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/CN2021/110859 08/05/2021; FOREIGN APPLICATIONS: CHINA 202010790872.8 08/07/2020.
Claims 11-17, 19-22 are pending.
Response to Restriction Election
2. Applicant’s election of group I and the species,
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in the reply filed on January 6, 2026 is acknowledged. Applicant states that this is the last compound in claim 17, however that compound has an F atom. The compound does appear in claim 17 on page 22/35 as the first compound in the 4th row. According to applicants’ representative claims 11-17, 21 read on the elected species. Applicant provides an incomplete variable description for the genus since the Cy as (v) is not fully defined. Applicant specifies that R1 is methoxy (C1alkyloxy), R2 is H, R3 is methyl (C1alkyl), R4 is H, R5 is H and R6 is H. A complete definition capturing the species of Cy, as best as can be understood, would require the piperidyl R8 group to be an aryl, which for the benzoate needs a substituent Rj, and Rj, apparently defined in (i), could be a C1 alkyl substituted by two Rp, which if one is oxo and the other is -OH a carboxylate would be formed. Since the piperidine is only disubstituted R11 must be H, leaving R10 as the other substituent to be defined as -O-CH2-c-Pr. The C3-40cycloalkyloxy could form the terminal group which is listed, however the structure requires an additional methylene group between the cycloalkyl and the oxygen. The only feasible possibility is where R10 is C1alkyloxy and a substituent Rk is C3cycloalkyl. To summarize for the elected species R1 is methoxy (C1alkyloxy), R2 is H, R3 is methyl (C1alkyl), R4 is H, R5 is H and R6 is H, Cy is (v), R8 is a C6 aryl (phenyl), substituted by Rj, Rj is a C1 alkyl substituted by two Rp, one is oxo and the other is -OH, R11 is H, R10 is C1alkyloxy and a substituent Rk is C3cycloalkyl.1 Claim 13 defines an entirely new set of Cy that is not (v), only a new definition, unsubstituted piperidyl (a) or (b) and (c) which are various bridged rings and as such does not 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 13, which does not read on the elected species is withdrawn.
Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
3. Claims 11-12, 14-17, 21 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 terms "preferably" and “more preferably” appear 29 times in the claims. “Preferably” and “more preferably” are relative terms which render the claims indefinite. It is improper to speak of preferred embodiments within a claim since this is the purpose of a dependent claim.
Regarding claim 16, the phrase “such as” in phrases such as “such as CD3 and C2D5” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The phrase "for example" for example in claim 11, 14 renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The phrases including "e.g." which appears 11 times in the claims, in claim 14 and 16 renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The claims also put various qualifications in parenthesis sometimes with qualifier “(e.g….)” as in among others “5- to 6-membered heteroaryl (e.g., pyrrolyl, pyridinyl, pyrazinyl, imidazolyl, or triazolyl)”, and sometimes not with qualifier for example “halogen (F, Cl, Br or I)”, “(wherein a sulfur atom is unoxidized or is oxidized to a -S(O)2)”, etc. This use of parenthesis also renders the claims indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
4. Claims 11-12, 14-16, 21 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. In claim 11 and 12 last line and twice in claim 14 reference is made to “more preferably, the N and S atoms of the above heterocyclyl, if present, may optionally be unoxidized or oxidized to various oxidized forms.” It is unclear what the oxidation state of the compound is if the option is not exercised, such that the option is not optional because the molecule can only be unoxidized or oxidized.
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.
5. Claim 11-12, 14-17, 21 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 racemates, stereoisomers, tautomers, isotopically labeled compounds, solvates, polymorphs, and tautomers of the claimed compounds, it does not reasonably provide enablement for prodrugs. 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.
Rejections Under the Judicially Created Doctrine of Improper Markush Grouping
6. Claims 1-14, 16, 18, are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons: The structure of claim 1 has only 10 non-variable atoms, the Cy has multiple variable rings of varying sizes, the R6 and R7 and R7 and R1 form various rings, and there are a high number of nested variables, subvariables and subgeneric preferred variables under Cy i) to v). There is no expectation that compounds of such diverse structure have similar properties. Schubart “Small-molecule factor B inhibitor for the treatment of complement-mediated diseases.” Proceedings of the National Academy of Sciences of the United States of America, 2019, 116(16), 7926-7931 (cited on the IDS) discusses the active site:
The indole NH forms a hydrogen bond with the Thr190 side chain, and its 7-methyl moiety expands toward the bottom of the pocket…a piperidine, which conserves the hydrogen bond interaction to Gly216 but shifts Pro172D outward by 2.8 Å (compound 2; Fig. 1 A and C). The crystal structure of FB with compound 2 also revealed a sulfate ion to be bound in close proximity to the piperidine ring and having multiple interactions with the protein (Fig. 1D). To further increase the potency of compound 2, we made use of this interaction network by introducing a benzoic acid moiety in position 2 of the piperidine ring, which forms hydrogen bonds to both the Asn220B side chain and the Asp218A-NH.
The compounds disclosed are relatively homogenous, all having a piperidine and benzoic acid group. In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1) (emphasis provided).
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.
7. Claim(s) 11-12, 14, and 21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Suehiro, Tadashi “Stepwise 4-benzylation of 5-hydroxy-2-methyl-3-ethoxycarbonylindole.” Chemische Berichte 100(3), 905-14 1967 (English abstract appended). Suehiro teaches compound 5 on page 906:
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This is the compound of claim 1 where R1 is C1alkoxy (methoxy), R2-R4 and R6 are H, R5 is methyl, R7 is H, Cy is C6 aryl (phenyl) substituted with 5 R8, R9, R10 and/or R11 where each is H.
8. Claim(s) 11-12, 14-16 and 21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Adams US 20160152605 (cited as a 3rd party disclosure). Adams teaches the compounds of claim 1 Formula I including but not limited to the compounds of Formula IIIa on page 3:
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This structure has all of the feature of the elected species including the piperidine of claim 17. There are a large number of specific examples of this formula shown including but not limited to those on pages 91 ff. such as e.g.:
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These are compounds reading on claim 11 where R1 is C1alkoxy (methoxy) or alkyl, R2, R4 -R6 are H, R3 is methyl, R7 is H, Cy is piperidine (iii), (iv) or (v) R8 is C6 aryl (phenyl) substituted with substituted by Rj, Rj is a C1 alkyl substituted by two Rp, one is oxo and the other is -OH or F, R11 is H, R10 is alkoxy or -OH; compound 17-29 has the spirocycles formed by the R8/R9 language on page 4/35 of claim 11 under “7-12 membered sprio…heterocycle” which meets the sufficient condition “up to only one N atom”.
9. Claim(s) 11-12, 14-16 and 21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schubart “Small-molecule factor B inhibitor for the treatment of complement-mediated diseases.” Proceedings of the National Academy of Sciences of the United States of America, 2019, 116(16), 7926-7931 (with supporting info). Schubart teaches
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on page 7927. This is a compound reading on claim 11 where R1 is C1alkoxy (methoxy) or alkyl, R2, R4 -R6 are H, R3 is methyl, R7 is H, Cy is piperidine (iii), (iv) or (v) R8 is C6 aryl (phenyl) substituted with substituted by Rj, Rj is a C1 alkyl substituted by two Rp, one is oxo and the other is -OH, R11 is H, R10 is alkoxy.
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.
10. Claim(s) 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schubart “Small-molecule factor B inhibitor for the treatment of complement-mediated diseases.” Proceedings of the National Academy of Sciences of the United States of America, 2019, 116(16), 7926-7931 as applied to claims 11-12, 14-16 and 21 and further in view of Talele “The “Cyclopropyl Fragment” is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules” J. Med. Chem. 2016, 59, 8712−8756.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determination of the scope and content of the prior art
(MPEP 2141.01)
Schubart teaches the compound as discussed above. In addition Schubart explains “Replacement of the methoxy by an ethoxy group and substitution of the 5-methyl by a methoxy group on the indole ring led to LNP023, a highly potent FB inhibitor (Fig. 1 A and D). LNP023 showed direct, reversible, and high-affinity binding to human FB as determined by surface plasmon resonance (SPR) (KD value of 0.0079 ± 0.0019 μM) (SI Appendix, Fig. S2). It inhibits FB with an IC50 value of 0.01 ± 0.006 μM (n = 6)” Suggesting that there
Talele explains that “[O]ne can expect to achieve a metabolically stable derivative upon replacement of the methyl group with a cyclopropane ring. This latter property occurs as proton abstraction from a cyclopropane ring would be more difficult than from a methyl group, which is required for oxidative metabolism to proceed.” [page 8713 col. 1 lines 3-8 ] “The cyclopropane scaffold may also contribute toward disruption of overall planarity due to increased sp3 character and three-dimensionality favoring noncoplanarity, less crystal packing, low melting point, and higher aqueous solubility.13” [page 8713 col. 1 lines 23-27].
Ascertainment of the difference between the prior art and the claims
The elected species differs from LNP-023 by the replacement of a methyl group with a cyclopropyl group.
Finding of prima facie obviousness
Rationale and Motivation
(MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to make a cyclopropyl analog of LNP-023 to produce the instant invention. The terminal methyl group is a metabolic hotspot susceptible to CYP450-mediated oxidation. The experienced medicinal chemist, who would make the elected species, would be motivated to replace the methyl group with the cyclopropyl on the expectation that the change would improve metabolic stability and upon the routine nature of such experimentation in the art of medicinal chemistry. In addition the expected higher aqueous solubility would improve oral bioavailability and improve overall drug properties. According to Talele “It is striking to find that eight of the 200 best selling drugs approved by the U.S. FDA contain a cyclopropyl ring.29 Further analysis of the top 100 ring systems appearing in the 2012 FDA Orange Book drug database indicated the cyclopropane ring system had a frequency value of 28 and a rank order of 10.30”
As explained by Talele above, the site where the methoxy binds to the enzyme had ample space to accommodate a larger group in the ethoxy moiety, which also increased potency.2 A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
11. Claim(s) 17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Schubart “Small-molecule factor B inhibitor for the treatment of complement-mediated diseases.” Proceedings of the National Academy of Sciences of the United States of America, 2019, 116(16), 7926-7931 as applied to claims 11-12, 14-16 and 21 and further in view of Shah “The role of fluorine in medicinal chemistry” Journal of Enzyme Inhibition and Medicinal Chemistry, October 2007; 22(5): 527–540. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art
As discussed above Schubert teaches the desfluoro compound LNP-023. Shah explains, “Fluorine substitution has been extensively investigated in drug research as a means of enhancing biological activity and increasing chemical or metabolic stability.” Page 527. “Despite the fact that fluorine is slightly larger than hydrogen, several studies have demonstrated that it is a reasonable hydrogen mimic and is expected to cause minimal steric perturbations with respect to the compound’s mode of binding to a receptor or enzyme.” Page 528 “1. Improved metabolic stability
Metabolic stability can determine the bioavailability of compounds and substitution with fluorine at the site of metabolic attack can prevent oxidative metabolism based on the fact that the C–F bond is more resistant to attack than the C–H bond. Also, substitution at adjacent or distal sites to the site of metabolic attack can also affect drug metabolism due to inductive/resonance effects or conformational and electrostatic effects.” Page 528
“One of the challenges faced in drug discovery is that of low metabolic stability. Lipophilic compounds are susceptible to oxidation by liver enzymes, namely cytochrome P450. This can be overcome by increasing the polarity of the compound or alternatively introducing a fluorine atom into the compound to alter the rate, route or extent of drug metabolism. The latter can be achieved by fluorine substitution at the metabolically labile site or at adjacent or distal sites to the site of metabolic attack provided that this does not compromise binding to the target protein.” [Page 528].
“The main rationale for introducing fluorine into compounds is either to improve the metabolic stability, alter the physicochemical properties or improve the binding affinity of these compounds. These strategies are already widely used and established by medicinal chemists in the processes of drug discovery and development. At present, fluorine is often introduced into molecules ad hoc but it can be speculated that it could be involved in a more rational approach to drug design where various techniques could be used to determine where to substitute fluorine atoms to maximise activity.” [Conclusions page 537]
Ascertaining the differences between the prior art and the claims at issue.
The species in claim 17 compound page 25/35:
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are fluorinated analog of the prior art compound LNP-0023.
Resolving the level of ordinary skill in the pertinent art
The differences between the prior art compounds and the LNP-023 compound of the prior art are H to F substitutions. The fluorinated analogs have a sufficient similarity in size and shape to the non-fluorinated analog to fit the active site of the target protein, so they would be expected to have similar inherent biological activity. One of ordinary skill would be further motivated to make these specific fluorinated analog because he or she would expect the compounds to have a greater biological half-life and improved biological properties, since benzylic and aromatic C-H bonds are oxidatively metabolically labile. This is the strongest rationale as set forth in the MPEP 2144 “II. THE EXPECTATION OF SOME ADVANTAGE IS THE STRONGEST RATIONALE FOR COMBINING REFERENCES
The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination.”
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.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
1 Mr. Xue clarified the election February 4, 2026, see attached interview summary.
2 As shown by Adams, even the propoxy substituted variant 17-11 gave highly potent compounds giving an IC50 of 0.015nM in Table 1, nearly identical to LNP-023.