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
Claim Status
Claims 27-46 were subjected to a Restriction Requirement/Specie Election.
Claims 27-41 and 43-45 are pending examination.
Priority
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Acknowledgment is made of applicant's claim for foreign priority based on two (2) application filed in the World Intellectual Property Organization (WIPO): CN 202110597053.6 & CN 202010978095.X (in PCT/CN2021/118671) on 09/16/2021.
Applicant claims priority to the foreign document, however, the foreign document is not in English. Therefore the effective filing date is 09/16/2021.
Information Disclosure Statement
All references have been considered in the four (4) IDS(s) filed 03/13/2023, 05/15/2024, 08/23/2024, 09/05/2024 unless marked with a strikethrough.
Drawings
No (0) drawings submission were filed in the Instant Application.
Response to Restriction/Election of Species
In Response to the Restriction and Species Election Requirement dated 07/23/2025:
I. Applicant election: Applicant elected Group I, Claims 27-41 and 43-45.
Applicant further elected the specie, Compound 96 (C96), as seen below:
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Election was made without traverse.
Groups II and III, Claims 42 and 46, are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions.
II. If the elected specie is not identified in the art, Examiner will expand her search as per MPEP §802.03.
The elected specie was not identified in the art.
The elected specie would be allowable if an independent claim were drafted with that specie, Compound 96, alone.
Examiner expanded search to the full scope of the claims and art was identified.
See the Expanded Specie rejection(s) below.
Expanded Specie found reads on the following Claims 27, 31-32, 39-40, 45.
Claims 28-30, 33-38, 41, 43-44 are withdrawn from consideration.
Claim Rejections - 35 USC § 112
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.
35 USC § 112(a)– Scope of Enablement
Claims 27-41 and 43-45 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 piperazine compounds, does not reasonably provide enablement for “…stereoisomer, a tautomer, …a prodrug thereofs. 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.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). These include: nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability or unpredictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention:
The instant claims recite “A compound represented by general formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a prodrug thereof” of Claims 27-41 and 43-45. The claims allow for any compound falling within general formula (I).
The specification discloses several synthetic methods to make piperazine compounds, but as parts of the specification are blurred or unclear, determination of which of the compounds presented in the instant claims were tautomers, stereoisomers, pharmaceutical salts or prodrugs was not detailed. Claims 42 & 46 details a method for inhibiting coagulation factor XIa or for inhibiting coagulation factor XIa and plasma kallikrein.
Breadth of the Claims:
The instant claims encompass several piperazine compounds with derivatives. As such, the claims are broad in “a pharmaceutical composition, wherein the pharmaceutical composition comprises an effective dose of the compound.” The claims also broadly speak to “a method for inhibiting coagulation factor XIa or for inhibiting coagulation factor XIa and plasma kallikrein.” The claims are broad in that any compound represented by general formula (I) is recited by the claims.
Guidance of the specification:
The only direction concerning “A compound represented by general formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a prodrug thereof …” in the instant specification is not seen in the synthesis or in the method of use as to which compounds are the compound or the stereoisomer, the tautomer, the pharmaceutically acceptable salt or the prodrug.
On page 252, beginning with Test Example 2 and continuing with Test examples, the Instant Specification defines the pharmacodynamics and pharmacokinetics parameters of the piperazine compounds and derivatives but does not address the context in how these compounds aid in defining the scope of the invention.“ The specification does not provide guidance on which of the compounds are “a compound represented by general formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a prodrug thereof,.”
State of the prior art & The predictability or unpredictability of the art:
Art used:
Xie Z, et al. Factor XIa Inhibitors in Anticoagulation Therapy: Recent Advances and Perspectives. J Med Chem. 2023 Apr 27;66(8):5332-5363; hereinafter “Xie”.
Al-Horani RA, et al. Recent advances in the discovery and development of factor XI/XIa inhibitors. Med Res Rev. 2018 Sep;38(6):1974-2023; hereinafter “Al-Horani.”
The state of the art in piperazine compounds and inhibitors of coagulation factor XIa involves the development of new drugs targeting these protein targets for treating and preventing thrombotic disorders. The focus is on creating drugs that inhibit coagulation factors such as factor Xa and factor XIa, which are crucial in the coagulation cascade.
As seen in Xie, their use as key structural scaffolds in the development of a new generation of anticoagulants. These small-molecule FXIa inhibitors aim to prevent thrombosis effectively while minimizing the risk of major bleeding associated with current anticoagulation therapies
Recent studies (as seen in Al-Horani) have shown that inhibitors of factor XIa can be effective in preventing thromboembolism and have been confirmed through experimental testing. These inhibitors are being developed to improve the safety of anticoagulation therapy while minimizing the risk of bleeding complications.
The development of these inhibitors is driven by the need for new, more advanced drugs that can prevent pathological conditions without disrupting normal hemostasis. FXIa appears to be a very attractive drug target and the development of molecules that interfere with its physiological functions, or even inhibit its hepatic biosynthesis, appears to have gained momentum. The use of computational methods, such as docking and quantum chemical calculations, is being employed to search for lead compounds and confirm their effectiveness as inhibitors.
These advancements in piperazine compounds and inhibitors of coagulation factor XIa are crucial for the development of safer and more effective anticoagulants that can be used in various medical settings. These varying ways indicate unpredictability as well. Thus, it is clear from at least this prior art that the treatment with piperazine compounds seems worthwhile, there is no explicit discussion as to how a compound represented by general formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a prodrug thereof is represented in the art.
Further, the art shows specific binding pockets (see for example page 57), and there is no data related how additional structures such as pro-drugs will impact such binding much less how any structural pro-drug attached to any potential position would impact binding, or quantity of free drug on metabolic release.
Thus, the art establishes that there is unpredictability in the field of piperazine compounds and its application to strategies to inhibit FXI/FXIa system. Several inhibitors of factor XI/XIa proteins have been discovered or designed over the last decade including polypeptides, active site peptidomimetic inhibitors, allosteric inhibitors, antibodies, and aptamers. involve polypeptides, active site peptidomimetic inhibitors, allosteric inhibitors, monoclonal antibodies, ASOs, and aptamers. The different strategies available to target FXI/FXIa system present multiple areas which indicates high unpredictability since on the thrombosis front, thrombotic diseases are either venous or arterial diseases. Particularly, the coagulation process, which represents a series of chemical bio-transformations, comprises the intrinsic pathway, the extrinsic pathway, and the common pathway (see below).
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Existence of working examples/specification:
There are working examples in the Instant Specification that lead to the enablement of piperazine lead compounds and the use of that compound through administration method, blood concentration, AUC, half-life, and bioavailability. The Instant Specification fails to show the stereoisomer, a tautomer, a pharmaceutically acceptable salt or a prodrug of their desired compound . As seen in Xie & Al-Horani (referenced above), several examples of the AD pipeline indicates the diverse range of possibilities as well as mechanisms, even those with unknown mechanisms (indicating unpredictability).
Amount of experimentation necessary:
Finding a compound able to inhibit disease progression is an empirical exercise. Predicting if a certain claimed compound/composition, for example, is in fact inhibiting/treating disease progression 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 composition to be enabled for inhibiting/treating disease progression, 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. First, preparing, then determining whether a particular compound meets these three criteria in a clinical trial setting requires an undue quantity of experimentation.
MPEP 2164.01(a) states, “[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).” That conclusion is clearly justified here. Thus, undue experimentation will be required to determine if any particular derivative is, in fact, a prodrug.
Conclusion
After consideration of nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability or unpredictability of the art and the amount of experimentation necessary, Applicant was not in possession of the entirety the genus of a “a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a prodrug.”
Claim Rejection – 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 31, 37-38 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.
Furthermore, Claims 27, 31, 37-38, and 46 have the following issues:
The phrases “for example”, “such as”, and “preferably” renders the claims indefinite because it is unclear whether the limitations following the phrase is a necessary part of the claimed invention. See MPEP § 2173.05(h).II. It should be noted that Claim 46 is withdrawn, but this issue could arise on rejoinder.
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 27, 31-32, 39-40, 45 are rejected under 35 U.S.C. 102(a)(1) & 102(a)(1) as being anticipated by A. Hutchison et al, in US 7,081,458 B2 (pub’d 07/25/2006; hereinafter “Patent’458”).
This rejection applies to the expanded specie.
With respect to Claim(s) 27, 31-32, 39-40, Patent’458 teaches the following for the compound shown below by general formula (I); which reads on the Instant Claims.
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X is C=O;
G is a bond;
Ring A is aryl or heteroaryl;
Ring B is cycloalkyl, aryl;
R1 are the same or different, and are each independently selected from hydrogen atom, -OR9; n is 1.
R2 is alkoxy;
R3 is selected from hydrogen atom;
R4 is selected from hydrogen atom, alkyl;
R5 are the same or different and are each independently hydrogen atom, -OR9; m is 2;
R8 is selected from hydrogen atom;
R9 is selected from hydrogen atom, alkyl.
With respect to Claim 40, Patent’458 teaches the pharmaceutically acceptable salt (col. 2, lns. 27-55).
Conclusions
Claim(s) 27, 31-32, 39-40, 45 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Josmalen M. Ramos-Lewis whose telephone number is (571)272-0084. The examiner can normally be reached M-F 9:30-5:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached at (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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Josmalen M. Ramos-Lewis, Ph.D.
Patent Examiner
Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621