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, 3-14 and 17-19 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.
Claim Rejections – Withdrawn
The prior rejection of claim 8 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the applicant), regards as the invention, has been overcome by Applicant’s amendment of claim 8, and is accordingly withdrawn. Applicant’s amendment of claim 8 to remove “when” from the language “and/or, when” has overcome the prior rejection.
The prior rejection of claim 2 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Biodiversity, v1, pp138-151; 2004) and Locke (Locke, G. M.; Chemistry A European Journal; v25, pp4590-4647; 2019), is withdrawn in response to Applicant’s cancellation of claim 2.
Claim Rejections - 35 USC § 103 – Maintained
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.
The prior rejection of claims 1, 3-14 and 17-18 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), is maintained. Applicant has traversed the prior rejection on the following grounds:
Applicant alleges that Liu’s results show a strong sensitivity to replacement of a planar ring at the Q position of instant formula I’ with a non-planar ring;
Applicant alleges that the instantly claimed compounds show unexpectedly superior biological activity compared to Liu’s compounds, including equivalent or better potency and superior safety;
Applicant demonstrates superior bioavailability of an instantly claimed compound over a compound not disclosed by Liu.
Applicant’s traverse has been considered, but is found to be not persuasive, for the following reasons:
A person of ordinary skill in the art would not consider Liu’s compound 13 as being comparable in structure to Liu’s compound 7 except for the replacement of a phenyl ring at Q for a pyrrolidine, because Liu’s compound 7 bears both a carboxylic acid and an ether at the Q ring, besides the Q ring being an aliphatic heterocycle, thus compound 7 has three heteroatomic aspects (ether, CO2H, amine) at the Q moiety compared to the one heteroatomic functional group (CO2H) of Liu’s compound 14;
The basis of bioisosteric equivalence between phenyl ring and aliphatic cage rings including propellane, cubane and adamantane is found in the commonality of rigidity in all these rings, thus rigidity, as taught by Locke, is the more important aspect than planarity. Liu’s compound 7, with a pyrrolidine at Q, is not a reasonable comparison to the bioisosteric equivalence between phenyl and aliphatic cage rings because the pyrrolidine ring of compound 7 is not rigid;
Applicant’s table, shown below, comparing Liu’s compound 13 to an instantly claimed compound (at left) did not show superior potency for the instantly claimed compound, as a difference of 1 nM, in the absence of evidence of a subnanomolar accuracy in both respective measurements can readily be attributed to assay variability; additionally, the instantly claimed compound shows inferior safety compared to Liu’s compound 14, rather than superior safety as alleged by Applicant, as lower CC50 corresponds to greater cytotoxicity to host cells;
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632
1012
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Applicant’s comparison of bioavailability data is not material to the prior rejection since the reference compound Applicant cites, with the cyclobutyl ring at Q, is not a compound of Liu and is itself not material to the bioisosteric rejection since the cyclobutyl ring at Q, much like the pyrrolidine ring of Liu’s compound 7, is not rigid like a benzene, propellane, cubane, or adamantane ring would be.
Reiterated Rejection:
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”) is modified to replace a para-substituted phenyl ring with either propellane (BCP) or cubane: both 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 3-12 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.
Allowable Subject Matter
Claim 19 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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
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