolate from the disclosure species to make and possibly use of the claimed invention. “A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F 3d at 923; Eli Lilly, 119 at 1568. Instead, the “disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described.”
The specification provides insufficient written description to support the genus encompassed by the claim, Vas-Cath Inc. Mahurkar, 19 USPQ2d 1111, makes clear the "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521,222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.").
Thus, the specification fails to provide adequate written description for the use of the therapeutic composition in treating lipotoxicity as claimed and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
Claim Objections
Claim 26 is objected to because of the following informalities: claim 26 recites a limitation of ‘wherein said administering is oral or intravenous administering’. The term administering is recited twice. It is suggested the claim be amended to ‘wherein said administering is oral or intravenous’. Appropriate correction is required.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 3, 10-12, 17, 19-21, 23-24, 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (IDS: CN 103705498 A).
Chen teach the use of fenofibrate in influenza infection (Abstract, claims). Chen demonstrates the anti-influenza virus activity of fenofibrate in MDCK cells with virus strain A/PuertoRico/8/34 (H1N1), A/Human/Hubei/1/2009 (HlNl) and B/human/Hubei/ 1/2007 (See [0019]-[0032], see also Figures 1-4). Chen further teach that fenofibrate administered early infection stage is capable of inhibiting influenza virus replication demonstrating its antiviral effects (See [0032]). Chen teach that the drug fenofibrate as medicine active component can be formulated as a pharmaceutically acceptable preparation, for example tablet, capsule, granule, oral liquid, injection etc. (See claims 1-4). The result shows that fenofibrate remarkably inhibit influenza virus replication, and dose-dependent relationship (see FIG. 3).
From Chen a person skilled in the art before the effective filing date of the invention would have found it obvious to administer fenofibrate to treat influenza infection in a subject in need thereof (e.g. subject with H1N1 viral infection). Thus administration of the same active agent, fenofibrate (metabolic regulatory drug) to a subject with influenza viral infection (H1N1) would result in the treatment of lipotoxicity because one of the causes of lipotoxicity is lung infection by H1N1. Lipotoxicity results from accumulation of phospholipid molecules and lipid intermediates in non-adipose tissue, e.g. epithelial or endothelial cells. A person skilled in the art would have been motivated to treat lipotoxicity in lung with a reasonable expectation of success and in treating the influenza in subjects. Thus claims 1, 3, 10-11 are obvious over Chen. Claims 19-21, 23-24 are addressed by Chen’s teaching of fenofibrate in treating influenza.
As to claim 12, a skilled artisan (e.g. physician) would have tested or confirmed that the subject has lipotoxicity, for e.g. because of viral influenza, by checking the symptoms or with a PCR test before the metabolic regulatory drug is administered.
In regards to claim 17, Chen teaches treating influenza in a subject. The subject population includes not currently or not previously treated with fenofibrate or suffer from metabolic disease or disorder treatable by fenofibrate.
Claim 26 is addressed by Chen’s teaching of oral administration, e.g. tablets.
As to claim 27, Chen’s data shows that fenofibrate remarkably inhibit influenza virus replication, and dose-dependent relationship (see Fig. 3). It within the skill of an artisan to administer the dosage amount based on the condition to be treated, symptoms, age etc. and it is routinely optimized.
As to claim 28, administration of fenofibrate to subjects with influenza will result in reduced viral load.
Claim(s) 8 is rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (IDS: CN 103705498 A) in view of An et al. (Medical Hypothesis, 77, 2011, 1054-57).
Chen teachings as above. The rejections are incorporated herein.
Chen is not explicit in teaching that H1N1 viral infection produces pneumonia.
An is explicit in teaching that H1N1 virus infection is associated with severe viral pneumonia, acute respiratory distress, syndrome (ARDS), renal failure and even shock (See p 1054, col. 1, Background).
Hence it would have been obvious to a person of ordinary skill in the art before the effective filing date of the invention from An’s teachings that H1N1 is associated with severe viral pneumonia. It would have been obvious to a skilled artisan from An’s teaching that the viral infection produces pneumonia in lung is from H1N1 and not from coronavirus infection. Thus claim 8 is obvious over the teachings of the prior art.
Claim(s) 22 is rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (IDS: CN 103705498 A) as applied to claims 1, 3, 10-12, 17, 19-21, 23-24, 26-28 above and in view of William et al. (KR 100773158, 2007, See English translation).
Chen’s teachings as discussed above. The above rejection is incorporated herein.
The reference is not explicit in teaching the CLA in the method as claimed.
William is explicit in teaching the food supplement comprising CLA (e.g. CLA-9) or its derivatives and its use in treating infections, e.g. influenza in humans and animals (see abstract, page 3, para 4, claims 1, 12-13, 15, 18-19).
From William a skilled artisan before the effective filing date of the invention would have found it obvious to use the conjugated linoleic acid food supplement, e.g. 9-CLA for treating influenza in humans and thus treat lipotoxicity caused by it. A skilled artisan would have been motivated to use 9-CLA in Chen’s method as an alternative to fenofibrate or in combination with fenofibrate to treat the influenza infection and attain synergistic effects. Thus claim 22 is addressed.
Claim(s) 1, 3, 17, 19-21, 23-24, 27-28 are rejected under 35 U.S.C. 103 as being unpatentable over Ehrlich (IDS: https://europepmc.org/article/ppr/ppr245172, 2020).
Ehrlich teach SARS-CoV-2 induced metabolic changes in lung cells could offer insight into COVID-19 pathogenesis. It is taught that the transcriptional response SARS-CoV-2 in primary lung epithelial cells and biopsies of COVID-19 patients is predominantly metabolic. This transcriptional signature was dominated by changes to lipid metabolism and the induction of IRE1 and PKR pathways of endoplasmic stress in a process regulated by several viral proteins. The upregulation of fatty acid and cholesterol synthesis showed a more complex control conditionally modulated by ER-stress activated PPARy, C/EBP, and PPARα (see Abstract). PPARα-agonist fenofibrate reversed the metabolic changes induced by SARS-CoV-2 blocking viral replication; the data suggest that elevated lipid metabolism may underlie aspects of COVID-19 pathogenesis (See Abstract). SARS-CoV-2 infection up-regulates lipogenesis (See p 3, para 3, Fig. 2D). PPARα agonist fenofibrate (Tricor®) blocked phospholipid accumulation (p<0.001) and as well as the increase in glycolysis (Fig. 4D-E). A 5-day treatment with fenofibrate reduced viral load by 2-logs (p<0.001) without affecting cell viability (Fig. 4F, Supplement Fig. S3). These results suggest that lipid metabolism is an important pathway for SARS-CoV-2 replication and a promising therapeutic target (See p 4, para 2).
A skilled artisan before the effective filing date of the invention would have found it obvious to arrive at the claimed method because Ehrlich is explicit in teaching that PPARα-agonist fenofibrate reversed the metabolic changes induced by SARS-CoV-2 blocking viral replication; the data suggest that elevated lipid metabolism may underlie aspects of COVID-19 pathogenesis. A skilled artisan would have been motivated administer a fibrate, e.g. fenofibrate in a subject with SARS-CoV-2 with a reasonable expectation of success. Thus administration of the same active agent, fenofibrate (metabolic regulatory drug) to a subject with SARS-CoV-2 would result in the treatment of lipotoxicity because one of the causes of lipotoxicity is lung infection by H1N1. Thus claims 1, 3, 19-21, 23-24 would have been obvious over the prior art teachings. In regards to claim 17, Ehrlich do not teach a specific population to be treated. Hence it is within the skill of an artisan to select specific subject population includes not currently or not previously treated with fenofibrate or suffer from metabolic disease or disorder treatable by fenofibrate.
As to claim 27, Ehrlich data shows that fenofibrate remarkably inhibit SARS-CoV-2 virus replication (see Fig. S3). It within the skill of an artisan to administer the dosage amount based on the condition to be treated, symptoms, age etc. and it is routinely optimized.
As to claim 28, administration of fenofibrate to subjects with SARS-CoV-2 will result in reduced viral load as Ehrlich show the reduction in the viral load in in vitro.
Claim(s) 1, 3, 6, 8, 10-14, 17, 19-21, 23-24, 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over An et al. (Medical Hypothesis, 77, 2011, 1054-57).
An teach in combination the effects of fibrates, statins and neuraminidase inhibitors in the survival of patients with lethal avian influenza pandemic (See Abstract, title). The survival rates for infected mice treated with oseltamivir simvastatin and fenofibrate (150 mg/kg) in a model infected by influenza A (H5N1) virus is taught (See Fig. 2). An is explicit in teaching that H1N1 virus infection is associated with severe viral pneumonia, acute respiratory distress, syndrome (ARDS), renal failure and even shock (See p 1054, col. 1, Background).
An teach that fibrates are agonists for peroxisome proliferator-activated receptor a (PPAR-α) which is one of ligand-activated transcription factors pertaining to the nuclear receptor superfamily. In an experimental model of LPS-induced airway inflammation, pretreatment with the PPAR-a agonist exhibited significantly anti-inflammatory effects such as the decreasing of airway inflammatory cell infiltrate, the production of cytokine/chemokine, and the downregulation of matrix metalloproteinase (MMP) activity in BALF (See p 1055, col. 2, para 3). Both PPARa and PPARc agonists can inhibit several intracellular signaling pathways including mitogen-activated protein kinases (MAPKs) such as p38-MAPK and Jun-N-terminal kinases (JNKs) [28,29], which appear to be crucial for influenza virus replication.
A skilled artisan before the effective filing date of the invention would have found it obvious to arrive at the claimed method because An is explicit in teaching a therapy with fibrates for treating influenza A. A skilled artisan would have been motivated administer a fibrate, e.g. fenofibrate in a subjects with influenza A with a reasonable expectation of success. Thus administration of the same active agent, fenofibrate (metabolic regulatory drug) to a subject with influenza viral infection (H5N1) would result in the treatment of lipotoxicity because one of the causes of lipotoxicity is lung infection by H1N1. Thus claims 1, 3, 6, 10-11, 19-21, 23-24 would have been obvious over the prior art teachings. It would have been obvious to a skilled artisan from An’s teaching that the viral infection produces pneumonia in lung is from H1N1 and not from coronavirus infection. Thus claim 8 is obvious over the prior art.
As to claim 12, a skilled artisan (e.g. physician) would have tested or confirmed that the subject has lipotoxicity, for e.g. because of viral influenza, by checking the symptoms or with a PCR test before the metabolic regulatory drug is administered.
As to claims 13-14, from An’s teachings it is obvious that PPAR pathway is crucial for influenza virus replication.
In regards to claim 17, An teaches treating H5N1 influenza in a subject. The subject population includes not currently or not previously treated with fenofibrate or suffer from metabolic disease or disorder treatable by fenofibrate.
As to claim 26 An teach fenofibrate (150 mg/kg) in a model infected by influenza A. It is within the skill of artisan to adjust the agent orally or intravenously.
As to claim 27, An’s data shows that the combination therapy comprising fenofibrate teach survival rates of rats infected with H5N1 (see Fig. 2). It within the skill of an artisan to administer the dosage amount based on the condition to be treated, symptoms, age etc. and it is routinely optimized.
As to claim 28, administration of fenofibrate to subjects with influenza will result in reduced viral load.
Claim(s) 15 is rejected under 35 U.S.C. 103 as being unpatentable over An et al. (Medical Hypothesis, 77, 2011, 1054-57) as applied to 1, 3, 6, 10-14, 17, 19-21, 23-24, 26-28 in view of Bougarne et al. (Endocrine Reviews, Volume 39, Issue 5, October 2018, Pages 760–802).
An et al teachings discussed as above. The above rejection are incorporated herein.
An is not explicit in teaching that the confirming comprises confirming reduced expression of CPT1A.
Bougarne et al. teach PPARα controls the expression of numerous genes involved in a plethora of lipid metabolic pathways including carnitine palmitoyl transferase 1, CPTIA gene (See Table 5). PPARα agonists have a pronounced effect on lipoprotein metabolism, which is involved in lipid and cholesterol transport (See p 779. Col. 2, para 2, lines 1-3). PPARα deficiency resulted in an increased bacterial load and exaggerated inflammatory responses during mycobacterial infection. In murine macrophages, PPARα activation was also shown to upregulate the expression of the classic PPARα target gene CPT1 (See p 780, col. 1, para 2).
A person skilled in the art before the effective filing date of the invention would have found it obvious to confirm or check the expression levels of the biomarker gene CPT1A from Bougarne because CPTIA gene expression is controlled by PPARα and PPARα deficiency resulted in an increased bacterial load and exaggerated inflammatory responses during mycobacterial infection. A person skilled in the art would have been motivated to confirm the expression of the biomarker CPT1 levels before treating the condition (lipotoxicity) is for early detection and assessment of the disease status. Thus claim 15 would have been obvious over the combined prior art teachings.
Claim(s) 22 is rejected under 35 U.S.C. 103 as being unpatentable over An et al. (Medical Hypothesis, 77, 2011, 1054-57) in view of Remmereit et al (US 8349894).
An et al teachings discussed as above. The above rejection are incorporated herein.
An is not explicit in teaching the use of CLA in the method.
Remmereit teachings provide a method of treatment of a human or non-human (e.g. mammalian, avian or reptilian) animal subject by the parenteral administration of a lipophilic pharmaceutical agent, the improvement comprising administering said pharmaceutical agent in an oil-in-water emulsion containing a conjugated linoleic acid or a physiologically tolerable derivative thereof (See col. 1, lines 55-62). It is also taught that CLA, also known as octadecadienoic acid, is a collective name for positional and geometric isomers of linoleic acid with conjugated double bonds at carbon atoms 10 and 12 or 9 and 11 in the various cis-trans configurations (See col. 1, lines 36-42).
From Remmereit a skilled artisan before the effective filing date of the invention would have found it obvious to use the conjugated linoleic acid e.g. 9-CLA for treating avian influenza. A skilled artisan would have been motivated to use 9-CLA in An’s method as an alternative to fenofibrate or in combination with fenofibrate to treat the avian influenza infection and attain synergistic effects. Thus claim 22 is addressed.
Conclusion
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/Umamaheswari Ramachandran/ Primary Examiner, Art Unit 1627