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
This application is a CON of PCT/US2021/022009 (03/11/2021)
PCT/US2021/022009 has PRO 62/987,946 (03/11/2020).
Status
Claims 1-31 are pending. Claim 31 was newly presented.
Rejections not reiterated in this action are withdrawn.
Election/Restrictions
Applicant previously elected the species of the compound TEPP-46 represented by claim 12 with the following structure:
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The Examiner determined that the above species reads on claims 1-12, 20-27, 29-30.
As detailed in the following rejections, the generic claim encompassing the elected species was not found patentable. Therefore, the provisional election of species is given effect, the examination is restricted to the elected species only, and claims not reading on the elected species are held withdrawn. MPEP 803.02; Ex parte Ohsaka, 2 USPQ2d 1460, 1461 (Bd. Pat. App. lnt. 1987). Accordingly, claims 13-19, and 28 are hereby withdrawn.
Should applicant, in response to this rejection of the Markush-type claim, overcome the rejection through amendment, the amended Markush-type claim will be reexamined to the extent necessary to determine patentability of the Markush-type claim. See MPEP 803.02.
Claim Rejections - 35 USC § 112
Claim 12 is 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.
Claim 12 has a structure which is illegible and further the claim does not end with a period. As a result, the claim is indefinite.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 4-5, 12, 20-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Qi et al. (Nature Medicine volume 23, pages 753–762 and supplemental data (2017)) as evidenced by Zhao et al. (Nature Reviews Drug Discovery, v. 19, pages 57–75 (2020) (Published: 23 September 2019).
Qi teaches administration of TEPP-46 to treat diabetes (Abstract: “TEPP-46 treatment
reversed metabolic abnormalities, mitochondrial dysfunction and kidney pathology”; p. 761: “our study has clearly shown that treatments with TEPP-46 after 3 months of diabetes can reverse many early biochemical and cellular abnormalities that subse-quently lead to a reduction of ACR, mesangial expansion, basement-membrane thickening and fibrosis in both glomeruli and tubules”; Fig. 5-6).
As evidenced by Zhao, diabetes is considered a fibrotic disease or a disease characterized by organ or tissue fibrosis (Zhao p. 57: “Common diseases associated with fibrosis include cirrhosis, hepatitis, non-alcoholic steatohepatitis (NASH), chronic kidney disease, myocardial infarction, heart failure, diabetes, idiopathic pulmonary fibrosis (IPF), and scleroderma.”; p. 63: “In diabetes, increased levels of fatty acid, triglyceride, and cholesterol synthesis have been demonstrated to elevate levels of TGFβ and downregulate ECM degradation via PAI1, with the subsequent development of tubule-interstitial fibrosis in diabetic nephropathy119. Similarly, high levels of very low density lipoprotein corresponded with an elevation in levels of PAI1 in endothelial cells120. In diabetes-induced renal fibrosis, the levels of key enzymes in fatty acid synthesis pathways, including sterol regulatory element-binding protein 1c (SREBP1c) and carbohydrate-responsive element-binding protein (CHREBP), are increased, with a corresponding decrease in fatty acid oxidation119.”). Thus, the claims are anticipated.
Response to Remarks - 35 USC § 102
Applicant argues that the claims as amended are to non-renal fibrosis which Qi does not disclose. This argument is not persuasive as the claims are not so limited and are instead to a scope of “a fibrotic disease or a disease characterized by organ or tissue fibrosis”. In addition, the wherein clause of claim 1 is considered an intended result that would be the natural result of administering the compound as taught by Qi, does not require specific steps to be performed, and therefore does not limit the claims as these are inherent in the administration of the compound. MPEP 2111.04 (“Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure.”, “a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’””). Rejection maintained as amended.
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.
Claims 1-12, 20-27, 29-31 are rejected under 35 U.S.C. 103 as being unpatentable over Qi et al. (Nature Medicine volume 23, pages 753–762 and supplemental data (2017)) in view of Zhao et al. (Nature Reviews Drug Discovery, v. 19, pages 57–75 (2020) (Published: 23 September 2019), Su (US20140148444), and Nakano et al. (Am J Gastroenterol. 1987 Dec;82(12):1283-6, Abstract).
As detailed in the 35 USC 102 rejection above, Qi teaches the successful use of TEPP-46 to treat metabolic conditions in vivo (Abstract: “TEPP-46 treatment reversed metabolic abnormalities, mitochondrial dysfunction and kidney pathology.”) and a reduction in disease related fibrosis (p. 761: “our study has clearly shown that treatments with TEPP-46 after 3 months of diabetes can reverse many early biochemical and cellular abnormalities that subse-quently lead to a reduction of ACR, mesangial expansion, basement-membrane thickening and fibrosis in both glomeruli and tubules”; Fig. 5-6).
Zhao reviews the therapeutic targets related to fibrosis, including diabetes, liver disease, and states “Fibrotic therapies are potentially relevant to numerous common diseases such as cirrhosis, non-alcoholic steatohepatitis, chronic renal disease, heart failure, diabetes, idiopathic pulmonary fibrosis, and scleroderma” (Abstract, p. 57-58, Fig. 1). Zhao teaches that PKM2 is an important factor in regulation of fibrosis (p. 62, 71). Zhao teaches that targeting PKM2 with a pharmaceutical was effective in renal fibrosis (p. 65-66, Table 1). Zhoa teaches the scope of disease relating to fibrosis includes that of the liver, lung, heart, kidney, and pancreas (Fig. 1, Table 1) from a variety of causes, including genetics and surgery (p. 69).
Su teaches use of compounds including TEPP-46 (compound 149) for “treating diseases or conditions that are associated with increased 2,3-diphosphoglycerate levels (e.g., liver diseases (Am J Gastroenterol, 1987; 82(12):1283)” ([0017]). Su’s citation to diseases associated with increased 2,3-DPG is Nakano et al. (Am J Gastroenterol. 1987 Dec;82(12):1283-6, Abstract). Su teaches combination with other agents ([0151]-[0152] parenteral administration, [0158]-[0159] combinations including excipients) in an amount that was optimized for therapeutic efficacy, a well-known results-effective variable (Su [0162]).
Nakano teaches high levels of “2,3-DPG in liver diseases occurred in the following increasing order: chronic persistent hepatitis, chronic active hepatitis, liver cirrhosis, and cirrhosis with hepatocellular carcinoma.”
Qi does not teach wherein the fibrosis is “cardiac fibrosis following myocardial infarction”, “alcoholic hepatitis”, “nonalcoholic steatohepatitis (NASH)”, “idiopathic pulmonary fibrosis”, or “fibrosis is in the surgery complications and scar”.
Zhao teaches that fibrosis is associated with each of the disease (Zhao p. 57: “Common diseases associated with fibrosis include cirrhosis, hepatitis, non-alcoholic steatohepatitis (NASH), chronic kidney disease, myocardial infarction, heart failure, diabetes, idiopathic pulmonary fibrosis (IPF), and scleroderma.”; Zhao p. 69: “Fibrosis can be induced genetically or iatrogenically (through surgery, radiotherapy, or use of chemicals)”).
Regarding claim 22, Qi does not teach administering additional chemotherapeutic agents. Zhao suggests combination therapies to address fibrosis (p. 71: “adapt combinatorial
treatment strategies to optimize ECM regulation”) as does Su ([0161]: “the active agent to be delivered is incorporated as part of a liposome, alone or in conjunction with a suitable chemotherapeutic agent.”).
Regarding claims 23-27, Qi does not teach administration to a human or specific compositions. Su teaches oral administration in suitable pharmaceutical compositions to human patients (Su [0158], [0177]-[0178]).
Regarding claim 30, Qi does not teach fibrosis associated with surgery. Zhao teaches fibrosis resulting from surgery shares the same pathway (Zhao p. 57: “Fibrosis … can result from diseases, iatrogenic injury or trauma.”; p. 69: “Fibrosis can be induced genetically or iatrogenically (through surgery, radiotherapy, or use of chemicals)”; Fig. 1: scars).
Regarding claim 31, Qi does not teach fibrosis following myocardial infarction. However, Zhao teaches myocardial infarction is associated with fibrosis (Zhao p. 57: “Common diseases associated with fibrosis include cirrhosis, hepatitis, non-alcoholic steatohepatitis (NASH), chronic kidney disease, myocardial infarction, heart failure, diabetes, idiopathic pulmonary fibrosis (IPF), and scleroderma.”).
One of ordinary skill in the art following the teaching of Qi in view of the secondary references would have considered that the compound disclosed therein would be useful for diseases as specifically referenced in Zhao, Su, and Nakano, including liver diseases such as cirrhosis and fibrosis-related disease due to PKM2’s role in regulation of fibrosis. One of ordinary skill in the art would have considered the teaching of Qi regarding the success of TEPP-46 in reducing fibrosis and treating metabolic conditions including those taught by Zhao. One of ordinary skill in the art would have considered the teaching of Zhao in the same field of endeavor, relating to liver diseases including cirrhosis, and considered the use of Qi and Su’s TEPP-46 compound for treating related diseases taught therein. One of ordinary skill in the art would consider administering an amount of the compound in order to achieve therapeutic result. Regarding the claim language of “wherein the the PKM2 activator reduces LOX protein expression and activates PKM2” the administration of the same compound in the same manner would have the same effect as such properties are inherent in the compound. Regarding the dependent claims specifying the particular fibrosis, one of ordinary skill in the art would have had reasonable expectation based on the teaching of Zhao that particular types of fibrosis including those of the claims would also be affected by the same therapeutic.
With each of the claims, the level of skill in the art is very high such that one of ordinary skill in the art would consider routine the combination of elements from the teaching of the art. One of ordinary skill in the art would have recognized that the results of the combination would be predictable due to the well-known nature and optimizations routinely performed in the art. Thus, one of ordinary skill in the art would have arrived at the invention as claimed before the effective filing date with a reasonable expectation of success.
Response to Remarks - 35 USC § 103
Applicant argues the references individually which is not persuasive because the rejection is over the combined teaching of the cited art. MPEP 2145 IV. (“[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA].” In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012)).
Applicant argues the cited references do not provide a legally sufficient rationale for obviousness because Zhao’s teaching is limited to generalized metabolic insights that one of ordinary skill in the art would not combine with the other cited references with a reasonable expectation of success. This is not persuasive because one of ordinary skill in the art would understand the fibrosis mechanism described in Qi and Zhao would be applicable to the disease that share the same pathway, including those taught by Zhao.
Applicant argues that a reduction of LOX protein expression was not established by the cited art. This is not persuasive because the prior art teaches and suggests the same compound administered in the same manner to the same patient such that the intended result would be the same. Applicant is welcome to submit evidence that establishes how administration of TEPP-64 to a subject as taught by the prior art would not result in reduction of LOX expression so that anticipation/obviousness as well as enablement may be fully considered on the record.
Applicant argues that the data in the specification establishes “PKM2 activation produces coordinated cross-organ therapeutic and mechanistic effects that were neither taught nor suggested by the cited references”. This argument is not persuasive because one of ordinary skill in the art following the combined teaching of the prior art, including Qi’s teaching that TEPP-64 reduced fibrosis via PKM2 activation would have had a reasonable expectation that the compound would be beneficial in other fibrosis disease that share the same pathway.
None of the arguments are persuasive and the rejection maintained as amended.
Conclusion
No claims allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ROBERT H HAVLIN whose telephone number is (571)272-9066. The examiner can normally be reached 9am - 6pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney Klinkel can be reached at (571) 270-5293. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ROBERT H HAVLIN/Primary Patent Examiner, Art Unit 1626
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