DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim(s) 1-20 are pending.
Preliminary Amendments
Applicant’s preliminary amendment filed on 10/10/2023 is acknowledged. The claim(s) were amended to (1) add claim(s) 14-18. Applicant’s preliminary amendment filed on 05/04/2026 is acknowledged. The specification was amended to incorporate the sequence listing.
Receipt is also acknowledged of an amendment, filed 10/16/2024, in which claims 9, 10, 12 and 18 were amended, and claims 19-20 were added.
It is noted that the amendment to the claims filed on 10/16/2024 does not comply with the requirements of 37 CFR 1.121(c) because claim 13 was not provided with the proper status identifier. The claim has the status identifier “Currently Amended.” It should have the status identifier “previously Presented.” However, in the interest of compact prosecution, the amendment to the claims has been entered.
Priority
Acknowledgement is made that this application is a 371 of PCT/DE2022/100262 filed 04/07/2022 and claims priority based on foreign application filed as DE10 2021 109 341.4 on 04/14/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
All claims are given the priority date of 04/14/2021.
Specification
The substitute specification filed 05/04/2026 has been entered.
The specification is objected to because of the following informalities: The specification refers to Table(s) on page 8, “In a further preferred embodiment, the TKTL1 inhibitor is a substance or mixture of substances suitable for limiting or preventing the formation of the TKTL1-TKT heterodimer complex. The invention is explained in more detail below by means of embodiment with tables and figures.”, as well as referring to Table 1 on page 10, “The results of these tests are shown in Table 1 and Figures 1 and 2.”, however, there is/are no table(s) in the substitute specification filed 05/04/2026.
It is acknowledged that there was a “Table 1” filed on 10/10/2023 but it was not a part of the specification or drawings and was not incorporated in subsequent filings of the substitute specification(s) or drawings. The filed Table 1 also lacks a page number, See 37 CFR 1.52(b)(5) – “Other than in a reissue application or a reexamination or supplemental examination proceeding, the pages of the specification including claims and abstract must be numbered consecutively, starting with 1, the numbers being centrally located above or preferably, below, the text.”.
It would be remedial to refile a substitute specification incorporating “Table 1” and adding a page number.
The use of the term Qiagen (page 9, lines 9), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 1 is objected to because of the following informalities: “(transkeolase-like-1)” should recite “(transketolase-like-1)”.
Claim 2-3, 5, 7, and 11 are objected to because of the following informalities: the recitation of “. . .wherein a substance or mixture of substances. . .” reads as a broader embodiment than “inhibitor” i.e., the language of claim 1, however, the specification does provide guidance that “The term "inhibitor" is used herein in context to mean an agent (i.e., in principle, any agent) and, in particular, a substance (or mixture of substances, including pharmaceutical compositions) capable of directly or indirectly effecting/causing a reduction in the activity of the TKTL1 polypeptide in an individual or in cells of an individual. Such agents or material substances include, in particular: . . .” (page 4, definitions).
Thus, it would be remedial to amend the claim(s) to recite, “. . . wherein the inhibitor comprises a substance or mixture of substances . . .”.
Claim 15 is objected to because of the following informalities: claim 14 recites “The method of claim 14, the RNA virus is the SARS-CoV-2 virus.” It would be remedial to amend the claim to recite, “The method of claim 14, wherein the RNA virus is SARS-Cov-2.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) – indefiniteness
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.
Claim(s) 2-4, 7-11, and 17-20 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.
The term “restrict/ing” in claim(s) 2-3, 7 and 11, is a relative term which renders the claim indefinite. The term “restrict/ing” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Merriam-Webster (Restrict Definition & Meaning – Merriam Webster, pages 1-5; accessed 06/26/2026) defines “restrict” as “to confine within bounds” (page 1) or “narrowing or tightening or restraining within or as if within an encircling boundary” (page 2). Thus, without a definition provided in the specification or claims to ascertain the “bounds” of the restriction of (1) transcription of TKTL1 gene; (2) activity of the TKTL1 promoter; (3) an enzyme reaction of TKTL1 and/or TKTL1-TKT heterodimer complex; and (4) formation of a TKTL1-TKT heterodimer complex, the claims are indefinite.
Claim(s) 4 is rejected for being dependent upon claim 3; and 8-10 and 17-20 are rejected for being dependent upon claim 7.
Claim Rejections - 35 USC § 112(a) – Written Description
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.
Claim(s) 1-3, 5, 7, 8, 11, 14, and 15 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 fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, Applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117.
Claim(s) 1-3, 5, 7, 11, 14, and 15 are drawn to a genus of “inhibitor of TKTL1” for the treatment of a viral infection in a patient in need thereof. The rejected claims thus comprise a genus of inhibitor of TKTL1 and are defined as belonging to the broad class of inhibitors and as having the function of treating a viral infection in a patient in need thereof.
Claim(s) 2-3 limit claim 1 to a “substance or mixture of substances . . . adapted to restrict or prevent transcription of TKTL1 gene.”, (of claim 2) and “substance or mixture of substances . . . which are adapted to bind to a TKTL1 promoter of a cell of the patient and thereby restricting or inhibiting an activity of the TKTL1 promoter.”, (of claim 3). The specification does not provide a definition for “restrict”, and as mentioned above in the 35 USC 112b rejection, Meriam-Webster (supra) teaches that “restrict” is defined as to “confine within bounds” (page 1). One of skill in the art would understand by interpreting the data/figures that the inventors provided, the “restricted” (reading on inhibited) promotion of the TKTL1 promoter (a species of restricting transcription of the TKTL1 gene) and that the bounds are anywhere between about 10% (with 5uM) to about 100% (with 50uM) with Resveratrol in Figure 5. The specification does not provide a definition for “prevent” therefore prevent is given its plain meaning of the word. Meriam-Webster 2 (PREVENT Definition & Meaning - Merriam Webster, pages 1-9; accessed 06/27/2026) defines prevent as “to keep from happening or existing” (p.1) and implies “taking advance measure against something possible or probable” (p. 2). Accordingly, claim(s) 2 and 3 are drawn to genus of inhibitor of TKTL1 with limited structural definition that must function as treating a viral infection in a patient in need thereof and (claim 2) must function to inhibit or completely stop TKTL1 transcription or (claim 3) inhibit an activity of the TKTL1 promoter.
Claim 5 limits claim 1 to a “substance or mixture of substances. . . adapted to inhibit translation of TKTL1 mRNA.” Accordingly, claim 5 is drawn to a genus of inhibitor of TKTL1 with limited structural definition that must function as treating a viral infection in a patient in need thereof and must function to inhibit translation of TKTL1 mRNA.
Claim(s) 7, 8 and 11 limit claim 1 to a “substance or mixture of substances . . . adapted to restrict or prevent an enzyme reaction of the TKTL1 and/or a TKTL1-TKT heterodimer complex.”, (of claim 7); “substance or mixture of substances is/are antagonists of cofactors of TKTL1 polypeptides” (of claim 8), and “substance or mixture of substances. . .is/are adapted to restrict or prevent formation of a TKTL1-TKT heterodimer complex.”, (of claim 11). Accordingly, claims 7, 8 and 11 are drawn to a genus of inhibitor of TKTL1 with limited structure definition that must function as treating a viral infection in a patient in need thereof and must function to (claim 7) inhibit or completely stop an enzyme reaction of TKTL1 and/or act as an antagonist of cofactors of TKTL1 polypeptides (claim 8) and/or TKTL1-TKT heterodimer or (claim 11) inhibit or completely stop formation of a TKTL1-TKT heterodimer complex.
Claim(s) 14 and 15 limit claim 1 to “wherein the viral infection is a RNA virus infection.”, (of claim 14) and “the RNA virus is the SARS-COV-2 virus.”, (of claim 15). Accordingly, claims 14 and 15 are drawn to a genus and species, respectively, of viral infections and do not limit the structure of “inhibitor of TKTL1” of claim 1. Accordingly, the inhibitor of TKTL1 set forth in claim 1 must be capable of treating RNA viral infections and SARS-COV-2 viral infections.
To satisfy the written description requirement, MPEP §2163 states, in part “… a patent
specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.” Moreover, the written description requirement for a genus may be satisfied through sufficient description of a representative number of species by “… disclosure of relevant, identifying characteristics, i.e.,
structure or other physical and/or chemical properties, by functional characteristics coupled with
a known or disclosed correlation between functional and structure, or by a combination of such
identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.”
The specification envisions the inhibitor of TKTL1 as the following:
Inhibitors of transcription of the TKTL1 gene, for example, substance that bind to the TKTL1 promoter thereby restrict or inhibit activity, such as resveratrol (also mentioned at p.6, lines 23-25), which inhibits the TKTL1 promoter in a dose-dependent manner (p. 4, lines 25-27);
Inhibitors of translation such as antisense constructs, siRNAs, sh-RNAs, or ribozymes (p.4 lines 28-29; and p.6, lines 26-30);
Inhibitors of the enzyme reaction of TKTL1 and/or of the TKT heterodimer complex, in particular active substance/ingredients that restrict or prevent this enzyme reaction. This include in particular antagonists of cofactors of TKTL1 polypeptides such as antithiamine compounds (p.4, lines 30-34);
Inhibitors of the formation of the TKTL1-TKT heterodimer complex, especially agents that restrict or prevent heterodimer formation (p. 5, lines 1-2; p.8 lines 9-10).
The specification continues to envision inhibitory thiamine analogs as an inhibitor of TKTL1 such as oxythiamine (p.7, lines 6-7) or benfo-oxythiamine (p.7, lines 9-11).
The specification describes using TKTL1 specific siRNA sequences such as SEQ ID NOs:1-3 all found in the art, and a TKT specific siRNA, SEQ ID NO: 4, found in the art (p.9, lines 15-24). SEQ ID NO: 1 and 4 can be found being used in tissue culture (CaCo2 cells) experiments in figure 1-4. The specification describes using resveratrol in figure 5. All siRNA can be found in Table 1.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims in regard to structure and function, the examples are only representative of 6 inhibitors (SEQ ID NOs: 1-4, Resveratrol, and benfo-oxythiamine) used for treating a viral infection in a patient in need thereof. These results are not necessarily predictive of all “inhibitors of TKTL1” capable of treating a viral infection in a patient in need thereof. Thus, it is impossible for one to extrapolate from the 6 examples of inhibitors of TKTL1 described herein that the broad genus of “inhibitors of TKTL1” would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of “inhibitors of TKTL1” capable of treating a viral infection in a patient in need thereof.
It is acknowledged that the art provided in the specification describes (1) benfo-oxythiamine in the treatment of a viral infection, namely SARS-Cov-2; and (2) that prior-used sequences of siRNA targeting TKTL1 or TKT (SEQ ID NOs: 1-4) also decrease viral load of SARS or HCMV in tissue culture (see figures).
The specification fails to describe (1) a genus of inhibitors that can adapt to inhibit or completely stop the transcription of the TKTL1 gene, (2) a genus of inhibitors that can bind to the TKTL1 promoter inhibit or completely stop activity of the TKTL1 promoter; (3) a genus of inhibitors that can adapt to inhibit translation of TKTL1 mRNA; (4) a genus of inhibitors that can adapt to inhibit or completely stop an enzyme reaction of TKTL1 and/or a TKTL1/TKT heterodimer complex; and (5) a genus of inhibitors that can adapt to inhibit or completely stop formation of a TKTL1-TKT heterodimer complex; all of which these genera must be capable of treating a viral infection and inhibiting TKTL1.
(1/2) Regarding inhibitors (besides resveratrol) that can bind to the TKTL1 promoter and inhibit or completely stop transcription of the TKTL1 gene for treatment of a viral infection in a patient in need thereof, the art does not appear to offset these deficiencies. A subgenus of inhibitors binding to a promoter to inhibit or completely stopping transcription of the TKTL1 gene could include: repressor proteins, DNA-binding repressors, chromatin repressors, DNA methylation, transcription factor inhibitors, RNA Polymerase inhibitors, and/or CRISPR interference.
For example, Sun et al (TKTL1 is activated by promoter hypomethylation and contributes to head and neck cell carcinoma carcinogenesis via increased aerobic glycolysis and HIF1a stabilization, Clin Cancer Res, vol 16, issue 3, pages 1-20, published Feb 1st 2011) teaches that methylation pattern of TKTL1 effects its transcription and protein level, “By evaluation of TKTL1 overexpression at transcriptional level and protein level, we observed that TKTL1 is significantly overexpressed in HNSCC cancers in comparison to that in normal tissues. It is likely that hypomethylation could be attributable to the overexpression of TKTL1. In support of this, we previously identified the HNSCC primary tissues showing both hypomethylation and overexpression of TKTL1. In the TKTL1 methylated human oral keratinocyte cell line OKF6, we reported transcriptional upregulation of TKTL1 after 5-aza/TSA treatment, supporting the concordance between methylation and expression”, (page 7, para 2).
(3) Regarding a genus of inhibitors that can adapt to inhibit translation of TKTL1 mRNA. Outside of directly targeting TKTL1 mRNA, many compounds inhibit cellular translation, and in turn inhibit translation of TKTL1 mRNA.
Novac et al (Inhibitors of protein synthesis identified by a high throughput multiplexed translation screen, Nucleic Acids Res, Vol 32, Iss 3, pages 902-915, published 02/09/2004) teaches 36 inhibitors of translation, e.g., cycloheximide and ethidium bromide (see table 1). However, SDS (Afla Aesar - Cycloheximide, CAS 66-81-9; pages 1-5; accessed 06/27/2026) teaches that cycloheximide is fatal if swallowed (see page 1 under 2, hazard identifications).
(4/5) Regarding a genus of inhibitors that can inhibit or completely stop an enzyme reaction of TKTL1 and/or a TKTL1/TKT heterodimer complex and/or inhibit or completely stop formation of a TKTL1-TKT heterodimer complex, Li et al (Chaetocin, a Natural Inhibitor of Transketolase, Suppresses the Non-Oxidative Pentose Phosphate Pathway and Inhibits the Growth of Drug-Resistant Non-Small Cell Lung Cancer, Antioxidants (Basel), vol 14, issue 3, pages 1-20, published 03/11/2025) teaches that Chaetocin is an inhibitor of TKTL1, more specifically, “Chaetocin can directly bind to TKT, inhibiting its enzyme activity and expression, interfering with intracellular metabolism and oxidation-reduction balance, and then regulating the PI3K/Akt signaling pathway to inhibit the growth of NSCLC and induce apoptosis.”, (see page 2, para 4). However, Zhang et al (Chaetoin reactivates the lytic replication of Epstein-Barr virus from latency via reactive oxygen species, Science China Life Science, vol 60, pages 66-71, published 01/05/2017) teaches that chaetocin reactivates the ebstein-barr virus, specifically, “We found that chaetocin remarkably up-regulated EBV lytic transcription and DNA replication at a low concentration (50 nmol L−1). The activation of latent EBV was accompanied by an increased cellular ROS level. N-acetyl-L-cysteine (NAC), an ROS inhibitor, suppressed chaetocin-induced EBV activation. Chaetocin had little effect on histone H3K9 methylation, while NAC also significantly reduced H3K9 methylation. These results suggested that chaetocin reactivates latent EBV primarily via ROS pathways.”, (abstract).
Thus, the art does not appear to offset the deficiencies of the specification. Merely describing a “inhibitor of TKTL1” capable of treating a viral infection in a patient in need thereof without sufficient detail relating to the genus of inhibitors of TKTL1 in treating a viral infection in a patient in need thereof does not allow the skilled artesian to reasonably conclude that the Applicants were in possession of the claimed invention in claim(s) 1-3, 5, 7, 8, 11, 14, and 15.
Claim Rejections - 35 USC § 112(a) – Enablement
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.
Claim(s) 1-3, 5, 7, 8, 11, 14, and 15 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for A method of treating a viral infection comprising: administering to a patient in need thereof an inhibitor of transketolase TKTL1 (transketolase-like-1) in an amount effective for treating a viral infection;
Wherein the inhibitor is a substance or mixture of substances comprising inhibitor mRNA(s) specific for TKTL1 mRNA, an inhibitory thiamine analogue, antagonists of cofactors of TKTL1 peptides, or resveratrol; does not reasonably provide enablement for (a) any/all inhibitors that can adapt to inhibit or completely stop the transcription of the TKTL1 gene, (b) any/all inhibitors that can bind to the TKTL1 promoter inhibit or completely stop activity of the TKTL1 promoter; (c) any/all inhibitors that can adapt to inhibit translation of TKTL1 mRNA; (d) any/all inhibitors that can adapt to inhibit or completely stop an enzyme reaction of TKTL1 and/or a TKTL1/TKT heterodimer complex; or (e) any/all inhibitors that can adapt to inhibit or completely stop formation of a TKTL1-TKT heterodimer complex. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention:
Claim 1 is are drawn to A method for treating a viral infection comprising: administering to a patient in need thereof an inhibitor of transketolase TKTL1 (transkeolase-like-1) in an amount effective for treating the viral infection. The nature of the invention is complex in that any/all inhibitor(s) of TKTL1 must be capable of treating any/all viral infection(s).
Claim(s) 2-3 limit claim 1 to a “substance or mixture of substances . . . adapted to restrict or prevent transcription of TKTL1 gene.”, (of claim 2) and “substance or mixture of substances . . . which are adapted to bind to a TKTL1 promoter of a cell of the patient and thereby restricting or inhibiting an activity of the TKTL1 promoter.”, (of claim 3). The nature of the invention is complex in that (1) the instant specification does not define “restrict/ing” or “prevent/ing”. “Restrict/ing”, will get it’s plain meaning, Meriam-Webster (supra) teaches that “restrict” is defined as to “confine within bounds” (page 1). As well as for “prevent/ing” Meriam-Webster 2 (supra) defines prevent as “to keep from happening or existing” (p.1). Regarding “restrict/ing”, one of skill in the art would understand by interpreting the data/figures that the inventors provided, the “restricted” (reading on inhibited) promotion of the TKTL1 promoter (a species of restricting transcription of the TKTL1 gene) and that the bounds are anywhere between about 10% (with 5uM) to about 100% (with 50uM) with Resveratrol in Figure 5. However, the specification does not allow one of skill in the art to ascertain “prevent/ing”, thus, prevent/ing will be defined as to completely stop. The nature of the invention is complex in that (2) the substance or mixture of substances must be capable of prevent transcription of TKTL1 gene or inhibiting activity of the TKTL1 promoter and treat any/all viral infection(s).
Claim 5 limits claim 1 and is drawn to a “substance or mixture of substances. . . adapted to inhibit translation of TKTL1 mRNA.” The nature of the invention is complex in that the inhibitor must be capable of inhibiting translation of TKTL1 mRNA and treating any/all viral infection(s).
Claim(s) 7, 8 and 11 limit claim 1 and are drawn to a “substance or mixture of substances . . . adapted to restrict or prevent an enzyme reaction of the TKTL1 and/or a TKTL1-TKT heterodimer complex.”, (of claim 7); “substance or mixture of substances is/are antagonists of cofactors of TKTL1 polypeptides” (of claim 8), and “substance or mixture of substances. . .is/are adapted to restrict or prevent formation of a TKTL1-TKT heterodimer complex.”, (of claim 11). The nature of the invention is complex in that the inhibitor must be capable of inhibiting or completely stopping an enzyme reaction TKTL1 and/or TKTL1-TKT heterodimer or inhibit or completely stop formation of a TKTL1-TKT heterodimer complex and treating any/all viral infection(s)/
Claim(s) 14 and 15 limit claim 1 and are drawn to “wherein the viral infection is a RNA virus infection.”, (of claim 14) and “the RNA virus is the SARS-COV-2 virus.”, (of claim 15). The nature of the invention is complex in that any/all inhibitors of TKTL1 must be capable of treating an RNA viral infection and/or a SARS-COV-2 viral infection.
Breadth of the claims:
Claim 1 is broad in that it encompasses to a method of treating any/all viral infections comprising administering to a patient in need thereof any/all inhibitors of TKTL1. Claim(s) 2-3 are broad in they encompass any/all inhibitors capable of inhibiting or completely stopping transcription of the TKTL1 gene and/or any/all inhibitors capable of binding the TKTL1 promoter. Claim 5 is broad in that it encompasses any/all inhibitors capable of inhibiting TKTL1 mRNA expression. Claim(s) 7, 8 and 11 are broad in that they encompass any/all inhibitors capable of inhibiting or completely stopping an enzyme reaction of TKTL1 and/or inhibotrs capable of acting as antagonists of cofactors of TKTL1 polypeptides and/or a TKTL1/TKT heterodimer complex, and/or inhibit or completely stop the formation of the TKTL1/TKT heterodimer.
The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims.
Guidance of the specification:
The specification provides guidance on the inhibitor of TKTL1 with the following:
Inhibitors of transcription of the TKTL1 gene, for example, substance that bind to the TKTL1 promoter thereby restrict or inhibit activity, such as resveratrol (also mentioned at p.6, lines 23-25), which inhibits the TKTL1 promoter in a dose-dependent manner (p. 4, lines 25-27);
Inhibitors of translation such as antisense constructs, siRNAs, sh-RNAs, or ribozymes (p.4 lines 28-29; and p.6, lines 26-30);
Inhibitors of the enzyme reaction of TKTL1 and/or of the TKT heterodimer complex, in particular active substance/ingredients that restrict or prevent this enzyme reaction. This include in particular antagonists of cofactors of TKTL1 polypeptides such as antithiamine compounds (p.4, lines 30-34);
Inhibitors of the formation of the TKTL1-TKT heterodimer complex, especially agents that restrict or prevent heterodimer formation (p. 5, lines 1-2; p.8 lines 9-10).
The specification continues to envision inhibitory thiamine analogs as an inhibitor of TKTL1 such as oxythiamine (p.7, lines 6-7) or benfo-oxythiamine (p.7, lines 9-11).
The specification teaches using TKTL1 specific siRNA sequences such as SEQ ID NOs:1-3 all found in the art, and a TKT specific siRNA, SEQ ID NO: 4, found in the art (p.9, lines 15-24). SEQ ID NO: 1 and 4 can be found being used in tissue culture (CaCo2 cells) experiments in figure 1-4. The specification describes using resveratrol in figure 5. All siRNA can be found in Table 1.
Working examples:
Example 1: Inventor uses three siRNAs targeting TKTL1 and one siRNA targeting TKT to demonstrate inhibition of TKTL1 to a degree that does not affect cell survival can significantly inhibit SARs-CoV-2 replication.
Example 2: Inventor does the same experiments except with the HCMV virus instead of SARs-CoV-2.
Example 3: Applicant describes a previous study that uses benfooxythiamine to inhibit mammalian cells infected with HCMV.
Example 4: Applicant describes the use of benfooxythiamine in patients with COVID-19.
Example 5: Inventor uses Resveratrol to inhibit viral replication of SARs-CoV-2 in infected Caco-2 cells.
Predictability and state of the art:
The prior art does not appear to offset the deficiencies of the instant specification in that it does not enable all “inhibitors of TKTL1” that must be capable of treating a viral infection in a patient in need thereof.
It is acknowledged that the art provided in the specification describes (1) benfo-oxythiamine in the treatment of a viral infection, namely SARS-Cov-2; and (2) that prior-used sequences of siRNA targeting TKTL1 or TKT (SEQ ID NOs: 1-4) also decrease viral load of SARS or HCMV in tissue culture (see figures).
The specification fails to provide an enabling disclosure for (1) a genus of inhibitors that can adapt to inhibit or completely stop the transcription of the TKTL1 gene, (2) a genus of inhibitors that can bind to the TKTL1 promoter inhibit or completely stop activity of the TKTL1 promoter; (3) a genus of inhibitors that can adapt to inhibit translation of TKTL1 mRNA; (4) a genus of inhibitors that can adapt to inhibit or completely stop an enzyme reaction of TKTL1 and/or a TKTL1/TKT heterodimer complex; and (5) a genus of inhibitors that can adapt to inhibit or completely stop formation of a TKTL1-TKT heterodimer complex; all of which these genera must be capable of treating a viral infection and inhibiting TKTL1.
(1/2) Regarding inhibitors (besides resveratrol) that can bind to the TKTL1 promoter and inhibit or completely stop transcription of the TKTL1 gene for treatment of a viral infection in a patient in need thereof, the art does not appear to offset these deficiencies. A subgenus of inhibitors binding to a promoter to inhibit or completely stopping transcription of the TKTL1 gene could include: repressor proteins, DNA-binding repressors, chromatin repressors, DNA methylation, transcription factor inhibitors, RNA Polymerase inhibitors, and/or CRISPR interference.
For example, Sun et al (TKTL1 is activated by promoter hypomethylation and contributes to head and neck cell carcinoma carcinogenesis via increased aerobic glycolysis and HIF1a stabilization, Clin Cancer Res, vol 16, issue 3, pages 1-20, published Feb 1st 2011) teaches that methylation pattern of TKTL1 effects its transcription and protein level, “By evaluation of TKTL1 overexpression at transcriptional level and protein level, we observed that TKTL1 is significantly overexpressed in HNSCC cancers in comparison to that in normal tissues. It is likely that hypomethylation could be attributable to the overexpression of TKTL1. In support of this, we previously identified the HNSCC primary tissues showing both hypomethylation and overexpression of TKTL1. In the TKTL1 methylated human oral keratinocyte cell line OKF6, we reported transcriptional upregulation of TKTL1 after 5-aza/TSA treatment, supporting the concordance between methylation and expression”, (page 7, para 2).
(3) Regarding a genus of inhibitors that can adapt to inhibit translation of TKTL1 mRNA. Outside of directly targeting TKTL1 mRNA, many compounds inhibit cellular translation, and in turn inhibit translation of TKTL1 mRNA.
Novac et al (Inhibitors of protein synthesis identified by a high throughput multiplexed translation screen, Nucleic Acids Res, Vol 32, Iss 3, pages 902-915, published 02/09/2004) teaches 36 inhibitors of translation, e.g., cycloheximide and ethidium bromide (see table 1). However, SDS (Afla Aesar - Cycloheximide, CAS 66-81-9; pages 1-5; accessed 06/27/2026) teaches that cycloheximide is fatal if swallowed (see page 1 under 2, hazard identifications).
(4/5) Regarding a genus of inhibitors that can inhibit or completely stop an enzyme reaction of TKTL1 and/or a TKTL1/TKT heterodimer complex and/or inhibit or completely stop formation of a TKTL1-TKT heterodimer complex, Li et al (Chaetocin, a Natural Inhibitor of Transketolase, Suppresses the Non-Oxidative Pentose Phosphate Pathway and Inhibits the Growth of Drug-Resistant Non-Small Cell Lung Cancer, Antioxidants (Basel), vol 14, issue 3, pages 1-20, published 03/11/2025) teaches that Chaetocin is an inhibitor of TKTL1, more specifically, “Chaetocin can directly bind to TKT, inhibiting its enzyme activity and expression, interfering with intracellular metabolism and oxidation-reduction balance, and then regulating the PI3K/Akt signaling pathway to inhibit the growth of NSCLC and induce apoptosis.”, (see page 2, para 4). However, Zhang et al (Chaetoin reactivates the lytic replication of Epstein-Barr virus from latency via reactive oxygen species, Science China Life Science, vol 60, pages 66-71, published 01/05/2017) teaches that chaetocin reactivates the ebstein-barr virus, specifically, “We found that chaetocin remarkably up-regulated EBV lytic transcription and DNA replication at a low concentration (50 nmol L−1). The activation of latent EBV was accompanied by an increased cellular ROS level. N-acetyl-L-cysteine (NAC), an ROS inhibitor, suppressed chaetocin-induced EBV activation. Chaetocin had little effect on histone H3K9 methylation, while NAC also significantly reduced H3K9 methylation. These results suggested that chaetocin reactivates latent EBV primarily via ROS pathways.”, (abstract).
Amount of experimentation necessary:
The quantity needed to carry out the scope of the invention is large. (1) One would need
to test representative substances of the genus of inhibitors that can adapt to inhibit or completely stop the transcription of the TKTL1; (2) One would need to test representative substances of the genus of inhibitors that can bind to the TKTL1 promoter inhibit or completely stop activity of the TKTL1 promoter; (3) One would need to test representative substances of the genus of inhibitors that can adapt to inhibit translation of TKTL1 mRNA; (4) One would need to test representative substances of the genus of inhibitors that can adapt to inhibit or completely stop an enzyme reaction of TKTL1 and/or a TKTL1/TKT heterodimer complex; and (5) One would need to test representative substances of the genus of inhibitors that can adapt to inhibit or completely stop formation of a TKTL1-TKT heterodimer complex; all of which (1)-(5) would need to be performed in an art accepted model of viral infection. This type of experimentation is not routine in the art and would require a large amount of inventive effort. Further considering that any positive results (e.g., successful treatment of any/all viral infections with the broad genus of TKTL1 inhibitors) would amount to a significant advancement in the state of the art, additional experimentation required is considered undue.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims claim(s) 1-3, 5, 7, 8, 11, 14, and 15 are not considered to be fully enabled, but are scoped to A method of treating a viral infection comprising: administering to a patient in need thereof an inhibitor of transketolase TKTL1 (transketolase-like-1) in an amount effective for treating a viral infection;
Wherein the inhibitor is a substance or mixture of substances comprising inhibitor mRNA(s) specific for TKTL1 mRNA, an inhibitory thiamine analogue, antagonists of cofactors of TKTL1 peptides, or resveratrol, by the instant disclosure.
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.
Claim(s) 1-4, and 11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by 834 (US 6,197,834 B1, published 03/06/2001).
Regarding claim(s) 1 and 4, 834 teaches inhibition of HSV-1 viral replication with differing concentrations of resveratrol in figure(s) 1-2. 834 teaches the treatment with resveratrol in HSV-1 infected cells. Moreover, 834 teaches the treatment of HSV-1 infected hairless mice with topical resveratrol in table 2.
Regarding claim(s) 2, 3, and 11, the product “resveratrol” to treat viral infections, inherently inhibits transcription of the TKTL1 gene (claim 2) through binding of the TKTL1 promoter (claim 3), and therefore inhibits formation of a TKTL1-TKT heterodimer complex (claim 11). See MPEP 2112.02 I, “Under the principles of inherency, if a prior art device, in its normal and usual operation, would necessarily perform the method claimed, then the method claimed will be considered to be anticipated by the prior art device. When the prior art device is the same as a device described in the specification for carrying out the claimed method, it can be assumed the device will inherently perform the claimed process.”
The instant specification discloses, “In a preferred embodiment, the inhibitor is a substance or mixture of substances that is capable and suitable of specifically restricting or preventing the transcription of the TKTL1 gene. In particular, a substance capable of and suitable for binding to the TKTL1 promoter of the cell and thereby restricting or preventing its activity is suitable for this purpose. In practice, resveratrol in particular has proven to be a suitable inhibitor of the TKTL1 promoter (Kumar B, 2018).”, (p.6, lines 19-25; also see p.13 lines 26-31, and figure 5). Moreover, the instant specification continues to describe, “Li et al. (2019) describes that the formation of TKTL1-TKT heterodimers allows cells to reprogram R5P metabolism: When more R5P is needed, which is especially the case for nucleotide and DNA synthesis during S phase of the cell, increased TKTL1 levels lead to increased formation of TKTL1-TKT heterodimers. These promote R5P production. In other words, and in simplified terms, Li et al. show that the basic R5P supply of a cell is provided by the TKT-TKT homodimer. If the cell requires an additional large amount of R5P, the expression of TKTL1 and the resulting TKT-TKTL1 heterodimer formation will, in a sense, start an "intracellular turbo program" that promotes increased production of R5P to enable cell division and thus cell proliferation.”, (p. 3, lines 12-20).
Accordingly, claim(s) 1-4, and 11 are anticipated by 834.
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.
Claim(s) 1 and 5-20 are rejected under 35 U.S.C. 103 as being unpatentable over Coy (EP 1701165 A1; published 09/13/2006) in view of Bokjova et al (Targeting pentose phosphate pathway for SARS-CoV-2 therapy, BioRxiv; published 08/21/2020; filed on IDS from 10/10/2023 NPL #3).
Regarding claim 1, Coy et al teaches methods of treating diseases associated with enhanced transketolase activity (abstract). More specifically, “The present invention relates to methods for treatment, detection and diagnosis of disorders associated with an altered transketolase (transketolase-like 1; TKTL1) with a modified substrate specificity and modified reaction modus.”, (para [0001]). Further, “In one embodiment the treatment of disorders associated with overexpression of TKTL1 gene may comprise restricted or enhanced administration of thiamine (benfotiamine or other thiamine derivatives) to the affected individuals. In another embodiment the treatment may comprise the administration of TKTL1 inhibitors, such as e.g. antithiamine compounds.”, (para [0086]). Coy et al teaches that pharmaceutical compositions are administered at a suitable dosage to ensure the pharmaceutical benefit, where the treatment should be chosen according to parameters including body weight (para [0116]).
Regarding claim(s) 5, 6, and 16, Coy teaches using TKTL1 polynucleotides for therapeutic purposes (para [0052]; [0114]), moreover, “Fragments of the TKTL1 sequence used herein may comprise oligonucleotides such as nucleic acid probes for hybridisation purposes, primers for amplification reactions or antisense constructs for use in antisense techniques. Nucleic acid probes according to the present invention may be any nucleic acid probe that has a sequence at least 80% identical to a part of at least 15 consecutive nucleotides of the TKTL1 gene nucleic acid sequence or is complementary or reverse complementary to such a sequence but does not hybridise to any other transketolase or transketolase like sequence.”, (para [0053]). Further, “Antisense oligonucleotides as used herein may be nucleic acid molecules reverse complementary to the transcripts of the disclosed coding sequence, that are able to bind to the transcripts by base pairing and such inhibit or reduce expression of said coding sequence.”, (para [0054]).
Regarding claim(s) 7-11 and 17-18 Coy teaches “In one embodiment the treatment of disorders associated with overexpression of TKTL1 gene may comprise restricted or enhanced administration of thiamine (benfotiamine or other thiamine derivatives) to the affected individuals. In another embodiment the treatment may comprise the administration of TKTL1 inhibitors, such as e.g. antithiamine compounds.”, (para [0086]). Coy et al further teaches, “Examples of TKTL1 inhibitors according to the invention are oxythiamine, benfooxytiamine, hydroxypyruvate, pyruvate, p-hydroxyphenylpyruvate, pyrithiamin, amprolium, 2-methylthiamin, benfotiamine, benfooxytiamine, 2-methoxy-p-benzochinon (2-MBQ) und 2,6-dimethoxy-p-benzochinon (2,6-DMBQ), genistein, and flavonols as e.g. quercetin, catechins, nitrilosides, anthocyanins and derivatives thereof.”, (para [0087]).
Coy does not teach (a) viral infections (i.e., RNA and/or SARS-CoV-2) or (b) specific concentrations of benfo-oxythiamine for use.
Regarding claim(s) 1, 7-11, 14-15, 17-18, and 20, Bokjova et al teaches “Notably, transketolase (TKT) and transaldolase 1 (TALDO1), two constituents of the non-oxidative PPP branch (Stincone et al., 2015), displayed increased levels in SARS-CoV-2-infected cells (Figure S1A), suggesting that the non-oxidative PPP branch is also regulated in response to SARS-CoV-2 infection. . . Recently, it has been shown that TKT activity may be strongly increased by the formation of a heterodimer with transketolase like 1 (TKTL1) (Li et al., 2019).”, (p.3, para 3 to p4, para 1). Further, Bokjova et al teaches, “Irreversible inhibitors of TKT such as oxythiamine (an inactive analogue of thiamine) have been developed (Tylicki et al., 2018). To investigate whether TKT inhibitors affect SARS-CoV-2 replication, we used benfooxythiamine (BOT), a prodrug of the TKT inhibitor oxythiamine, currently evaluated in pre-clinical experiments (Coy, 2017). Indeed, non-toxic BOT concentrations inhibited the replication of two different SARS-CoV-2 isolates (FFM1 and FFM7) in a concentration-dependent manner, as indicated by immunostaining for the SARS CoV-2 Spike (S) protein and the detection of genomic RNA by qPCR (Figure S1B-S1D).”, (p.4, para 2).
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Regarding claim(s) 12-13, and 19, Bokjova et al teaches a range of concentrations of benfo-oxythiamine (BOT) used to measure RNA copies/mL in figure S1D (see below).
The instant specification explains that 5.00mM as being at least to 1g of BOT per 1kg of body weight (see p.3 lines 29-30). Thus, the ranges set forth in figure S1D, when converted by the equation set forth in the instant specification of 5mM = 1g, are as followed: control, 1g, 250mg, 310ug, and 16ug.
Therefore, it would have been obvious to one of skill in the art before the effective filing date of the claimed invention to combine the teachings of Coy, i.e., treating disorders associated with overexpression of TKTL1 with the teachings of Bokjova et al, using a known TKTL1 inhibitor, benfo-oxythiamine, to decrease SARS-COV-2 RNA copies, to yield the predictable results of treating a viral infection in a patient in need thereof via administering an inhibitor of TKTL1. One would have been motivated to combine the teachings of Coy and Bokjova et al because Coy teaches treating disorders associated with overexpression of TKTL1 with inhibitors such as antisense oligonucleotides or antithiamine inhibitors, e.g., oxythiamine and benfooxythiamine and Bokjova et al teaches that TKT is overexpressed in SARS-CoV-2 infection and that administering benfooxythiamine at an amount that equates to 310 μg per kg of body weight of the patient per day can significantly inhibit RNA copies/mL.
Accordingly, claim(s) 1 and 5-20 are rejected as being unpatentable over Coy in view of Bokjova et al.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim(s) 1 and 7-20 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 22 and 25 of copending Application No. 18/937,150 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because of the following.
Claim 22 of 150 recites, “A method for successive slowing of anabolic, catabolic and/or energy- releasing metabolic processes of cells in the body of a patient suffering from a disease comprising: administering as part of a treatment of the patient oxythiamine (OT) and/or benfo- oxythiamine (B-OT) in an amount effective to cause a successive slowdown of the anabolic, catabolic and/or energy-releasing metabolic processes in the cells in the body of the patient, wherein the cells comprise healthy cells of the body of the patient and degenerated cells and any exogenous cells, wherein the slowdown is controlled during a treatment phase via a dosage regime of oxythiamine (OT) and/or benfo-oxythiamine (B-OT), wherein following the treatment phase, the metabolism of a majority of the healthy cells reactivates (claim 21)”, wherein the disease is selected from the group consisting of: bacterial disease, disease originating from/ caused by fungi, sepsis or impending sepsis, viral disease, immunological disease, traumatic brain injury, nerve transection, cardiac or cerebral infarction, painful blunt injuries.”
Claim 22 of 150 anticipates claim(s) 1, 7-11, 14-18, and 20.
Claim 25 of 150 recites, “The method according to claim 21(above), wherein the dosage regimen comprises individual doses of the OT and/or the B-OT for a patient having 60 kg body weight, wherein the individual doses range from about 0.1 mg to about 80 mg.”
Claim 25 of 150 anticipates claim(s) 12-13, and 19.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims allowed.
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/L.M.T./Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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