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 .
Election/Restrictions
Applicant's election with traverse of
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in the reply filed on 07/25/2024 is acknowledged. The traversal is on the ground(s) regarding election of species.
Applicant states that claim 1 has been amended to be directed to a single compound, and therefore, that no further election of a compound species is necessary. Applicant further elects, without traverse, sulfobutyl ether-β-cyclodextrin as the cyclodextrin species and citric acid monohydrate as the buffer species, and asserts that claims 1-3, 5-6, and 9-14 are readable on the elected species. The amendment to claim 1 is acknowledged. Because amended claim 1 is now limited to a single compound species, a further election among the previously identified compound species is unnecessary. For purposes of continued examination, the compound presently recited in amended claim 1 is regarded as the elected compound species. Applicant’s election, without traverse, of sulfobutyl ether-β-cyclodextrin and citric acid monohydrate are likewise acknowledged. Accordingly, examination is directed to the presently claimed compound in combination with the elected sulfobutyl ether-β-cyclodextrin and citric acid monohydrate species, as applicable to the pending claims.
Applicant’s remarks, however, appear in part to address the claims as they existed prior to the present amendment. The present amendment replaces the prior listing of claims and materially changes the scope of the pending claims, including amendment of claims 1 and 2 and cancellation of claims 46, 49, and 52-53. Accordingly, the patentability of the presently pending claims is determined based upon the current claim language, as amended, and not the superseded claim language addressed in the prior election requirement or Applicant’s characterization thereof.
Applicant further argues that the presently claims are novel and inventive over the references cited in connection with the election/restriction requirement because the cited references allegedly fail to teach or suggest the presently claimed pharmaceutical composition comprising the elected compound and cyclodextrin at the claimed weight ratio. Applicant additionally relies on Tables 11 and 12 of the specification as allegedly demonstrating improved exposure and inhibition relative to a formulation without cyclodextrin. These arguments are noted. However, the prior art discussion made in connection with the election/restriction requirement was directed to whether the identified species shared the requires special technical feature and was not a determination of patentability of the presently amended claims over the prior art. Patentability of the elected subject matter is addressed separately herein under 35 U.S.C. § 103 based upon the presently pending claims and the prior art applied in this Office Action. Accordingly, Applicant’s arguments concerning patentability over the references previously relied upon for the election/restriction do not overcome the rejection set forth herein.
Applicant’s reliance upon MPEP §§ 806.04(d) and 809.02(a), concerning consideration or rejoinder of nonelected spices upon allowance of a generic claim, is also noted. Such consideration is premature at this stage, because no generic claim has presently been foiund allowable. The presently pending claims readable on the elected subject matter remain under examination and are rejected for the reasons set forth below. The question of rejoinder or examination of otherwise nonelected subject matter will be considered, if appropriate, upon a subsequent determination of allowability in accordance with applicable office practice.
Accordingly, the election is maintained for purposed of examination, with the compound now expressly recited in claim 1, sulfobutyl ether-β-cyclodextrin, and citric acid monohydrate constituting the elected species as applicable to the presently pending claims. Claims 1-3, 5-6, and 9-14 are examined to the extent they read on the elected subject matter.
The requirement is still deemed proper and is therefore made FINAL.
Priority
This application is a national phase application, filed pursuant to 35 U.S.C § 371 of PCT Application No. PCT/1B2023/050766 filed on January 30, 2023, which claims foreign priority of Chinese Patent Application No. 202210107273.0 filed on January 28, 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/25/2024 has been considered by the examiner.
Status of Claims
Claims 1-3, 5-6, and 9-14 are pending claims are examined to the extent they read on the elected species. Claims 4, 7-8, and 15-58 are canceled.
Claim Objections
Claim 1 is objected to because of the following informalities: portions of the chemical structures and associated textual limitations appearing in claim 1 are faint, incomplete, and/or insufficiently legible to permit clear reproduction of the claim. In particular, portions of the depicted chemical structures, bonds, atom designations, stereochemical designations, and associated claim text are not clearly reproduced. Applicant is required to submit a corrected claim listing in which the entirety of claim 1, including each chemical structure, bond, atom, substituent, stereochemical designation, and textual limitation, is clearly and legibly reproduced. For purpose of examination, the compound in claim 1 is construed to be
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. Appropriate correction is required.
Claim 2 is objected to because of the following informalities: the claim employs repeated “and/or” terminology in reciting the limitations that “the cyclodextrin is β-cyclodextrin; and/or the pharmaceutical composition is a solution; and/or .. the pharmaceutical composition further comprises a buffer.” The repeated use of “and/or” results in unnecessarily ambiguous and awkward recitation of alternative combinations of limitations and should be clarified to positively identify the limitation or combination of limitations intended to further limit claim 1. Applicant is required to amend claim 2 to clearly recite the intended combination or alternative combinations of limitations. Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-3, 5-6, and 9-14 are rejected under 35 U.S.C. 103 as being unpatentable over Mosher et al (US10,512,697 B2) in view of Takahashi et al. (Journal of Pharmaceutical and Biomedical Analysis 48 (2008) 1219–1224), and Zhu (US 2021/0093624 A1), and Dubowchik et al. (WO2021072140 A1).
Mosher teaches pharmaceutical composition comprising clopidogrel or a pharmaceutical acceptable salt thereof and a cyclodextrin, particularly sulfoalkyl ether cyclodextrin (SAE-CDs), including sulfobutyl ether-β-cyclodextrin (SBE-β-CD; Captisool®). Mosher teaches that SAE-β-CD derivatives are particularly useful for solubilizing clopidegrel and specifically identifies SBE7-β-CD as providing a high degree of dissolution. See col. 36, Discussion of Fig. 1. Mosher further teaches aqueous formulations containing about 20-600 mg/ml, 50-500 mg/ml, or 100-400 mg/ml SAE-CD, and clopidogrel concentrations of about 1.5-20 mg/ml, or 0.15-1.5 mg/ml. See col. 8, II. Approximately 35-55. Mosher’s disclosed ranges therefore encompass combinations falling within the presently claimed cyclodextrin: compound weight ratio of 60:1-200:1; for example, Mosher’s expressly disclosed 20 mg/ml cyclodextrin and 0.15 mg/ml clopidogrel concentrations correspond to a weight ratio of approximately 133:1. Mosher also teaches that the appropriate SAE-CD/clopidogrel ratio can be varied depending upon formulation conditions, including pH and other excipients.
Mosher additionally exemplifies formulations containing 92.5 g SBE-β-CD and clopidogrel bisulfate equivalent to 1.88 g clopidogrel, together with citric acid/sodium citrate buffer, thereby, confirming the use of presently relevant cyclodextrin with clopidogrel in an aqueous buffer pharmaceutical composition. See Example 12, col. 47, approximately II. 10-30.
Mosher does not expressly teach the particular compound recited in claim 1 in please of clopidogrel.
Claim 1 Compound Clopidogrel Clopidogrel active metabolite
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Takahashi however, teaches that clopidogrel is converted to a pharmacologically active metabolite and expressly reports that active clopidogrel metabolite contains a thiol group requiring stabilization in biological samples.
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. Takahashi accordingly derivatized the thiol using the alkylating reagent 2-bromo-3’-methoxyacetophenone to stabilize the active metabolite. See Fig. 1; p. 1219 and Abstract.
Thus, Takahashi establishes that the pharmacologically active clopidogrel metabolite possesses a reactive thiol functionality and that derivation of that thiol provides a means for stabilizing the active metabolite.
Zhu more specifically teaches the clopidogrel active metabolite H1-H4
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and states that these metabolites are chemically unstable and reactive, such that their structures were established in stabilized derivative forms. See ¶[0007], p. 1. Zhu further teaches that the circulating thiol metabolites are stabilized as derivatives. See ¶[0008], pp. 1-2. Significantly, Zhu expressly teaches that direct administration of clopidogrel active metabolites or its releasable derivatives may overcome the problems associated with clopidogrel activation and describes releasable conjugates of the active metabolites as drug candidates that do not require metabolic bioactivity. See ¶[0007], p. 2.
Thus, Zhu provides an express reason to prepare a releasable prodrug derivative of the active thiol metabolite, rather than requiring administration of clopidogrel followed by metabolic formation of the active metabolite.
Dubowchik teaches prodrugs designed to be converted in vivo to an active parent drug and explains that prodrug derivatization may be used to improve pharmaceutical properties, including bioavailability. See p. 1, approximately II. 15-20. Dubowchik further teaches prodrug substituents having the general alkoxycarbonyloxymethyl arrangement -CH2-O-C(O)-OR, including sulfur-linked embodiments. Most significantly, Dubowchik actually exemplifies compound 91, whose name identifies the substituent: 2-[{[propan-2-yloxy) carbonyl] oxy} methyl] sulfanyl and whose structure therefore contains: -S-CH2-O-C(O)-CH(CH3)2 i.e., the same S-[(isopropoxycarbonyloxy)methyl] connectivity present in the presently claimed clopidogrel-active-metabolite prodrug. See Example/Compound 91, pp. 67-68, table of compounds 89-96. Dubowchik’s disclosure is expressly directed to prodrugs rather than merely to protecting-group chemistry.
It would therefore have been obvious to one of ordinary skill in the art at the relevant time to replace the parent clopidogrel employed in Mosher’s cyclodextrin-containing pharmaceutical composition with a releasable derivative of the pharmacologically active clopidogrel thiol metabolite taught by Takahashi and Zhu, and especially to derivatize the metabolite’s thiol with the S-CH2-O-C(O)-OiPr connectivity. The combined teachings therefore would have provided a reason to use Dubowchik’s known sulfur-prodrug form of the pharmacologically active metabolite.
One of ordinary kill would also have had a reasonable expectation of success because Zhu expressly teaches preparing stabilized/releasable derivatives of the clopidogrel active thiol metabolite, Takahashi demonstrates that the thiol is susceptible to compound. The proposed modification therefore employs a known prodrug derivatization for its art-recognized purpose rather than requiring development of an unknown reaction or unknown class of promoiety. Mosher’s teaching of cyclodextrin-containing pharmaceutical compositions would have provided further a reason to formulate the resulting prodrug with cyclodextrin, because Mosher teaches cyclodextrin as a pharmaceutical formulation component for the same clopidogrel therapeutic system and teaches its use for increasing solubilization and obtaining useful aqueous pharmaceutical formulations.
Regarding claims 2 and 3, Mosher expressly teaches β-cyclodextrin derivatives, including sulfobutyl ether-β-cyclodextrin, and specifically identifies SBE7-β-CD/Captisol®. Mosher teaches aqueous solutions containing clopidogrel SBE-β-CD and further teaches inclusion of buffers. Mosher’s Example 10, for example, employs Captisol® (SBE7-β-CD) and citric acid/sodium citrate buffer. See col. 47, approximately II. 10-30. Accordingly, the additional limitations of claim 2 and 3 would have been obvious for the reasons stated above.
Regarding claims 5, Mosher teaches clopidogrel concentration of approximately 0.15-1.5 mg/ml and 1.5-20 mg/ml, which overlap the claimed ranges including 0.1-10, 0.2-10, 0.3-5, 0.4-2, 0.5-1, and 0.6-0.9 mg/ml.
Regarding claim 6, Mosher teaches SAE-CD concentrations of approximately 20-600 mg/ml, 50-500 mg/ml, and 100-400 mg/ml, which overlap the presently claimed cyclodextrin concentration ranges. Mosher further teaches the increasing SAE-CD concentration permits greater amounts of clopidogrel to be dissolved and allowed preparation of more concentration formulations. See Discussion of Figs. 5-6, approximately col. 36.
It would have been obvious to employ concentrations within the overlapping ranges because the prior art expressly encompasses such concentrations and identifies cyclodextrin concentration as affective drug solubilization.
Regarding claims 9, 10 and 13, Mosher expressly teaches pharmaceutical compositions comprising clopidogrel and SBE-β-CD in an aqueous buffered solution and expressly exemplifies the use of citric acid/sodium citrate buffer. Mosher further teaches that formulation pH and buffer conditions may be varied and teaches formulation pH ranges overlapping the presently claimed pH of 3-4. Accordingly, it would have been obvious to one of ordinary skill in the art to employ an acidic citrate buffer in the modified pharmaceutical composition discussed above in order to maintain the pharmaceutical composition at a desired pH.
With respect to claims 11-12, the use of citric acid monohydrate as the citric acid source and optimization of the amount thereof would have been within ordinary skill in the art because Mosher expressly teaches citrate-buffer pharmaceutical compositions and recognizes pH and buffer conditions as formulation variables. The particular amount of citric acid monohydrate necessary to obtain and maintain the desired acidic pH would have been a result-effective formulation variable, the workable amount of which could have been determined through routine optimization. The instant specification itself is consistent with the art-recognized relationship between citric acid monohydrate concentration and its conventional buffering function: ¶[0138] teaches use of an acidic buffer to adjust the pharmaceutical composition to about pH 34-l; and Examples 7-11 employ citric acid monohydrate as the “buffer” at approximately 1.04 mg/ml 1.57 mg/ml, and 1.26 mg/ml, respectively. ¶¶[00284], [00286], [00288], Tables 7-9. Thus, the claimed 1-3 mg/ml range represents a workable amount within the routine optimizable buffer concentration rather than a different function or use of citric acid monohydrate.
Regarding claim 14, Mosher expressly converting its clopidogrel/SBE-CD solution to a solid by lyophilization. For example, Mosher teaches an SBE-β-CD/clopidogrel bisulfate solution that is filled into vials with the resulting lyophiles being reconstitutable with sterile water. See Examples 11/12 region, cols. 47-48. Mosher further expressly states that liquid formulations may be lyophilized or otherwise dehydrated to form reconstitutable solids. Accordingly, formation of the pharmaceutical composition by lyophilization of the solution would have been obvious.
In summary, Mosher provides the claimed cyclodextrin pharmaceutical-formulation platform that contains clopidogrel and overlapping formulation parameters; Takahashi establishes the reactive, stabilization-requiring thiol functionality of the clopidogrel active metabolite; Zhu expressly teaches the pharmacologically. Zhu expressly teaches the pharmacologically active H4 thiol metabolite and proposes releasable derivatives/prodrugs thereof; and Dubowchik teaches and actually exemplifies, in compound 91, the particular -S-CH2-O-C(O)-O-iPr prodrug connectivity recited in the presently claimed compound.
The proposed combination therefore does not rely upon the hindsight selection of an arbitrary substituent. Rather, the prior art identifies both problems-instability/reactivity and of the active clopidogrel thiol metabolite-and the known solution-conversion of such an active parent drug into a releasable prodrug, with Dubowchik supplying an actually exemplifies sulfur-linked isopropoxycarbonyloxymethyl promoiety.
Conclusion
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
