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 claims status as a 371 (National Stage) of PCT/KR2021/019660 filed December 22, 2021; and claims priority under 119(a)-(d) to Korean Application No. KR10-2020-0180640 filed on December 22, 2020.
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d) for Korean Application No. KR10-2020-0180640, which papers have been placed of record in the file. Please note that the application is in Korean and thus cannot be verified.
Claim Status
Claims 1-11 were originally filed and amended on 06/21/2023. The amendment cancelled claims 6-11 and amended claims 1-5.
The amendment filed on 05/22/2026, amended claim 1 and cancelled claim 2.
Response to Arguments
1. Applicants’ arguments, see Remarks, filed 05/22/2026, with respect to the 35 U.S.C. 112(b) rejection have been fully considered and are persuasive. The 35 U.S.C. 112(b) of claims 1-5 has been withdrawn.
2. Applicants’ arguments, see Remarks, filed 05/22/2026, with respect to the 35 U.S.C. 112(b) rejection have been fully considered and are persuasive. The 35 U.S.C. 112(b) of claim 2 has been withdrawn.
3. Applicants’ arguments, see Remarks, filed 05/22/2026, with respect to the 35 U.S.C. 112(b) rejection have been fully considered and are persuasive. The 35 U.S.C. 103 of claims 1-5 has been withdrawn.
New Rejections Necessitated by Amendment
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.
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness
(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
1. Claims 1, and 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over US 2004/0072739 A1 Pub Date: April. 15, 2004 (cited in the IDS filed on 06/21/2023) (herein after “Anderson”) in view of Garcia-Aguilar et al. Frontiers in Physiology, 2019, vol. 9, article 1322, pp. 1-10 (herein after “Garcia-Aguilar et al.”); Smith et al. Am J Physiol Endocrinol Metab. 2016, 311:E730-E740 (herein after “Smith et al.”); Gastaldelli et al. JHEP Reports. 2019, vol. 1, pp. 312-328 (here in after “Gastaldelli et al.”).
Regarding claim 1, Anderson teaches compositions and methods for altering mitochondrial ATP production, including fusion proteins comprising IF1 polypeptide-derived sequences (see front pg., abstract). Anderson adds that the mitochondrial function being improved is in functional (i.e., not uncoupled) mitochondria such that ATP production within the cell is increased (see pg. 29, para[0255]). Anderson includes that the cells can be any cells within the subject, preferably insulin producing cells or insulin sensitive cells (see pg. 29, para[0256]); and that the preferred insulin sensitive cells are those cells involved in glucose metabolism, homeostasis and/or storage, such as liver cells and/or muscle cells (see pg. 29, para[0256]).
Furthermore, one additional benefit to increasing mitochondrial function in liver cells is that the activity of the liver can increase such that these cells can perform detoxification functions, such as for reducing the toxicity or increasing the solubility of compounds (see pg. 29, para(0256]). Additionally, subjects that have liver diseases or disorders, such as hepatitis, cirrhosis, toxic intake of compounds, can have their liver function increased (see pg. 29, para[0256]).
With respect to the composition, Anderson also teaches that the pharmaceutical compositions of the invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose (see pg. 26, para[0319]).
As such, Anderson’s teachings read on a method for treating comprising administering a pharmaceutical composition comprising ATPase inhibitory factor 1 (IF1) as an active ingredient to an individual in need of treatment thereof.
However, Anderson does not expressly teach that the method treats non-alcoholic steatohepatitis (NASH), as recited in instant claim 1.
Garcia-Aguilar et al. review the Inhibition of the Mitochondrial ATP synthase by IF1 in vivo: Reprograming Energy Metabolism and Inducing Mitohormesis (see pg. 1, Title). Garcia-Aguilar et al. discuss that IF1 besides regulating the production of ATP, exerts additional functions in mitochondrial physiology (see pg. 5, left column, second paragraph). In this regard, there is growing evidence supporting that a mild mitochondrial stress can protect cells from subsequent insults, a concept termed mitohormesis, eliciting mitohormetic responses can impact on both an increase in organismal lifespan and/or an improved health (see pg. 5, left column, paragraph 2). Garcia-Aguilar et al.’s review includes information with respect to overexpression of IF1 in tissue-specific conditional transgenic mice. In particular overexpression of IF1-H49K in Hepatocytes (see pg. 5, right column, last paragraph; and pg. 6, Fig. 2). Consistent with the inhibition of the ATP synthase, transgenic mice revealed the activation of the stress kinases AMPK and p38 MAPK (see pg. 6, left column and Fig. 2).
Smith et al. review the role of AMPK in the treatment of nonalcoholic fatty liver disease (NAFLD) which is characterized by hepatic lipid accumulation of >5% of liver (see pg. E730, left column, first paragraph). The literature reviewed by Smith et al. add teach that NAFLD was initially believed to result from insulin resistance, however studies indicate that the accumulatio of liver fat is a cause, not a consequence, of hepatic insulin resistance (see pg. E730, left column). Additionally, that liver lipid accumulation can also trigger inflammation and lead to more serious liver disorders such as nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatic cellular carcinoma (HCC) (see pg. E730, left column).
Smith et al. disclose that a common characteristic of many proposed NAFLD treatment options involves activation of the energy-sensing enzyme of the cell, AMPactivatedprotein kinase (AMPK) (see pg. E790, right column). Resolving NAFLD reduces circulating low-density lipoproteins (LDL); therefore, identifying strategies to reduce liver lipid content is critical for the reduction of NAFLD and its potential consequences (NASH and HCC) in addition to lowering the risk for type 2 diabetes and cardiovascular disease (see pg. E730, left column). Smith et al. propose three primary mechanisms by which AMPK may improve NAFLD: 1) suppression of de novo lipogenesis (DNL) in liver, 2) increased fatty acid oxidation in the liver, and 3) promotion of mitochondrial function/integrity in adipose tissue (see pg. E731, left column, second paragraph). Smith et al. also teach that AMPK is essential for the maintenance of mitochondrial function in the adipose tissue; and that reducing NAFLD may prevent the onset of more severe diseases such as nonalcoholic steatohepatitis (NASH) (see pg. E732, Figure 1 and figure description).
Gastaldelli et al.’s review is titled “From NASH to diabetes and from diabetes to NASH: Mechanisms and treatment options” (see pg. 312). The literature reviewed by Gastaldelli et al. teaches that the majority of patients with NAFLD are insulin resistant, even if they are non-obese, however most individuals with NAFLD/NASH do not develop hyperglycemia despite displaying higher insulin concentrations (see pg. 313, right column). This is because the liver, as it accumulates triglycerides and toxic lipid-derived metabolites, becomes resistant to the effect of insulin and decreases its capacity to clear insulin (see pg. 313, right column).
Thereby it is understood that lipid liver accumulation can trigger inflammation and cell damage and develop into more serious conditions such as nonalcoholic steatohepatitis (NASH), cirrhosis, and hepatic cellular carcinoma (HCC). It is also understood that, accumulation of liver fat is a cause, not a consequence, of hepatic insulin resistance; with respect to hepatic insulin resistance, it is also understood that the liver decreases its capacity to clear insulin due to the accumulation of triglycerides and toxic lipid-derived metabolites thereby the liver stops responding to insulin. As a result, the majority of individuals with lipid liver accumulation are insulin resistant even if they are non-obese and do not develop hyperglycemia (i.e., high blood sugar) despite displaying higher insulin concentrations. As such, it would make sense to alter mitochondrial ATP production in insulin sensitive cells (i.e., cells involved in glucose metabolism, homeostasis and/or storage), with IF1 derived polypeptides, in order to activate AMPK for the maintenance of mitochondrial function in the adipose tissue which would result in the reduction of hepatic lipid accumulation and treatment of the onset of more severe diseases such as nonalcoholic steatohepatitis (NASH).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art to follow Anderson’s method for altering mitochondrial ATP production by administering a composition comprising IF1 polypeptide-derived sequences in order to arrive at the instantly claimed method for treating non-alcoholic steatohepatitis (NASH). One of ordinary skill in the art before the effective filing date of the claimed invention would have been motivated to do so because:
- it was known that IF1 improves uncoupled mitochondrial function, as in increased ATP production within insulin sensitive cells (i.e., liver cells), as taught by Anderson;
- it was known that the stress kinases AMPK was activated in transgenic mice with overexpression of IF1-H49K in hepatocytes, which is consistent with the inhibition of ATP synthase, as taught by Smith; and
-because it was known that the majority of patients with NAFLD/NASH are insulin resistant and do not develop hyperglycemia despite displaying higher insulin concentrations because as the liver accumulates triglycerides and toxic-lipid derived metabolites, its capacity to clear insulin decreases and liver becomes resistant to the effect of insulin.
One of ordinary skill in the art would have had a reasonable expectation of success in achieving the claimed invention given that subjects that have liver diseases or disorders, such as hepatitis, cirrhosis, toxic intake of compounds, can have their liver function increased using the methods Anderson’s invention. And given that three primary mechanisms by which AMPK may improve NAFLD: 1) suppression of de novo lipogenesis (DNL) in liver, 2) increased fatty acid oxidation in the liver, and 3) promotion of mitochondrial function/integrity in adipose tissue, as taught by Smith et al.
Accordingly, Anderson’s teachings would support the instantly claimed method for treating non-alcoholic steatohepatitis (NASH), comprising administering a pharmaceutical composition comprising IF1 as an active ingredient to an individual in need thereof by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention, pursuant to KSR.
Regarding claims 3-5, Anderson teaches that mitochondrial energy production is related to glucose homeostasis primarily through the regulation of glucose stimulated insulin secretion (GSIS) (see pg. 2, para[0015]). In cellular studies manipulation of mitochondrial function can alter normal glucose homeostasis; thus, for instance, glucose-stimulated insulin secretion can be abrogated at the cellular level by a variety of metabolic inhibitors (see pg. 3, para[0018]).
As previously mentioned, Anderson teaches that the increase in ATP production related to the increase in mitochondrial function in insulin producing cells results in an increase in insulin production and/or insulin secretion (see pg. 29, para[0255]). Alternatively, the increase in ATP production can increase the sensitivity of insulin sensitive cells to insulin (see pg. 29, para[0255]).
Also, Smith et al. teach that resolving NAFLD reduces circulating low-density lipoproteins (LDL); therefore, reduction of NAFLD and its potential consequences (NASH and HCC) in addition to lowering the risk for type 2 diabetes and cardiovascular disease (see pg. E730, left column).
Thus, since Anderson’s methods and compositions for altering mitochondrial ATP production comprises IF1 polypeptide-derived sequences, and since the manipulation of mitochondrial function can restore insulin sensitivity in cells involved in glucose metabolism, homeostasis and/or storage (i.e. liver cells); then it must follow that the claimed pharmaceutical composition comprising IF1 suppresses an increase in blood lipid concentration; lipid accumulation in liver tissue; and suppresses liver fibrosis as recited in instant claims 3-5.
Additionally, the court has found that the determination of whether clauses such as “wherein” and “whereby" is a limitation in a claim is dependent on the specific facts of the case. If the “wherein" or “whereby” clause limits a process claim where the clause gives meaning and purpose to the manipulative steps, it should be given patentable weight. However, the court also found (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)) that a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” In the instant case wherein the pharmaceutical composition suppresses an increase in blood lipid concentration, suppresses lipid accumulation in liver tissue, and suppresses liver fibrosis, as recited in instant claims 3-5, respectively; are intended inherent results of administering a pharmaceutical composition comprising ATPase inhibitory factor 1 (IF1) as an active ingredient to an individual in need thereof. Accordingly, claims 3-5 recite intended results that do not appear to render material to patentability.
MPEP 2112-2112.02 also states that when a reference discloses all the limitations of a claim except for a property or function, and the Examiner cannot determine whether or not the reference inherently possesses properties which anticipate or render obvious the claimed invention but has basis for shifting the burden of proof to applicant as in In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980). In the instant case, Anderson et al teach compositions and methods for altering mitochondrial ATP production, including fusion proteins comprising IF1 polypeptide-derived sequences. Additionally, Garcia-Aguilar teach that IF1 activates the stress kinase AMPK; a mitohormetic response which can impact on both an increase in organismal lifespan and/or an improved health. Smith et al. teach that AMPK is essential for the maintenance of mitochondrial function in the adipose tissue; and that reducing NAFLD may prevent the onset of more severe diseases such as nonalcoholic steatohepatitis (NASH). And Gastaldelli et al. teach that most individuals with NAFLD/NASH do not develop hyperglycemia despite displaying higher insulin concentrations because the liver, as it accumulates triglycerides and toxic lipid-derived metabolites, becomes resistant to the effect of insulin and decreases its capacity to clear insulin.
The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not a pharmaceutical composition comprising IF1 as an active ingredient suppresses an increase in blood lipid concentration, suppresses lipid accumulation in liver tissue, and suppresses liver fibrosis, as recited in instant claims 3-5.
The cited art taken as a whole demonstrates a reasonable probability that compositions and methods for altering mitochondrial ATP production, including fusion proteins comprising IF1 polypeptide-derived sequences is ether identical or sufficiently similar to the instantly claimed method wherein the pharmaceutical composition suppresses an increase in blood lipid concentration as recited in instant claim 3, suppresses lipid accumulation in liver tissue as recited in instant claim 4, and suppresses liver fibrosis as recited in instant 5; and that whatever differences exists are not patentably significant. Therefore, with the showing of the reference, the burden of establishing novelty or non-obviousness by objective evidence is shifted to the Applicants.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claims are 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 CLAUDIA E ESPINOSA whose telephone number is (703)756-4550. The examiner can normally be reached Monday-Friday 9:30-5:30 EST.
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/CLAUDIA ESPINOSA/Patent Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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