DETAILED ACTION
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 .
Status of the Claims
Claims 1-14 and 17-18 are pending in the instant application and subject to examination herein.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/CN2022/075494, filed on 02/08/2022.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/08/2023 and 03/04/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
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.
Claims 8 and 17 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 8 further limits claim 1, regarding genus of compounds, to a narrower genus of compounds. Claim 8 is indefinite because the claim includes conditional language without specifying the consequence of the condition(s): “and/or, when R2, R3, and R4 are independently H, fluorine, chlorine, bromine or methyl”. The language is indefinite, because the claim does specify what limitation is to be applied when the condition is met. In contrast, other claims in the instant claims set include a limitation to be applied when a structural condition is met, as shown in the example below from claim 4: “when R11 is halogen, the halogen is fluorine, chlorine, bromine, or iodine”. A person of ordinary skill in the art would understand exemplary the conditional language of claim 4, because the consequence of the condition (R11 is halogen) is provided: the halogen is F, Cl, Br or I. No consequence is provided for the condition anywhere in claim 8, and because no consequence is not provided directly following the condition, a person of ordinary skill in the art would not understand whether the limitations following the condition are separate limitations or are additional aspects of the condition.
Claim 17 depends from claim 1 and recites the limitation "the pharmaceutical composition thereof" in the context of a compound of claim 1or pharmaceutically acceptable salt thereof as part of a Markush group of compositions to be administered in a method for inhibiting Hepatitis B virus (HBV) to a subject in need thereof. There is insufficient antecedent basis for this limitation in the claim, as neither claim 1 does not claim or disclose any pharmaceutical composition.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-14 and 17-18 are unpatentable over Liu in view of Brown and Locke.
Claims 1-14 and 17-18 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (U.S. Patent No. 11,261,190 B2) in view of Kier (Kier, L.B. and Hall, L.H.; Chemistry and Biodiversity, v1, pp138-151; 2004) and Locke (Locke, G. M.; Chemistry A European Journal; v25, pp4590-4647; 2019).
Claim 1 is drawn to a genus of dihydropyrimidine compounds bearing pendant phenyl, carboxylate and dihydroimidazopyrazine-methyl groups as well as additional substituents and limations, designated as formula I’ and shown in the table below. Liu discloses genera of dihydropyrimidine compounds and their uses, especially as a medicament for treating and preventing hepatitis B virus. Liu discloses many compounds that fall within bioisosteric equivalence of instant formula I’, for example Liu’s compounds 131 and 1402, shown in the table below (Col. 103, lines 40-65):
Claim Number(s) of Instant Application
Instant Application
Liu (U.S. Patent No. 11,261,190 B2)
1
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326
174
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wherein:
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598
276
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Compound 13
1
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326
174
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wherein:
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638
302
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Compound 140
Liu’s compounds 13 and 140 differ from the scope of instant formula I’ at the position Q, which is a phenyl ring in Liu’s compounds 13 and 140 but is limited by claim 1 to а 5-8-membered bridged (i.e., bicyclic) cycloalkyl or а bridged (i.e., bicyclic) 5-8-membered heterocyclyl, wherein the 5-8-membered heterocyclyl is bridged-linked, the heteroatoms in the 5-8-membered heterocyclyl are selected from N, О, and S, and the number of heteroatoms is one, two, or three. However, a person of ordinary skill in the art would have a reasonable expectation of success in making and using bioisosteric derivatives of Liu’s compounds 13 and 140 wherein a propellane, cubane or adamantane is selected in place of the phenyl ring, because the practice of making bioisosteric equivalents by swapping out equivalent rings was known in the art of medicinal chemistry, per the teaching of Kier, and the isosteric equivalency of propellane, cubane and adamantane to benzene was known in the art, per the teaching of Locke.
Kier teaches that “The concept of bioisterism is perhaps the oldest source of a chemical-information model for molecular modification in the process of drug design and development. It was intended to provide some answer to the question facing the chemist: ‘what do I synthesize next?’ Bioisosterism is now an integral part of the intuition that the chemist brings to bear on this challenge” (page 138). Kier teaches that isosterism is the relationship between sets of atoms of groups that impart similar properties to them (page 138) and that bioisosterism is the application of similarity in molecular design to biological activity and bioisosteric replacements are the interchange of one group for another in the molecular modification process (page 139). Kier further teaches that the effects of the replacement of one ring for another transcends the influential effect of a small functional group on the attached molecular fragment. A ring imparts a significant role in its own right due to its intrinsic structure and surface area, which influence lipophilicity and polarity (page 146). Kier provides a table showing a list of bioisosterically equivalent ring types.
Locke teaches a review of nonconjugated hydrocarbons as rigid-linear motifs, including propellane, adamantane and cubane among other bicyclic rings (pages 4590-4591, including Figure 1). Locke discusses the application of these bicyclic rings in small molecule drugs, specifically in regard to their applicability for bioisosteric replacements. Locke teaches that pharmacokinetic properties (PK) such as bioavailability, solubility, metabolic stability, and toxicity limit a drugs’ application even though good potency and selectivity may be observed in vitro. Alternatively, bioisosteres have been employed simply to expand the scope of a family of compounds but also to investigate structure–activity relationships (page 4627). Locke also teaches that benzene, chosen for its rigidity, unique electronics and synthetic accessibility, is known to be one of the leading causes for compound attrition in drug discovery (page 4627). Locke further teaches general effects for substitution of propellane (bicyclopentane or BCP), adamantane (bicyclooctane or BCO) and cubane for para-substituted benzene groups in drug compounds: It was shown that BCP improves aqueous solubility by at least 50-fold and markedly decreases nonspecific binding wherease, BCO increased the lipophilicity of the molecules but did not show the same benefits regarding nonspecific binding or solubility, and cubane showed improvements for both parameters (page 4628). Locke teaches that substituting propellane (BCP) for a phenyl ring in resveratrol provided a bioisosteric analogue “284a” that showed superior in vivo pharmacokinetic properties over resveratrol (page 4629, including Figure 56):
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86
400
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Locke also teaches an example wherein the anticancer ABL1 inhibitor imatinib (compound “286”) was modified to replace a para-substituted phenyl ring with either propellane (BCP) or cubane: both derivatives showed improved water solubility, and the cubanyl derivative (286b) showed increased cytotoxicity toward cancer cell lines K562 and SUP-B15 (page 4629, Figure 57):
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200
400
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Applicant’s invention is unpatentable over the discloser of Liu in view of the teaching of Kier and Locke, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in making and using bioisosteric derivatives of Liu’s compounds 13 and 140 wherein a propellane, cubane or adamantane is selected in place of the phenyl ring, because it was known in the art that bioisosteric replacements on the structures of known drug compounds are a standard practice in the pursuit of new drug compounds, per the teaching of Kier, and it was known in the art that propellane, adamantane and cubane are bioisosterically replaceable groups for phenyl rings in drug compound structures, per the teaching of Locke.
Thus, the invention was prima facie obvious at the time of filing.
Claims 2-12 further limit the genus of compounds of claim 1, each to a narrower genus that is met by the rejection above, particularly regarding Liu’s compound 140.
Claim 13 further limits claim 1 to a preparation method comprising the step of reacting a compound of instant formula II with a compound of instant formula III’ in a solvent, in the presence of a base:
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406
52
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Liu discloses the synthesis of compound 13 that includes the reaction of intermediates that fall with the scope or bioisosteric equivalence of instant formulae II and III’ in ethanol as solvent in the presence of the known base potassium carbonate, as shown below:
“To a 25 mL two neck flask were added (S)-3-(4-(3-oxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)phenyl)propionic acid hydrochloride (0.09 g, 0.28 mmol), (R)-methyl-4-(2-chloro-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxy late (0.12 g, 0.28 5 mmol), potassium carbonate (76 mg, 0.55 mmol) and ethanol (10 mL)” (Col. 223, lines 1-7). The structures of the reactants used in this reaction are shown in the table below:
Claim Number(s) of Instant Application
Instant Application
Liu
(U.S. Patent No. 11,261,190 B2)
13
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406
52
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wherein:
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464
418
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(R)-methyl-4-(2-chloro-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate
1
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406
52
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wherein:
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566
238
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(S)-3-(4-(3-oxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)phenyl)propionic acid hydrochloride
Claim 14 further limits claim 1 to a pharmaceutical composition comprising a compound of formula I’ and pharmaceutical excipients. Liu discloses that the invention disclosed therein includes a pharmaceutical composition comprising a compound disclosed therein and a pharmaceutically acceptable adjuvant (Col. 47-49).
Claim 17 is drawn to a method for inhibiting Hepatits B virus (HBV) comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof, or “the pharmaceutical composition thereof”. Claim 18 further limits claim 17 to wherein the method further comprises preventing and/or treating infections associated with HBV.
Liu discloses that heteroaryl-substituted dihydropyrimidine compounds, a class of compounds that includes the compounds disclosed therein, are known to inhibit nucleocapsid formation in Hepatis B virus (Col. 1, lines 40-53), and further discloses a method of preventing, treating or lessening an HBV disease in a patient, comprising administering a therapeutically effective amount of a pharmaceutically acceptable effective amount of the compound to a patient (Col. 11, lines 13-17).
Applicant’s invention is unpatentable over the discloser of Liu in view of the teaching of Kier and Locke, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in making and using bioisosteric derivatives of Liu’s compounds 13 and 140 wherein a propellane, cubane or adamantane is selected in place of the phenyl ring, including in a pharmaceutical composition thereof and in a method of inhibiting and preventing or treating Hepatitis B virus comprising administering such a compound or pharmaceutical composition, because it was known in the art that bioisosteric replacements on the structures of known drug compounds are a standard practice in the pursuit of new drug compounds, per the teaching of Kier, and it was known in the art that propellane, adamantane and cubane are bioisosterically replaceable groups for phenyl rings in drug compound structures, per the teaching of Locke.
Thus, the invention was prima facie obvious at the time of filing.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 3-(4-((S)-7-(((R)-6-(2-chloro-4-fluorophenyl)-5-(methoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)-3-oxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)phenyl)propionic Acid
2 2-{4-[(8aS)-7-{[(6S)-6-(3,4-difluoro-2-methylphenyl)-5-(methoxycarbonyl)-2-(1,3-thiazol-2-yl)-3,6-dihydropyrimidin-4-yl]methyl}-3-oxo-octahydroimidazo[1,5-a]pyrazin-2-yl]phenyl}acetic acid