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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on June 19, 2026 has been entered.
The Applicants’ Amendment to the Claims filed on June 19, 2026 is entered.
Claims 17-55, 57-62, 64-84, and 86-92 are cancelled.
Claims 1-16, 56, 63, 85, and 93-104 are pending.
Claims 1-16, 63, and 85 are withdrawn.
Claims 56, and 93-104 are under examination in this office action.
Priority
This US17/775,473 filed on 05/09/2022 which is a 371 of PCT/US2020/059991 filed on 11/11/2020 claims US priority benefit of US Provisional 62/933,656 filed on 11/11/2019.
Response to Amendment
All objections and rejections made in the previous Office Action and not repeated in this Office Action are withdrawn in view of the Applicants’ Amendment to the Claims filed on June 19, 2026.
Claim Rejections - 35 USC § 112 – maintained-in-part
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 102 and 104 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 102 fails to further limit base claim 56 upon which it depends because claim 56 recites that the druggable biomolecular site is an active site of a peroxidase.
Claim 104 fails to further limit base claim 56 upon which it depends regarding parts (a) and (b). Also, part (c) recites “ameliorating inflammation and oxidative stress in the subject” which is not explicitly recite in base claim 56. Note that as presently written, each of parts (a) thru (c) are written in the alternative. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to argument: The response filed on 06/19/2026 has been fully considered but is unpersuasive because the amendment did not address the limitation stating the druggable biomolecular site is an active site of a peroxidase.
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.
Written Description - maintained
Claims 56, and 93-104 stand 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 full scope of the claimed invention.
Presently amended claims are drawn to a method of treating a disease or condition in a subject comprising administering to the subject a “systems chemico-pharmacology drug (SCPD)”. Claims require the critically essential element of a genus of an SCPD that has the required functional properties whereby the SCPD interacts with a first target that comprises a druggable biomolecular site which is an active site of a peroxidase, whereby the SCPD modifies the properties of the first target and is itself chemically modified by oxidative activation or electron transfer excitation to create a chemically modified SCPD structure, and further whereby the chemically modified SCPD interacts with one or more second targets via thiolation of the one or more second targets, thus modifying the second targets' function; whereby the disease or condition is treated in the subject.
Presently amended base claim 56 further limits the generic SCPD structure to where the SCPD consists of a tripeptide KXZ having the formula AA1-AA2-AA3, wherein AA1 (K) is an amino acid comprising a basic side chain (aka positive charged: Lys, Arg, His), AA2 (X) is a polar, non-polar or aromatic amino acid (aka Ser, Thr, Cys, Asn, Gln, Tyr), and AA3 (Z) is an amino acid possessing a heteroatom that is capable of stabilizing a free radical, wherein one or more of the second targets is a pro-inflammatory protein being HMGB1, TRL4, or KEAP-1. Note that in the context of amino acids, "heteroatom" generally refers to any atom that is not carbon or hydrogen. Common heteroatoms found in amino acids include nitrogen, oxygen, and sulfur. These atoms play a crucial role in the structure, function, and properties of amino acids and the proteins they form. Claims 93-104 depend from claim base claim 56. Claims 93-101 further specify types of diseases and conditions to be treated. Claim 103 limits claim 102 to wherein the peroxidase is a myeloperoxidase (MPO) or eosinophil peroxidase (EPO). Claim 104 limits base claim 56 to where the inflammation and oxidative stress in the subject is ameliorated.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include:
(1) Actual reduction to practice,
(2) Disclosure of drawings or structural chemical formulas,
(3) Sufficient relevant identifying characteristics such as:
i. Complete structure,
ii. Partial structure,
iii. Physical and/or chemical properties,
iv. Functional characteristics when coupled with a known or disclosed structure, and correlation between function and structure,
(4) Method of making the claimed invention,
(5) Level of skill and knowledge in the art, and
(6) Predictability in the art.
Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
The state of the art shows that tripeptide drugs were known in the art for purpose of treating certain diseases or conditions. For example, Chen et al disclose that a three amino acid tripeptide RGD was tested for use as a drug for alpha5beta1 integrin binding in human urothelial carcinoma cells. The results showed that RGD-MAP8 failed to have a significant effect on CEBP or NRF2 activation, gene expression or cell viability. Chen et al show the unpredictable nature of tripeptide drug molecules for treating a disease or condition. (See Chen et al “A Synthetic Polyvalent Ligand for alpha5beta1 Integrin Activates Components of the Urothelial Carcinoma Cell Response to Bacillus Calmetter-Guerin” The Journal of Urology March 2013, Vol 189, pages 1104-1109). Further, in post-filing art Ma et al disclose use of a tripeptide drug GHK for use in treating lung fibrosis. (See Ma et al in “Protective effects of GHK-Cu in bleomycin-induced pulmonary fibrosis via anti-oxidative stress and anti-inflammation pathways” Life Sciences 2020 Vol 241, available online December 4, 2019.) Ma et al disclose that GHK has been known in the prior art for use in wound healing and anti-aging skin care. Ma et al disclose that adding copper to the GHK drug shows improved results in lung tissue for treating pulmonary fibrosis (see FIG 5-7). Ma et al conclude in their post-filing art that GHK-Cu “may be a candidate for pulmonary fibrosis treatment”. In addition, Minelli et al disclose administering a Gly-Pro-Glu tripeptide bound to L-dopa in a Parkinson’s animal model. (See Minelli et al Amino Acids 2012 Vol 43, pages 1359-1367”.
For a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. The MPEP states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not a sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP § 2163. The MPEP does state that for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad generic. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618.
However, the state of the art does not appear to disclose a representative set of drugs having the required functional properties recited in the instant claims so that one of ordinary skill in the art would be able to envision whether a given drug structure would possess these required functional properties. The Court of Appeals for the Federal Circuit has recently held that a "written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as be structure, formula [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials." University of California v. Eli Lilly and Co., 1997 U.S. App. LEXlS 18221, at *23, quoting Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) (bracketed material in original). To fully describe a genus of genetic material, which is a chemical compound, applicants must (1) fully describe at least one species of the claimed genus sufficient to represent said genus whereby a skilled artisan, in view of the prior art, could predict the structure of other species encompassed by the claimed genus and (2) identify the common characteristics of the claimed molecules, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these.
The instant specification describes a working example of treating a mouse model with a specific species of drug which is called “KYC” made for targeting myeloperoxidase (MPO) in neonatal lungs exposed to hyperoxia (See para 0062; FIG 4-20, 22-28, 32, and 34-38, and 41-44 targeting the second target proteins HMGB1, RAGE, TLR4, and Nrf2, and Keap1). The specification does not show any other species of an SCPD drug structure performing the required functional properties. However, the species of “KYC” does not adequately support the claimed genus because the specification does not provide common identifying characteristics of the claimed molecules, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or a combination of these result where such species may be used to treat disease in a subject and also possess the specific functions required of the present claims. While having written description of the working example identified in the specification tables and/or examples, the specification does not provide sufficient descriptive support for the myriad of embodiments embraced by the claims. Given this lack of description of representative species encompassed by the genus of the claim, the specification does not sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants were in possession of the entire scope of the claimed invention.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description' inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the amount and time period for a representative set of combinations of methods of reducing methylation, cell types, and markers to produce the claims invention. Therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method. For example, adequate written description requires more than a mere statement that a compound is part of the invention and reference to a potential method of isolating a compound. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
In the instant case, listing variants for an SCPD is not sufficient because such variants are not shown to perform the required functional properties required of the instant claims. Thus, one of ordinary skill in the art would not be able to envision whether a given structure would be encompassed by the invention. Rather, a specific structure is required.
Response to Arguments
The Applicants’ response filed on 06/12/2026 has been fully considered but is unpersuasive. The applicants argue that applicants have “amended claim 56 to specify that the SCPD consist of a structure of tripeptide KXZ having the formula AA₁-AA₂-AA₃, wherein AA₁ (K) is an amino acid comprising a basic side chain, AA₂ (X) is a polar, non-polar or aromatic amino acid, and AA₃ (Z) is an amino acid possessing a heteroatom that is capable of stabilizing a free radical which is capable of performing the various method steps discussed previously”. Further, the applicants argue:
Thus, in accordance with the discussion provided by the Examiner that applicants must (1) fully describe at least one species of the claimed genus (i.e., KYC) sufficient to represent said genus whereby a skilled artisan, in view of the prior art, could predict the structure of other species encompassed by the claimed genus and (2) identify the common characteristics of the claimed molecules, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure (tripeptide KXZ capable of being modified by peroxidase to form KXZ* capable of thiolating a pro-inflammatory protein, such as those in the recited listing), claim 56 as amended clearly meets the standard for complying with the written description requirement.
However, this argument is unpersuasive for reasons provided in the body of the rejection above and because the addition of the limitation “consists of” to the base claim 56 is not commensurate with the applicants’ argument regarding the species of KYC. The claims do not recite the species of KYC. Thus, the claims as written recite a genus of SCPDs which genus rather than a species.
Scope of enablement- maintained
Currently amended claims 56, and 93-104 stand 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 the embodiment shown in the working examples in the instant Specification, does not reasonably provide enablement for the methods of treating diseases and disorders using the myriad of embodiments of drugs included in the present claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Many factors are to be considered when determining if sufficient evidence exists to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue". These factors include 1) the breadth of the claims, 2) the nature of the invention, 3) the state of the prior art, 4) the level of one of ordinary skill, 5) the level of predictability in the art, 6) the amount of direction provided by the inventor, 7) the existence of working examples, and 8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The nature of the invention: The nature of the invention is a method of treating a disease or disorder using a genus of drugs that target a druggable biomolecular site.
The breadth of the claims: The claims are broad to treating any disease or disorder. Claims 93-101 further specify types of diseases and conditions to be treated. Further, amended base claim 56 limits the generic drug structure to wherein the druggable biomolecular site is an active site of peroxidase and a second target site is a protein being a HMGB1, TRL4, or KEAP-1. Claims are broad to a genus of a drug that has the required functional properties of interacting with a first target that comprises a druggable biomolecular site, whereby the drug modifies the properties of the first target and is itself chemically modified, and further interacts with one or more second targets, thus modifying each of the second targets' functions; whereby the disease or condition is treated in the subject. The structure of the claimed drug is broad to variants of a tripeptide KXZ described in instant claim 56. Claim 103 limits the peroxidase to a myeloperoxidase (MPO) or eosinophil peroxidase (EPO).
However, this drug structure is broad to consisting of a tripeptide KXZ having the formula AA1-AA2-AA3, wherein AA1 (K) is an amino acid comprising a basic side chain (aka positive charged: Lys, Arg, His), AA2 (X) is a polar, non-polar or aromatic amino acid (aka Ser, Thr, Cys, Asn, Gln, Tyr), and AA3 (Z) is an amino acid possessing a heteroatom that is capable of stabilizing a free radical. Note that in the context of amino acids, "heteroatom" generally refers to any atom that is not carbon or hydrogen. Common heteroatoms found in amino acids include nitrogen, oxygen, and sulfur. These atoms play a crucial role in the structure, function, and properties of amino acids and the proteins they form.
The state of the prior art: The state of the prior art discloses tripeptide drugs suggested for treating certain human diseases or conditions. The state of the art shows that the exact structure of such drug is critical for efficacy as a drug for treating such conditions. For example, Chen et al disclose that a three amino acid tripeptide RGD was tested for use as a drug for alpha5beta1 integrin binding in human urothelial carcinoma cells. The results showed that RGD-MAP8 failed to have a significant effect on CEBP or NRF2 activation, gene expression or cell viability. Chen et al show the unpredictable nature of tripeptide drug molecules for treating a disease or condition. (See Chen et al “A Synthetic Polyvalent Ligand for alpha5beta1 Integrin Activates Components of the Urothelial Carcinoma Cell Response to Bacillus Calmetter-Guerin” The Journal of Urology March 2013, Vol 189, pages 1104-1109). Further, in post-filing art Ma et al disclose use of a tripeptide drug GHK for use in treating lung fibrosis. (See Ma et al in “Protective effects of GHK-Cu in bleomycin-induced pulmonary fibrosis via anti-oxidative stress and anti-inflammation pathways” Life Sciences 2020 Vol 241, available online December 4, 2019.) Ma et al disclose that GHK has been known in the prior art for use in wound healing and anti-aging skin care. Ma et al disclose that adding copper to the GHK drug shows improved results in lung tissue for treating pulmonary fibrosis (see FIG 5-7). Ma et al conclude in their post-filing art that GHK-Cu “may be a candidate for pulmonary fibrosis treatment”. In addition, Minelli et al disclose administering a Gly-Pro-Glu tripeptide bound to L-dopa in a Parkinson’s animal model. (See Minelli et al Amino Acids 2012 Vol 43, pages 1359-1367”.
The predictability in the art: It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F. 2d 833,166 USPQ18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instantly claimed invention is highly unpredictable since one skilled in the art would recognize that in regards to the therapeutic effects of all diseases, the specific structure of the drug being applied is critical. In the absence of a showing of a nexus between treating any disease or disorder or treating the conditions recited in the instant claims 93-101, one of ordinary skill in the art is unable to fully predict possible results from the administration of the compound of claim 56 due to the unpredictability of the role of druggable biomolecular sites.
However, due to the unpredictability in the pharmaceutical art, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro and in vivo screening to determine which compounds exhibit the desired pharmacological activity and which diseases would benefit from this activity.
The amount of direction or guidance present and the presence or absence of working examples: The instant specification describes a working example of treating a mouse model with a specific species of drug which is called “KYC” made for targeting myeloperoxidase (MPO) in neonatal lungs exposed to hyperoxia (See para 0062; FIG 4-20, 22-28, 32, and 34-38, and 41-44 targeting the second target proteins HMGB1, TLR4, and Keap1). The specification does not show any other species of an SCPD drug structure performing the required functional properties.
The level of the skill in the art: The level of skill in the art is high, at the level of an MD or PhD medical researcher.
The quantity of experimentation needed: The quantity of experimentation needed is undue. One skilled in the art would need to determine what diseases and disorders would be benefited by administration of the broadly claimed drug structures.
Thus, the specification fails to provide sufficient support for the broad use of the genus of drug compounds of base claim 56 and dependent claims, for the treatment of any disease or disorder as presently claimed.
Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, states that "a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable".
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, one of ordinary skill in the art would have to engage in undue experimentation to test which diseases can be treated by the compounds of the instant claims, with no assurance of success.
Response to Arguments
The Applicants’ response filed on 06/12/2026 has been fully considered but is unpersuasive. The applicants argue that applicants have “amended claim 56 to specify that the SCPD consist of a structure of tripeptide KXZ having the formula AA₁-AA₂-AA₃, wherein AA₁ (K) is an amino acid comprising a basic side chain, AA₂ (X) is a polar, non-polar or aromatic amino acid, and AA₃ (Z) is an amino acid possessing a heteroatom that is capable of stabilizing a free radical which is capable of performing the various method steps discussed previously”. Further, the applicants argue:
Thus, in accordance with the discussion provided by the Examiner that applicants must (1) fully describe at least one species of the claimed genus (i.e., KYC) sufficient to represent said genus whereby a skilled artisan, in view of the prior art, could predict the structure of other species encompassed by the claimed genus and (2) identify the common characteristics of the claimed molecules, e.g., structure, physical and/or chemical characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure (tripeptide KXZ capable of being modified by peroxidase to form KXZ* capable of thiolating a pro-inflammatory protein, such as those in the recited listing), claim 56 as amended clearly meets the standard for complying with the enablement requirement shown in the working examples.
However, this argument is unpersuasive for reasons provided in the body of the rejection above and because the argument is not commensurate with the scope of the amended claims. For example, the argument is drawn to a sub-genus of SCPD being KYC and KXZ but the claims do not recite KYC.
In addition, the applicants argument is unpersuasive because generally, arguments of counsel cannot take the place of evidence on the record.
Claim Rejections - 35 USC § 103 - new grounds
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 (i.e., changing from AIA to pre-AIA ) 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 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.
Currently amended claims 56, and 93-104 are rejected under 35 U.S.C. 103 as being unpatentable over EP2873675 A1 to Zhang et al, (published May 20, 2015; IDS ref), in view of Hausheer (WO 2015/023553 published 02/19/2015).
Regarding claim 56, Zhang et al discloses tripeptide drugs comprising peptide-based (myelo)peroxidase inhibitors having the formula AA1-AA2-AA3, including the tripeptide consisting of KYC, Ac-KYC-amide, KWC. (See Example 2). Zhang et al disclose the use of these drugs for administering to subjects to treat diseases or conditions attributable to aberrant peroxidase activity. Zhang et al discloses tripeptide drugs comprising peptide-based (myelo)peroxidase inhibitors. (See Example 2). Regarding claim 56, Zhang et al discloses their KYC drug which meets the limitation of comprising a tripeptide KXZ having the formula AA1-AA2-AA3, wherein AA1 (K) is an amino acid comprising a basic side chain (aka positive charged: Lys, Arg, His), AA2 (X) is a polar, non-polar or aromatic amino acid (aka Ser, Thr, Cys, Asn, Gln, Tyr), and AA3 (Z) is an amino acid possessing a heteroatom that is capable of stabilizing a free radical Note that in the context of amino acids, "heteroatom" generally refers to any atom that is not carbon or hydrogen. Common heteroatoms found in amino acids include nitrogen, oxygen, and sulfur. The KYC tripeptide drug of EP2873675 meets this limitation because the C represents a cysteine which provides a sulfur atom.
Regarding the functional limitations of the instant claims, Zhang et al discloses that their tripeptide drug is capable of undergoing a redox reaction with a radical of amino acid AA2 or a retro or retro-inversion analog thereof. (See Abstract). Further, EP2873675 disclose that the result of administering their tripeptide drug is a highly effective inhibitor of peroxidase activity that has potent anti-inflammatory properties. See Abstract. Thus, the method of EP2873675 meets the limitations that the drug interacts with a first target that comprises a druggable biomolecular site whereby the drug modifies the properties of the first target and is itself chemically modified, and further whereby the chemically modified drug interacts with one or more second targets, thus modifying a second targets' function; whereby the disease or condition is treated in the subject.
Regarding claims 93-94, and 99 Zhang et al suggest use of their tripeptide drugs comprising peptide-based (myelo)peroxidase inhibitors for treating Alzheimer’s disease, Parkinson’s, and kidney disease. (See para 0004).
Regarding claim 95, Zhang et al discloses that the disease or condition may be atherosclerosis.
Regarding claim 96, Zhang et al discloses that the disease or condition may be pulmonary inflammation.
Regarding claims 97 and 98, Zhang et al discloses that the disease or condition may be a metabolic or endocrine disorder, and specifically diabetes.
Regarding claim 100, Zhang et al discloses that the disease or condition being treated may be sepsis. (See para 12; 0056; 0102).
Regarding claim 101-102, Zhang et al discloses that the disease or condition being treated may be inflammatory bowel disease, Crone's disease, and necrotizing enterocolitis (see para 12; 0057).
Regarding claims 102-104, Zhang et al discloses tripeptide drugs comprising peptide-based (myelo)peroxidase inhibitors. (See Example 2).
However, Zhang et al does not disclose wherein one or more of the second targets is a protein which is HMGB1, TRL4, or KEAP-1.
Hausheer discloses use of a tripeptide drug for use in treating disease. (See para bridging pages 76-77.) For example, Hauscheer disclose that:
Glutathione (GSH), a tripeptide (γ-glutamyl-cysteinyl-glycine) serves a highly important role in both intracellular and extracellular redox balance. It is the main derivative of cysteine, and the most abundant intracellular non-protein thiol, with an intracellular concentration approximately 10-times higher than other intracellular thiols. Within the intracellular environment, glutathione (GSH) is maintained in the reduced form by the action of glutathione reductase and NADPH. Under conditions of oxidative stress, however, the concentration of GSH becomes markedly depleted. Glutathione functions in many diverse roles including, but not limited to, regulating antioxidant defenses, detoxification of drugs and xenobiotics, and in the redox regulation of signal transduction. As an antioxidant, glutathione may serve to scavenge intracellular free radicals directly, or act as a co-factor for various other protection enzymes. In addition, glutathione may also have roles in the regulation of immune response, control of cellular proliferation, and prostaglandin metabolism. Glutathione is also particularly relevant to oncology treatment because of its recognized roles in tumor-mediated drug resistance to cancer treating agents and ionizing radiation. Glutathione is able to conjugate electrophilic drugs such as alkylating agents and cisplatin under the action of glutathione S-transferases. Recently, GSH has also been linked to the efflux of other classes of agents such as anthracyclines via the action of the multidrug resistance-associated protein (MRP). In addition to drug detoxification, GSH enhances cell survival by functioning in antioxidant pathways that reduce reactive oxygen species, and maintain cellular thiols (also known as non-protein sulfhydryls (NPSH)) in their reduced states…
…Gamma-glutamyl cysteine synthetase up-regulates glutathione and multidrug resistance-associated protein in patients with chemoresistant epithelial ovarian cancer.
Further, regarding the Keap1 protein, Hauscheer disclose (see page 267) that:
The Nrf2-Keapl system is recognized as a major cell-defense mechanism against oxidative stress and xenobiotics and plays a key role in upregulating phase 2 enzymes. In cytoplasm, the transcription factor Nrf2 is associated with a specific repressor protein, Keapl, that inhibits its translocation to the nucleus, but also acts as a participant in causing the rapid turnover of Nrf2 by ubiquitination and degradation. Keap-1 is a redox-sensitive protein with several cysteines. Some of them (Cys and Cys ) act as "reactive cysteines" and, on interaction with ROS or electrophiles, undergo oxidation or covalent modification, thereby facilitating the dissociation of the Nrf2-Keapl . Consequently, Nrf2 can translocate to the nucleus, where it accelerates the transcription of phase 2 genes, including thioredoxin and thioredoxin reductase genes (aka Trx).
Further, Hauscheer discloses that the role of Trx in cell growth and development, its anti-inflammatory effect in circulation, its antioxidant action, and thiol redox regulation of transcription factors provides a rationale for the observed upregulation of thioredoxin in several types of cancers. (See page 294.)
The level of skill in the art was high before the effective filing date of the presently claimed invention.
One of ordinary skill in the art would have been motivated to include the Keap-1 proteins as a target for the tripeptides drugs of Zhang et al for the rationale of the potential anti-inflammatory/antioxidant effects of the drug regarding treating disorders as suggested by Hauscheer.
It would have been obvious to include the Keap-1 protein as a target for the tripeptides drugs of Zhang et al because Zhang et al specifically disclose targets for reducing inflammatory conditions in a subject.
In view of the high skill level in the art it is considered that one of ordinary skill in the art having the cited references before the effective filing date of the presently claimed invention would have had a reasonable expectation of success to use the Keap-1 protein as a secondary target using tripeptide anti-inflammatory drugs of Zhang et al.
Thus the claims as a whole are rendered obvious over the combination of cited references.
Response to Arguments
The Applicants’ response filed on June 12, 2026 has been fully considered but is unpersuasive as it may relate to this new grounds of rejection. The applicants argue that the present base claim 56 is amended to delete the second targets being RAGE or NRf2.
However, this new grounds of rejection relies on Hauscheer to teach KEAP-1.
Conclusion
No claim is allowed.
Related art which may be applied in a future office action if applicable:
Zhang et al (Journal of Lipid Research Vol 54, No 11, published 11/01/2013, pages 3016-3029; IDS ref);
US Patent 8,937,039 to Zhang et al (01/20/2015; IDS ref).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE S HIBBERT whose telephone number is (571)270-3053. The examiner can normally be reached M-F 8:00-5:00.
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CATHERINE S. HIBBERT
Primary Examiner
Art Unit 1658
/CATHERINE S HIBBERT/Primary Examiner, Art Unit 1658
