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
1. This application is a 371 of PCT/EP2022/055561 03/04/2022. FOREIGN APPLICATIONS: EP 21160742.9 03/04/2021 and EP 21206420.8 11/04/2021.
Claims 1-10, 12 are pending.
Response to Restriction Election
2. Applicant’s election of the species, compound claim 8 in claim 14, in the reply filed on January 23, 2026 is acknowledged. The election was made without traverse. According to applicants’ representative claims 1-4, 6-10, 12 read on the elected species. As detailed in the following rejections, the generic claim encompassing the elected species was not found patentable. The search and examination was continued until prior art was found that anticipated or rendered obvious a non-elected species that falls within the scope of the generic Markush claim reading on the elected species. As per MPEP 803.02 II. C. “[T]he examiner must continue to search the species of the claim unless the claim has been found to be unpatentable over prior art.” The examiner “need not continue to search the claim if the claim is rejected over prior art”. [ibid. D.] Therefore, the search and examination is restricted to the claims reading on the elected species, and claims not reading on the elected species are held withdrawn. Accordingly, claim 5, which does not read on the elected species is withdrawn.
Claim Rejections - 35 USC § 112 (a)
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.
3. Claim 1-4, 6-10, 12 are 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 stereoisomers, tautomers, solvates, hydrates, and tautomers of the claimed compounds, it does not reasonably provide enablement for prodrugs in the claimed method. 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. There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to the following:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Finding a prodrug is an empirical exercise. Predicting if a certain ester of a claimed alcohol, for example, is in fact a prodrug or derivative that produces the active compound metabolically in man at a therapeutic concentration and at a useful rate, is filled with experimental uncertainty. Although attempts have been made to predict drug metabolism de novo, this is still an experimental science. For a compound to be a prodrug, it must meet three tests. It must itself be biologically inactive. It must be metabolized to a second substance in a human at a rate and to an extent to produce that second substance at a physiologically meaningful concentration. Thirdly, that second substance must be clinically effective. Determining whether a particular compound meets these three criteria in a clinical trial setting requires a large quantity of experimentation. There is no working example of a prodrug of a compound the formula I. Directions concerning how to make the prodrugs are not found in the specification. The nature of the invention is clinical use of compounds and the pharmacokinetic behavior of substances in the human body. Wolff, Manfred E. "Burger's Medicinal Chemistry, 5ed, Part I", John Wiley & Sons, 1995, pages 975-977 summarizes the state of the prodrug art. The table on the left side of page 976 outlines the research program to be undertaken to find a prodrug. The second paragraph in section 10 and the paragraph spanning pages 976-977 indicate the low expectation of success. In that paragraph the difficulties of extrapolating between species are further developed. Since, the prodrug concept is a pharmacokinetic issue, the lack of any standard pharmacokinetic protocol discussed in the last sentence of this paragraph is particularly relevant. Banker, G.S. et al, "Modern Pharmaceutics, 3ed.", Marcel Dekker, New York, 1996, pages 451 and 596 in the first sentence, third paragraph on page 596 states that "extensive development must be undertaken" to find a prodrug. Wolff (Medicinal Chemistry) in the last paragraph on page 975 describes the artisans making Applicants' prodrugs as a collaborative team of synthetic pharmaceutical chemists and metabolism experts. All would have a Ph. D. degree and several years of industrial experience. Rautio et. al. “Prodrugs: design and clinical Applications” Nature Reviews Drug Discovery 2008, 7, 255-270 discusses the difficulties and complexities of prodrug design, “Several important factors should be carefully examined when designing a prodrug structure, including: • Parent drug: which functional groups are amenable to chemical prodrug derivatization? • Promoiety: this should ideally be safe and rapidly excreted from the body. The choice of promoiety should be considered with respect to the disease state, dose and the duration of therapy. • Parent and prodrug: the absorption, distribution, metabolism, excretion (ADME ) and pharmacokinetic properties need to be comprehensively understood. • Degradation by-products: these can affect chemical and physical stability and lead to the formation of new degradation products.” No explanation is provided in the specification as to what the structure of the compounds may be or how to make them.
Even for the most basic type of prodrugs, such as esters, extensive experimentation must be undertaken. Each step is fraught with experimental difficulties, see Beaumont “Design of Ester Prodrugs to Enhance Oral Absorption of Poorly Permeable Compounds: Challenges to the Discovery Scientist” Current Drug Metabolism, 2003, 4, 461-485, “Overall, the barriers confronting the oral delivery of prodrugs are considerable. In addition, to improving membrane permeability of a polar active principle, a prodrug should avoid transporter mediated efflux and be designed to yield the active principle into the systemic circulation. Incomplete membrane permeation, efflux, non-esterase metabolism or biliary elimination will lead to a reduction in the potential oral bioavailability of the active principle. Thus, in order to be successful, a prodrug approach must consider the balance of all these issues.” ( Beaumont pg. 463 first column). Beaumont goes on to review several case studies of both successes and failures, leading to the conclusion “Clearly, prodrug strategies have been successful for a number of important therapeutic agents. However, further investigation suggests that the hurdles to oral delivery of an ester prodrug are not trivial. These include maintaining sufficient aqueous solubility, lipophilicity and chemical stability at the same time as enabling rapid and quantitative release of active principle post absorption. In addition, significant nonesterase metabolism and transporter mediated clearance of the prodrug is not desirable. For these reasons, it appears that achieving high oral bioavailability values with a prodrug approach is extremely difficult and a realistic target for oral bioavailability would be 50%. In addition, designing an ester prodrug that balances all of these issues is a difficult undertaking and a robust screening sequence is required in the Discovery environment. However, due to the difficulty in predicting the human disposition of an ester prodrug, it may be necessary to evaluate several examples in human pharmacokinetic studies. Given the complexities outlined in this review, it is recommended that the prodrug strategy is only considered as a last resort to improve the oral bioavailability of important therapeutic agents.” “Predicting the pharmacokinetics (PK) of prodrugs and their corresponding active drugs is challenging, as there are many variables to consider. Prodrug conversion characteristics in different tissues are generally measured, but integrating these variables to a PK profile is not a common practice.” [Abstract Malmborg “Predicting human exposure of active drug after oral prodrug administration, using a joined in vitro/in silico–in vivo extrapolation and physiologically-based pharmacokinetic modeling approach” Journal of Pharmacological and Toxicological Methods 67 (2013) 203–213.] This process is very labor intensive and fraught with experimental uncertainty as discussed in Malmborg page 204, column 1:
Literature advice on prodrug lead optimization and selection strategies include the use of relevant human biological matrices such as plasma, intestinal and liver microsome preparations to predict conversion rates in vivo using an in vitro–in vivo-extrapolation (IVIVE) approach (Simplicio, Clancy, & Gilmer, 2008). On the other hand, others believe that in vitro assays lack the ability to anticipate the actual conditions in vivo and propose to primarily use preclinical in vivo data in the optimization and selection processes (Hsieh, Hung, & Fang, 2009). However, preclinical in vivo data also has limitations in predicting the human situation. For instance, plasma esterase and gut wall CYP3A activity in man is frequently much lower compared to rats (Berry, Wollenberg, & Zhao, 2006; Cao et al., 2006; Fagerholm, 2007b). In that respect, a combination of relevant in vitro assays in an IVIVE approach with in vivo confirmation studies, as recently proposed by Jana et al. (2010), might be the most promising screening strategy. At the same time, this strategy has the drawback of labor-intensity, as it includes finding an in vitro–in vivo correlation in two preclinical species.
It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved", and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The breadth of the claims includes all of the billions of compounds of formula I of claim 1 as well as the presently unknown list of potential prodrugs. Since the structures of these prodrugs and are uncertain, direction for their preparation must also be unclear. Directions to a team of synthetic pharmaceutical chemists and metabolism experts of how to search for a prodrug or derivative does not constitute instructions to the chemist of how to make such a compound.
4. Claim 1-4, 6-10, 12 are 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 treating cancer with the compounds of claim 8, it does not reasonably provide enablement for the full scope of compounds and the full scope of diseases and no method of prevention of any disease. 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. There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
The claims are very broad encompassing a very large number of compounds with various substituents forming various rings, all heterocycles, carbocycles and other groups bearing multiple substitutions. This is a medical invention, but requires the synthesis of compounds or other method obtaining the compounds and such compounds should have biological activity. The specification gives 8 examples of compounds, those in claim 8, which appear on page 72. There is no direction or source for obtaining the compounds from the specification. The examiner conducted a search and found that the compounds are commercial compounds.1 They are sold by various companies, Ambinter, Enamine and Aurora. These companies, while selling some compounds, offer no details of how they are made. As per MPEP:
A key issue that can arise when determining whether the specification is enabling is whether the starting materials or apparatus necessary to make the invention are available. In the biotechnical area, this is often true when the product or process requires a particular strain of microorganism and when the microorganism is available only after extensive screening. The Court in In re Ghiron, 442 F.2d 985, 991, 169 USPQ 723, 727 (CCPA 1971), made clear that if the practice of a method requires a particular apparatus, the application must provide a sufficient disclosure of the apparatus if the apparatus is not readily available. The same can be said if certain chemicals are required to make a compound or practice a chemical process. In re Howarth, 654 F.2d 103, 105, 210 USPQ 689, 691 (CCPA 1981).
According to the U.S. Court of Customs and Patent Appeals in In re
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, De Boer, Eble, and Herr 168 USPQ 99 at 101, "[o]rdinarily no problem in this regard arises since the method of preparing almost all starting materials can be set forth in writing if the materials are not already known and available to the workers in the art, and when this is done the specification is enabling to the public". In re
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, De Boer, Eble, and Herr 168 USPQ 99 at 104, "it is essential that there be no question that, at the time an application for patent is filed, (emphasis in original) the invention claimed therein is fully capable of being reduced to practice (i.e., that no technological problems, the resolution of which would require more than ordinary skill and reasonable time, remain in order to obtain an operative, useful embodiment)." That is not the situation here. Rather we find no direction as to how any compound could be obtained. Assuming one would come up with some new synthetic methods, the many required staring materials with these vast substituents are also not known. The limitations of synthetic chemistry is readily apparent as stated in the preface to a recent treatise:
“Most non-chemists would probably be horrified if they were to learn how many attempted syntheses fail, and how inefficient research chemists are. The ratio of successful to unsuccessful chemical experiments in a normal research laboratory is far below unity, and synthetic research chemists, in the same way as most scientists, spend most of their time working out what went wrong, and why. Despite the many pitfalls lurking in organic synthesis, most organic chemistry textbooks and research articles do give the impression that organic reactions just proceed smoothly and that the total synthesis of complex natural products, for instance, is maybe a labor-intensive but otherwise undemanding task. In fact, most syntheses of structurally complex natural products are the result of several years of hard work by a team of chemists, with almost every step requiring careful optimization. The final synthesis usually looks quite different from that originally planned, because of unexpected difficulties encountered in the initially chosen synthetic sequence. Only the seasoned practitioner who has experienced for himself the many failures and frustrations which the development (sometimes even the repetition) of a synthesis usually implies will be able to appraise such work……Chemists tend not to publish negative results, because these are, as opposed to positive results, never definite (and far too copious) [preface]…….even structurally simple compounds often turn out not to be so easy to make as initially thought. [pg. 2]……….…….. As illustrated by the examples discussed below, a good retrosynthesis requires much synthetic experience, a broad knowledge of chemical reactivity, and the ability to rapidly recognize synthetically accessible substructures [pg. 3]…….. As will be shown throughout this book, the outcome of organic reactions is highly dependent on all structural features of a given starting material, and unexpected products may readily be formed. [8]……...Even the most experienced chemist will not be able to foresee all potential pitfalls of a synthesis, specially so if multifunctional, structurally complex intermediates must be prepared. The close proximity or conformational fixation of functional groups in a large molecule can alter their reactivity to such an extent that even simple chemical transformations can no longer be performed. Small structural variations of polyfunctional substrates might, therefore, bring about an unforeseeable change in reactivity [pg. 9]…..” Dorwald F. A. Side Reactions in Organic Synthesis, 2005, Wiley: VCH, Weinheim pg. IX of Preface pg. 1-15.
In re Howarth, 210 USPQ 689, (claimed derivatives of clavulanic acid not enabled by specification lacking information of how prepare the clavulanic acid or directions to reference materials containing such information), Ex parte Schwarze 151 USPQ 426 (where starting material is not known to art as of date of filing application, there must be included a description of preparation thereof to enable one skilled in this art to carry out applicant's invention), Ex parte Moersch 104 USPQ 122 (claims to process for the production of (1)-y1-p-nitrophenyl-2-dichloracetamindo-propane-1,3-diol not enabled because of failure to describe source or method of obtaining starting compound; although starting compound is identified by means of appropriate name and by structural formula).
While these chemical limitations are significant, there is no explanation as to the important structural features for interaction with “receptor tyrosine protein kinase” “(ERBB4)”. ERBB4 (Erb-b2 receptor tyrosine kinase 4), also known as HER4, is a transmembrane tyrosine kinase receptor in the epidermal growth factor (EGFR) family. Receptor tyrosine protein kinases (RTKs) include approximately 20 different classes: RTK class I (EGF receptor family) (ErbB family), RTK class II (Insulin receptor family), RTK class III (PDGF receptor family), RTK class IV (VEGF receptors family), RTK class V (FGF receptor family), RTK class VI (CCK receptor family), RTK class VII (NGF receptor family), RTK class VIII (HGF receptor family), RTK class IX (Eph receptor family), RTK class X (AXL receptor family), RTK class XI (TIE receptor family), RTK class XII (RYK receptor family), RTK class XIII (DDR receptor family), RTK class XIV (RET receptor family), RTK class XV (ROS receptor family), RTK class XVI (LTK receptor family), RTK class XVII (ROR receptor family), RTK class XVIII (MuSK receptor family), RTK class XIX (LMR receptor) and RTK class XX (Undetermined). Each family has a number of members, for example the ErbB protein family consists of 4 members: ErbB-1, also named epidermal growth factor receptor (EGFR)ErbB-2, also named HER2 in humans and neu in rodents, ErbB-3, also named HER3, and ErbB-4, also named HER4.
The claims are not limited to ERRB4 even though it is the only kinase tested. The medicinal chemistry of ERRB4 is relatively well-developed and many limitations are well known in the art. It is sensitive to structural changes that may be relatively minor in the chemical sense see Elwaie J. Med. Chem. 2020, 63, 24, 15906–15945. Figure 1 shows the binding site:
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In this case these compounds bear a remarkable structural resemblance to one another, yet the claims are not commensurate in scope. The factors outlined in In Re Wands mentioned above apply here, and in particular As per the MPEP 2164.01 (a): “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” It is very clear that one could not make/use this very broad invention that has only eight working examples in this unpredictable art without undue experimentation.
Regarding the prevention and treatment of various diseases. The compounds are shown to inhibit ErbB4. While originally developed for treating breast cancer, Roy “Beyond Trastuzumab: Small Molecule Tyrosine Kinase Inhibitors in HER-2–Positive Breast Cancer” The Oncologist 2009;14:1061–1069, Excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor. ErbB-1 and ErbB-2 are found in many human cancers, and their excessive signaling may be critical factors in the development and malignancy of these tumors.
Oh “HER2-targeted therapies — a role beyond breast cancer” Nature Reviews Clinical Oncology Reviews January 2020 volume 17 | | 33, figure 2 shows expression profiles of HER2 in other cancers:
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Her 2 is expressed in additional cancers and these compounds can also treat other cancers. While success is not guaranteed, at least gastric cancer was treated this way. Beyond these cancers there is no indication that HER2 inhibitors could be used to treat all the diseases in claims 9-10.
Claim Rejections - 35 USC § 112 (b)
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.
5. Claim 1-4, 6-10, 12 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.
Claim 1 recites “receptor tyrosine protein kinase” followed by a parenthetical “(ERBB4)”. ERBB4 (Erb-b2 receptor tyrosine kinase 4), also known as HER4, is a transmembrane tyrosine kinase receptor in the epidermal growth factor (EGFR) family. Receptor tyrosine protein kinases (RTKs) include approximately 20 different classes: RTK class I (EGF receptor family) (ErbB family), RTK class II (Insulin receptor family), RTK class III (PDGF receptor family), RTK class IV (VEGF receptors family), RTK class V (FGF receptor family), RTK class VI (CCK receptor family), RTK class VII (NGF receptor family), RTK class VIII (HGF receptor family), RTK class IX (Eph receptor family), RTK class X (AXL receptor family), RTK class XI (TIE receptor family), RTK class XII (RYK receptor family), RTK class XIII (DDR receptor family), RTK class XIV (RET receptor family), RTK class XV (ROS receptor family), RTK class XVI (LTK receptor family), RTK class XVII (ROR receptor family), RTK class XVIII (MuSK receptor family), RTK class XIX (LMR receptor) and RTK class XX (Undetermined). Each family has a number of members, for example the ErbB protein family consists of 4 members: ErbB-1, also named epidermal growth factor receptor (EGFR)ErbB-2, also named HER2 in humans and neu in rodents, ErbB-3, also named HER3, and ErbB-4, also named HER4.
The parenthetical phrase "(ERBB4)" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention or merely exemplary. See MPEP § 2173.05(d).
Claim 10 has the same issues with “(chronic) diabetic nephropathy”. The parenthetical phrase "(chronic)" renders the claim indefinite because it is unclear whether the limitation(s) following is part of the claimed invention or merely exemplary. See MPEP § 2173.05(d).
6. Claim 8 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. In claim the following compuodns are shown:
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The ring as a circle implies aromaticity.2 A compound is aromatic it has 4n + 2 π electrons, a pyridazinone is a non-aromatic six-membered heterocyclic ring containing two adjacent nitrogen atoms and a carbonyl group. The carbonyl carbon would have to have five bonds to it if an additional double bond were in the ring.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], 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.
7. Claim 8 is 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. In claim 8, two of the structures have the pyridazinone ring as an aromatic ring, represented with a circle.
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If a compound is aromatic, it has 4n + 2 π electrons. A pyridazinone is a non-aromatic six-membered heterocyclic ring containing two nitrogen atoms and a carbonyl group. In claim 8 there are only 4 π electrons and the structures above add an additional 2 electrons. 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.
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.
8. Claim(s) 1-4, 6-10, 12 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Carson US 20180110784 A1. Carson teaches compounds of general formula II on page
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Specific examples include but are not limited to those given on page 22:
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These are compounds of claim 1 formula I where n is 0, A1 is NR6, R6 is 0, A2 and A3 are CR5, two R5 forms an unsaturated 6 membered ring, R1 is aryl (phenyl), R2 is H, A is O, R3/R4 is H and various (alkyl, aryl substituted with Z3/Z4, cycloalkyl, aryl, heteroaryl). According to page 1 the compounds are used to treat liver fibrosis:
[ 0009 ] In one embodiment , the invention provides methods of preventing , inhibiting or treating liver disease or fibrosis . In one embodiment , the method includes administering to a mammal in need thereof a composition having a TLR4 ligand and / or a TLR7 ligand or a conjugate thereof, in an amount effective to prevent , inhibit or treat liver disorders or fibrosis.
Fibrotic disorders, of which liver fibrosis is a member, is said to be a disease of claim 1, in claim 9. Methods of administration are given on page 26 ff at [0260] with various routes.
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.
9. Claim(s) 1-4, 6-7, 9, 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Khalil “Substituted quinazolines, Part 2. Synthesis and in-vitro anticancer evaluation of new 2-substituted mercapto-3H-quinazoline analogs.” Archiv der Pharmazie. 2003, 336(2), 95-103. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Khalil teaches various compounds of the instant claims including but not limited to those shown below in Schemes 1, 2 and 3
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These are compounds of formula (I) where A1-A4 are CR5, R5 is H and halo (I), n is 1, R1 is arylalkyl (phenyl-CH2-), substituted alkyl (methyl substituted with Z1 where Z1 is aryl), or aryl (benzyl)3, R2 is H (7, 8, 13, 16, 17, 18, 21, 22, 27) or R2 and R3 form a 5 or 6-membered saturated ring (20, 28), A5 is O (7, 8, 13, 16, 17, 21, 22, 27, 28) or NR7 (18), R3/R4 are H or alkyl substituted with -OH (27), or R3 and R7 form an unsaturated 6 membered monocycle (18), or R3 and R4 form an unsaturated nitrogen containing monocycle (21, 22) or R3 or R4 is H and a heterocycle (dihydrothiazolin-one, 16), (azetidinone, 17), (succinimide 8) ( phthalimide 7), where Z3 is halo or aryl. These are compounds of IIA/IIB in claim 3, formula IA and IC in claim 2.
These compounds were active in various assays with tumor cell lines (Table 2 page 99, and Table 3 page 100). In leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer cell lines.
Ascertaining the differences between the prior art and the claims at issue.
The compounds were not administered to subjects4 only cells.
Resolving the level of ordinary skill in the pertinent art and considering objective evidence present in the application indicating obviousness or nonobviousness.
According to claim 9, cancer is a disease to be treated with the compounds of claim 1. Since the prior art compounds were anti-cancer agents, it would be obvious to administer them to cancer patients. This is the only utility of the prior art compounds. The therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animals to achieve a circulating plasma concentration range that includes the IC50 as determined in cell culture. Such information can be used to determine useful doses in humans.
10. Claim(s) 1-4, 6-7, 10, 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chan “Identification of Substituted Pyrimido[5,4‑b]indoles as Selective Toll Like Receptor 4 Ligands” J. Med. Chem. 2013, 56, 4206−4223 and Yu “The Role of Toll-Like Receptor Signaling in the Progression of Heart Failure” Mediators of Inflammation Volume 2018, Article ID 9874109, 11 pages. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
The Chan teaches the same compounds as Carson in Table 1 on page 4211:
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Many of the compounds reduced various interleukins and antagonized TLR4.
According to Yu page 4, Table 1, “Inhibition of TLR4 is beneficial for the progression of HF;”
“All known human TLRs have been detected in the heart and most importantly, TLR4, whose levels are the highest compared with other TLRs in the heart. TLR4 plays a critical role in myocardial inflammation, including myocarditis, MI, myocardial I/R injury, HF, aortic valve diseases, atherosclerosis, and hypertension…..Studies have shown that TLR4 expression increases in the hearts of patients with advanced HF [73, 74]. Other studies indicated that unstimulated monocyte TLR4 expression was significantly higher in patients with chronic HF compared to controls and upregulation of monocyte TLR4 may con-tribute to pathophysiology of chronic HF [47]. TLR4 is associated with deleterious inflammatory effects that exacerbate heart damage, and inhibition of TLR4 reduces the progression of HF (Table 1).Pharmacological blocking of TLR4 by different mole-cules is influenced. Statins are among the early-developed drugs with newly discovered inhibitory activity on TLR4signaling. Among the statin family, fluvastatin, simvastatin, and atorvastatin, all have shown potent inhibitory activity onTLR4 and subsequent inflammatory pathways to reduce inflammation in vascular systems [48]. Another molecule eritoran, the antagonist of TLR4, is very helpful. Inhibition of TLR4 with eritoran can attenuate myocardial ischemia-reperfusion injury [75] and the development of cardiac hypertrophy ..” [page 5]
Ascertaining the differences between the prior art and the claims at issue.
The compounds were not administered to subjects only cells. Chan was interest in TLR4 ligands as adjuvants or immune modulators, no mention of heart disease is made.
Resolving the level of ordinary skill in the pertinent art and considering objective evidence present in the application indicating obviousness or nonobviousness.
According to claim 10, heart failure is a disease to be treated with the compounds of claim 1. Since the prior art compounds antagonized TLR4, they would find use in treating heart failure. According to Yu page 4, Table 1, “Inhibition of TLR4 is beneficial for the progression of HF;” It would be obvious to administer the compound of Chan to heart failure patients. The therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animals to achieve a circulating plasma concentration range that includes the IC50 as determined in cell culture. Such information can be used to determine useful doses in humans.
Information Disclosure Statement
11. The information disclosure statement filed August 9, 2023 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because reference 8 is cited without a date. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Conclusion
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
1 See attached 5 page STN printout from March 16, 2026.
2 William B. Jensen “The Circle Symbol for Aromaticity” J. Chem. Educ., 2009, 86, 423-424.
3 According to the specification on page 17 line 15 ff., “The term "aryl", as a group or part of a group, refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphthyl), or linked covalently, typically comprising 6 to 12 carbon atoms; wherein at least one ring is aromatic, preferably comprising 6 to 10 carbon atoms, wherein at least one ring is aromatic. The aromatic ring may optionally include one to two additional rings (either cycloalkyl, heterocyclyl or heteroaryl) fused thereto. Examples of suitable aryl include C6-12aryl, preferably C6-10aryl, more preferably C₆-₈aryl.” Benzyl is the only known uncharged C7 aryl see, THE VAN NOSTRAND CHEMIST'S DICTIONARY 1953, entry for “aryl” Pg. 44. “ARYL. A radical derived from an aromatic hydrocarbon by the elimination of one atom of hydrogen, so producing a univalent unit. Examples are phenyl C6H5- derived from benzene; tolyl (or benzyl) C7H7 derived from toluene, etc.”
4 The subject is not explicitly defined in the specification, but on page 68 human and animals are mentioned, “The dosage or amount of the agent as taught herein, optionally in combination with one or more other active compounds to be administered, depends on the individual case and is, as is customary, to be adapted to the individual circumstances to achieve an optimum effect. Thus, the unit dose and regimen depend on the nature and the severity of the disorder to be treated, and also on factors such as the species of the subject, the sex, age, body weight, general health, diet, mode and time of administration, immune status, and individual responsiveness of the human or animal to be treated..” The examiner interprets subjects to not include tumor cells in isolation which received administration of the claimed compounds in the prior art.
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