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 preliminary amendment dated 17 February 2023, in which claims 8, 15-19, 22-24, 27-28 have been amended, is acknowledged.
Claims 1-28 are pending in the instant application.
Claims 5-7, 13-14, 17-18, 22-28 are withdrawn as being drawn to a nonelected invention or to a nonelected species.
Claims 1-4, 8-12, 15-16, 19-21 are being examined on their merits herein.
Priority
The instant application is a National Stage entry of International Application No. PCT/US2021/012516, filed on 7 January 2021, which claims priority from U.S. Provisional Patent Application 62/958,116, filed on 7 January 2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 17 February 2023 and 19 March 2026 are acknowledged and considered.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-4, 8-16, 19-22, drawn to a method of treating a disorder associated with excess NADH in a subject in need thereof, comprising administering an effective amount of an inhibitor of serine metabolism to the subject, in the reply filed on 19 March 2026, is acknowledged. Claims 5-7, 17-18, 23-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse.
Applicant’s election without traverse of
respiration impairment as the disorder associated with excess NADH to be treated;
subjects suffering from Leigh syndrome as the patient population treated for respiratory impairment;
KDG112 (SHIN2) (compound 74, Table 1, instant Specification, page 65)
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as the specific inhibitor of serine metabolism and the specific inhibitor of serine catabolism, administered in the method;
metformin as the species of an electron transport chain inhibitor “received” by the subject, including in combination with KDG112 (SHIN2);
in the reply filed on 19 March 2026, is acknowledged. Claims 1-4, 8-12, 15-16, 19-21 read on the elected species. Claims 13, 14, 22 are withdrawn, as being drawn to a non-elected species.
Since Applicant has set forth no arguments against the requirement for restriction/election, it is considered that the election was made without traverse, and the restriction/election requirement is maintained and is herein made FINAL.
Claims 1-4, 8-12, 15-16, 19-21 have been examined to the extent they read on the elected species, and the following objections are rejections are made below.
Claims Objection
Claims 5-7, 13-14, 17-18, 22-28, while currently withdrawn, are objected to because of the following informality: The withdrawn claims are objected to for being presented in a non-compliant form. Specifically, the status identifiers state the claims are “(Previously presented)”, but the claims are withdrawn because of the election made by the Applicant on 19 March 2026. As such, claims 5-7, 13-14, 17-18, 22-28 should be identified as "(Withdrawn)" until such time as examiner rejoins the claims for examination. Appropriate correction is required. See MPEP 714(C).
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 1-4, 8-12, 15-16 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 pre-AIA the applicant regards as the invention. Independent claim 1 is indefinite because it recites “a disorder associated with excess NADH”.
The Specification does not provide a definition for the term “excess NADH”. The Specification teaches [0006], [0007], [0013], [0014], [0125], [0126], [0128], [0135] that the disclosure provides methods of treating disorders associated with excess NADH, such as, e.g., respiration impairment, in a subject (e.g., a subject in need thereof).
The Specification discloses [00121] that it was unexpected that serine catabolism could be a major source of NADH and affect cellular redox state.
The Specification discloses [00123] that excess NADH can also be a problem in ischemic diseases like heart attack, stroke, etc. Enhanced NADH likely plays a role in other diseases as well.
Thus, the Specification uses terms such as “excess NADH”, “enhanced NADH”, “NADH elevation”.
The term “excess NADH” in claim 1 renders the claims indefinite because it is unclear how the excess is to be measured, as the claims fail to establish a standard or threshold level. For example, the excess could be relative to the level (of NADH) in another sample taken from the same subject previously, either before acquiring the disease or after acquiring the disease. Alternatively, the excess could be relative to the level (of NADH) in a healthy subject, i.e., a different subject than the subject currently afflicted with disease. Further, the claims fail to identify the biological sample in which the biomarker, level of NADH, is being measured, and fail to clarify if the biological sample in which the level of NADH is determined in a sample from the subject who is being treated, compared with a sample from a subject providing a reference sample.
In other words, it appears that the claims are directed towards measuring levels of biological molecules NADH in two different biological samples and comparing said levels between the two different biological samples, to determine “an excess NADH”; however, the claims fail to clearly establish the origins of the two different biological samples, or the reference or standard by which one would make a comparison of levels of the biomarker/NADH. One wishing to practice the instantly claimed invention would thus not recognize the metes and bounds for which Applicant seeks protection.
For these reasons, the metes and bounds of the present claims cannot be determined and one having ordinary skill in the art would not necessarily be reasonably apprised of the scope of the claims.
Appropriate clarification/correction is required.
Claims 15-16 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 pre-AIA the applicant regards as the invention. Claim 15 recites that the subject “has received” an electron transport chain inhibitor. Claim 16 recites that the subject “is receiving” an electron transport chain inhibitor. These recitations render the claims indefinite because it is unclear how the subject “receives” (perhaps via mail?) said therapeutic agent/inhibitor of electron transport chain.
If the subject is administered the inhibitor of electron transport chain (as part of the method of treatment), the claims should state that.
Appropriate clarification is required.
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 1-4, 8-12 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Dekhne et al. (Mol Pharmacol 2020, 97, 9-22, January 2020, cited in IDS), as evidenced by Yang et al. (Trends in Cell Biology 2026, 36 (3), 177-189, cited in PTO-892).
Dekhne teaches a method of treating pancreatic cancer by administering an effective amount of AGF347, which is an SHMT2 inhibitor (Abstract) as in instant claims 9, 10.
Dekhne teaches (Abstract, Fig. 1) that mitochondrial C1 metabolism including serine hydroxymethyltransferase 2 (SHMT2) generates glycine for de novo purine nucleotide and glutathione biosynthesis. Thus, Dekhne implicitly teaches that SHMT2 inhibitor AGF347 is an inhibitor of serine metabolism, as in instant claim 1, which modulates serine metabolism, as in instant claim 2, by inhibiting serine metabolism, as in instant claims 3-4.
Dekhne teaches (page 10, left column, second paragraph) that the serine catabolic pathway is nearly universally activated in cancer, with SHMT2 and MTHFD2 among the most differentially expressed metabolic genes in all human cancers; the pathway for serine catabolism and glycine synthesis occurs in the mitochondria. Thus, Dekhne implicitly teaches that SHMT2 inhibitor AGF347 is an inhibitor of serine catabolism, as in instant claim 8.
While Dekhne does not teach that pancreatic cancer is a disorder characterized by NADH reductive stress, cancer is known to be a disease associated with NADH reductive stress, as evidenced by Yang (Figure 4). Yang teaches (Fig. 1) that tumor environment/hypoxia is a major cause for NADH reductive stress, which occurs when NADH production exceeds oxidation capacity, disrupting redox homeostasis.
As such, a method of instant claims 1-4, 8-12 is anticipated by Dekhne.
Claims 1-4, 8-12 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Dekhne et al. (Mol Cancer Ther 2019, 18, 1787-1799, published on line 9 July 2019, cited in IDS), as evidenced by Yang et al. (Trends in Cell Biology 2026, 36 (3), 177-189, cited in PTO-892).
Dekhne teaches (Table 1) a method of treating lung, colon, or pancreatic cancer by administering an effective amount of AGF347, which is an SHMT2 inhibitor (Abstract) as in instant claims 9, 10.
Dekhne teaches (Abstract, Fig. 1) that mitochondrial C1 metabolism including serine hydroxymethyltransferase 2 (SHMT2) generates glycine for de novo purine nucleotide and glutathione biosynthesis. Thus, Dekhne implicitly teaches that SHMT2 inhibitor AGF347 is an inhibitor of serine metabolism, as in instant claim 1, which modulates serine metabolism, as in instant claim 2, by inhibiting serine metabolism, as in instant claims 3-4.
Dekhne teaches (page 1788, left column, first paragraph) that the serine catabolic pathway is nearly universally activated in cancer, with SHMT2 and MTHFD2 among the most differentially expressed metabolic genes in all human cancers; the pathway for serine catabolism and glycine synthesis occurs in the mitochondria. Thus, Dekhne implicitly teaches that SHMT2 inhibitor AGF347 is an inhibitor of serine catabolism, as in instant claim 8.
Dekhne teaches that pyrrolo[3,2-d]pyrimidine compounds tested AGF291, AGF320 and AGF347 are inhibitors of SHMT2 and inhibitors of SHMT1, as in instant claims 9-12.
While Dekhne does not teach that lung, colon, or pancreatic cancer are disorders characterized by NADH reductive stress, cancer is known to be a disease associated with NADH reductive stress, as evidenced by Yang (Figure 4). Yang teaches (Fig. 1) that tumor environment/hypoxia is a major cause for NADH reductive stress, which occurs when NADH production exceeds oxidation capacity, disrupting redox homeostasis.
As such, a method of instant claims 1-4, 8-12 is anticipated by Dekhner.
Claims 1-4, 8-12 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Ducker et al. (PNAS 2017, 114 (43), 11404-11409, cited in IDS), as evidenced by Yang et al. (Trends in Cell Biology 2026, 36 (3), 177-189, cited in PTO-892).
Ducker teaches (page 11407, left column, second paragraph) a method of treating diffuse large B-cell lymphoma (DLBCL) by administering an effective amount of pyrazolopyran compound 2 below, or of SHIN-1
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where said pyrazolopyrans are dual SHMT1 and SHMT2 inhibitors (Fig. 2A), as in instant claims 9-12.
Ducker teaches (page 11404, left column, first paragraph, Fig. 1) that the predominant source of 1C units in cancer cells is the amino acid serine; the enzyme serine hydroxymethyl transferase (SHMT2) catalyzes the conversion of serine into glycine (serine catabolism). Thus, Dekhne implicitly teaches that SHMT2 inhibitor SHIN1 is an inhibitor of serine metabolism, as in instant claim 1, which modulates serine metabolism, as in instant claim 2, by inhibiting serine metabolism, as in instant claims 3-4, and is an inhibitor of serine catabolism, as in instant claim 8.
While Ducker does not teach that DLBCL is a disorder characterized by NADH reductive stress, cancer is known to be a disease associated with NADH reductive stress, as evidenced by Yang (Figure 4). Yang teaches (Fig. 1) that tumor environment/hypoxia is a major cause for NADH reductive stress, which occurs when NADH production exceeds oxidation capacity, disrupting redox homeostasis.
As such, a method of instant claims 1-4, 8-12 is anticipated by Ducker.
Claims 1-4, 8-12 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Rabinowitz et al. (US 2017/0000769, cited in PTO-892), as evidenced by Rabinowitz et al. (US 2018/0072751, cited in PTO-892) and Yang et al. (Trends in Cell Biology 2026, 36 (3), 177-189, cited in PTO-892).
Raboniwitz (US 2017/0000769) teaches a method of treating cancer in a subject in need thereof by administering to the subject an antifolate compound which is an inhibitor of SHMT1[0206], specifically HK-16, enantiomer 2 preferred [0206].
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Rabinowitz teaches [0206] that tumor cells that are defective in mitochondrial folate metabolism may be recognized by the production of deuterated NADPH in the cytosol from 2H-serine, or by the consequent production of deuterated fatty acid molecules. The invention relates to diagnosing the presence of such tumor cells by detecting such deuterated compound(s) and treating such cancers with one or more agents that antagonize or block cytosolic folate metabolism. Preferred agents that antagonize or block cytosolic folate metabolism include inhibitors of the enzyme SHMT1, namely compound HK-16, whose Enantiomer-2 is preferred.
While Raboniwitz (US 2017/0000769) does not specifically teach the pharmacological profile of compound HK-16, or its enantiomers, Rabinowitz et al. (US 2018/0072751) teach (Table 3, last compound on page 67) that compound HK-16, Enantiomer-2, is a dual SHMT2 and SHMT1 inhibitor (SHMT2 IC50 = 15 nM; SHMT1 IC50 = 5 nM), as in instant claims 9-12.
Rabinowitz (US 2017/0000769) teaches (Fig. 3A) that the predominant source of 1C units in cancer cells is the amino acid serine; the enzyme serine hydroxymethyl transferase (SHMT2) catalyzes the conversion of serine into glycine (serine catabolism). Thus, Rabinowitz implicitly teaches that SHMT2 inhibitor HK-16 enantiomer 2 is an inhibitor of serine metabolism, as in instant claim 1, which modulates serine metabolism, as in instant claim 2, by inhibiting serine metabolism, as in instant claims 3-4, and is an inhibitor of serine catabolism, as in instant claim 8.
While Rabinowitz does not teach that cancer is a disorder characterized by NADH reductive stress, cancer is known to be a disease associated with NADH reductive stress, as evidenced by Yang (Figure 4). Yang teaches (Fig. 1) that tumor environment/hypoxia is a major cause for NADH reductive stress, which occurs when NADH production exceeds oxidation capacity, disrupting redox homeostasis.
As such, a method of instant claims 1-4, 8-12 is anticipated by Ducker.
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 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-4, 8-12, 15-16, 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Rabinowitz et al. (US 2018/0072751, cited in PTO-892) in view of Ducker et al. (Cell Metabolism 2017, 25, 27-42, cited in IDS), in further view of Kruse et al. (Cell Metabolism 2008, 7, 312-320, cited in PTO-892).
Rabinowitz et al. (US 2018/0072751) teaches (Table 2, page 48) compound 74 below:
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which is the instant elected species (SHIN2), as a dual SHMT1 and SHMT2 inhibitor, as in instant claims 9-12, useful to treat cancer [0009].
Rabinowitz teaches (Figure 1B, [0003-0005]) that serine catabolism is initiated by serine hydroxymethyltransferase (SHMT) activity, catalyzed in the cytosol by SHMT1 and in the mitochondria by SHMT2. SHMTs catalyze a reversible reaction converting serine to glycine, with concurrent methylene - tetrahydrofolate (THF) generation. Thus, Rabinowitz implicitly teaches that SHMT inhibitor compound 74 above is an inhibitor of serine metabolism, as in instant claim 1, which modulates serine metabolism, as in instant claim 2, by inhibiting serine metabolism, as in instant claims 3-4, and is an inhibitor of serine catabolism, as in instant claim 8.
Rabinowitz teaches ([0003]-[0005]) that increased SHMT enzyme activity has been detected in human breast cancer, colon cancer, and in rat sarcoma. SHMT functions to generate one - carbon units for cellular folate metabolism. Rabinowitz teaches [0005] that hypoxia occurs in the tumor environment, and the mitochondrial form of SHMT, SHMT2, is induced under hypoxic stress. SHMT expression may help tumor cells survive under hypoxic conditions, thus promoting cancerous cell growth, survival and metastasis. Hypoxic cells are generally more resistant to radiation and chemotherapy treatment, further permitting the tumor to grow and metastasize. SHMT2 overexpression has been observed in various different cancers, including neuroblastoma, bladder cancer, colorectal cancer, kidney cancer, etc.
Thus, Rabinowitz teaches that dual SHMT1 and SHMT2 inhibitor compound 74 is effective to treat cancer as a disease associated with dysregulated one-carbon metabolism.
Rabinowitz (US 2018/0072751) does not teach that dual SHMT1 and SHMT2 inhibitor compound 74 above is effective to treat Leigh syndrome, which is a disease of instant claims 1, 19-21.
Ducker et al. (Cell Metabolism 2017, 25, 27-42) teach (page 29, Fig. 2, Fig. 3A, page 30, left column, second paragraph) that serine is catabolized in mitochondria via SHMT2 and MTHD2, generating 1C units, glycine, NADH and NADPH.
Ducker teaches (page 30, left column, last paragraph) that production of NADH by mitochondrial 5,10-methylene-THF dehydrogenase activity links 1C metabolism to the respiratory state of the cell.
Ducker also teaches (page 30, left column, last paragraph) that metformin targets mitochondrial complex I and thus decreases the NAD+/NADH ratio.
Kruse teaches (page 312, left column, last 4 lines, right column, first paragraph) that mitochondrial complex I (CI)-associated defects are the most common mitochondrial disorders. CI is the primary entry point for electrons into the electron transport chain (ETC) and is comprised of at least 45 different proteins. Defects in the nonenzymatic, nuclear-encoded CI protein NADH: ubiquinone oxidoreductase iron-sulfur protein 4 (NDUFS4, 18 kDa) cause a Leigh-like phenotype in humans that results in death within 3–16 months after birth. Kruse teaches (page 316, left paragraph) that respiratory CI activity is impaired in the absence of NDUFS4. Thus, Kruse teaches that Leigh syndrome is a mitochondrial disease characterized by respiration impairment caused by genetic deficiency of the electron transport chain, as in instant claims 19-21.
Kruse teaches (page 316, right column, second paragraph) that CI deficiency results in accumulation of NADH, as in instant claim 1.
Kruse discloses a Ndufs4 KO mouse as a genetic model for studying CI deficiencies.
It would have been obvious to a person of ordinary skill in the art to combine the teachings of Rabinowitz, Ducker, Kruse to arrive at the instantly claimed method.
The person of ordinary skill in the art would have been motivated to administer SHIN2 (Applicants’ elected species) in a method of treating Leigh syndrome, because
Rabinowitz teaches that compound 74 (SHIN2) is a SHMT2 inhibitor, effective to treat cancer as a disease associated with dysregulated one-carbon metabolism,
Ducker teaches the role of SHMT2 in catabolizing serine in mitochondria with generation of NADH, and Ducker teaches that production of NADH by mitochondrial 5,10-methylene-THF dehydrogenase activity links 1C metabolism to the respiratory state of the cell, and
Kruse teaches Leigh syndrome, which is a mitochondrial complex I deficiency, is a mitochondrial disease characterized by respiration impairment, where the mitochondrial complex I deficiency results in accumulation of NADH.
Thus, the person of ordinary skill in the art would have administered a SHMT2 inhibitor compound 74 Rabinowitz (SHIN2) to a subject suffering from Leigh syndrome, with a reasonable expectation that pharmacological inhibition of SHMT2 with SHIN2 will reduce serine driven NADH production in cells with impaired respiration in patients with Leigh syndrome.
The person of ordinary skill in the art would have been motivated to co-administer SHIN2 and metformin to patients in a method of treating mitochondrial complex I deficiency which is Leigh syndrome, because Ducker teaches that metformin targets mitochondrial complex I and thus decreases the NAD+/NADH ratio. Therefore, one of ordinary skill in the art would have reasonably expected that combining SHIN2 and metformin, known/expected to be useful for the same purpose, i.e. decrease /attenuate excessive NADH levels, would result in therapeutic effect. At least additive therapeutic effects would have been reasonably expected. See In re Kerkhoven, 205 USPQ 1069 (CCPA 1980).
As such, claims 1-4, 8-12, 15-16, 19-21 are rejected as prima facie obvious.
Conclusion
Claims 1-4, 8-12, 15-16, 19-21 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IRINA NEAGU whose telephone number is (571)270-5908. The examiner can normally be reached Mon-Fri 8-5.
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/IRINA NEAGU/Primary Examiner, Art Unit 1629
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