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
Status of 18/127,160
Claims 1-20 are currently pending.
Priority
Instant application 18/127,160, filed 3/28/2023, claims priority as follows:
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The foreign priority documents submitted in the file wrapper are not translated to English and as a result, priority cannot be established. Thus, claims 1-20 are granted the effective filing date of 9/30/2021.
Objection to Abstract
The abstract is objected to for minor informalities. Specifically, the abstract states, “Provided are a novel compound that effectively antagonizes P2X3 receptor,” which intermixes singular and plural terminology. Appropriate correction is required.
Election/Restriction
Applicant’s election of Group I, claims 1-17, drawn to compounds and compositions of Formula I, without traverse in the reply filed 11/7/2025 is acknowledged. Applicant’s election of compound I-27:
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In the same reply, is also acknowledged.
Examination will begin with the elected species. In accordance with MPEP § 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended. If prior art is then found that anticipates or renders obvious the non- elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be examined again. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during further examination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
The elected species was searched and prior art was identified. See the 103 rejection below. The full scope of the claims has not yet been searched in accordance with Markush search practice. Claims 1-6, 8-11, and 13-17 read on the elected species. Claims 7, 12, and 18-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species and/or group, there being no allowable generic or linking claim.
Claim Objections
Claim 9 is objected to for a minor informality. Specifically, claim 9 is objected to because it recites, “identical or difference” with respect to the halogen atoms of a C1-C3 substituted alkyl of Re, but should read, “identical or different”. Appropriate correction is required.
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 3-6 and 8-9 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.
Claims 3-6 and 8-9 recite the term, “preferably”, in multiple instances in reference to preferred substituents or variables. The term is indefinite because the phrase is exemplary language and it is not clear if the contents after the term are required, or just examples of what is required. Appropriate correction is required.
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.
Claims 1-6, 8-11, and 13-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The courts have stated that, “To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated that, “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus …”) Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed genus is sufficient. See MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
In the instant case, the claims of the instant application embrace compounds of Formula I, or a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt, or a prodrug thereof. Particularly, the term “prodrug”, recited in claims 1-6, 8-11, and 13-17 invokes the 35 U.S.C. 112(a) rejection. Even a cursory calculation of the number of compounds embraced in the instant claims would result in thousands of compounds.
Level of skill and knowledge in the art
The level of skill and knowledge in the art is high.
Partial Structure
Compounds of Formula I have been disclosed and example compound species that would be within the general formula have been disclosed. However, as to the claimed prodrugs, no specific examples are given that would demonstrate possession or put the public in possession of all the claimed prodrugs of Formula I. It is generally accepted that prodrugs may vary by chemical formulae and may also differ in properties and the arrangement of atoms in the molecule.
Physical and/or chemical properties/functional characteristics
The compounds of Formula I, and prodrugs thereof, are compounds which are allegedly useful in methods for treating P2X3-related diseases, for example in the treatment of pain, a respiratory disease, or a urogenital disease. Although the art recognizes generally accepted definitions, the terms are not explicitly defined by the specification in such a way as to demonstrate that the inventor had possession of the prodrug of Formula I.
A review of the prior art identifies Najjar (Najjar, A. & Karaman, R. Expert Opinion on Drug Discovery, 2018, 14(3), 199-220), which discloses successes and failures of prodrugs of known pharmaceuticals (abstract and page 212, section 3). Najjar teaches hetacillin, an ester prodrug of ampicillin, which was withdrawn since it did not have a superior advantage when compared to ampicillin. In light of Najjar, it is unknown which of the prodrugs of compounds of Formula (I) claimed by Applicant is will be active or inactive. Further, one of ordinary skill in the art would not be able to predict which compounds, of the vast number that are claimed, will be active or inactive absent evidence. There is no structure/function correlation in the specification showing which prodrugs would or would not be active.
Since Applicant has not set forth compounds or substituents on Formula I in the specification which Applicant considers prodrugs, it is not clear what compounds fall under Formula I. Applicant has not described which prodrugs have the ability to antagonize P2X3, and which do not. Stated differently, there is no structure/function correlation and no representative number of specific examples of prodrugs that demonstrate which compounds retain activity. Further, one of ordinary skill in the art would not be able to predict the biological activity of the claimed prodrugs of Formula I.
Predictability of the art
Medicinal chemistry is an experimental science with a low predictability level. Small changes in the structure of a compound can lead to large differences in their pharmacological activity. Regarding prodrugs, predicting if a certain claimed compound retains the activity and function of the original drug is filled with experimental uncertainty because prodrugs contain variation by chemical and physical properties of the molecules.
Method of making the claimed invention
Although the specification provides a method for making the compounds of Formula I, no method for making all of the compounds, including the prodrugs, encompassed by the instant claims has been disclosed. Methods of synthesizing compounds are, in general, known to a person of ordinary skill; however, methods of making the myriad of compounds encompassed by the instant claims is beyond the skill of the artisan, particularly when certain elements, such as prodrugs are merely described partially.
As such, the instant specification and instant claims do not provide sufficient description such that one could anticipate what additional elements may be present in the prodrugs of Formula I because the examples illustrated in the experimental section are limited to only compounds of Formula I.
Substantial and undue experimentation would be needed to practice Applicant’s invention because the specification lacks sufficient detail to show how to use the prodrugs of the instant invention. Further, there is no guarantee that all of the prodrugs embraced by the scope of the claims would be use in methods for treating P2X3-related diseases, for example in the treatment of pain, a respiratory disease, or a urogenital disease.
Even with the undue burden of experimentation, there is no guarantee that one would obtain the product of a desired prodrugs of an instant compound of Formula I. Although some functional characteristics are disclosed or would be known to a person of ordinary skill in the art, in the absence of a disclosed structure, there can be no correlation between the function and structure of the claimed prodrugs in the instant application.
The MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. It is unquestionable that the claim(s) are broad and generic with respect to all possible compounds encompassed by the claims: the possible structural variations are limitless to any prodrugs of the genus. In the instant case, however, the specification does not disclose a sufficient variety of species to reflect this variance in the genus. Specification does not provide sufficient descriptive support for the myriad of compounds embraced by the claims such as, prodrugs of Formula I.
The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”) Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention. This rejection would be overcome by amending the claims to remove the term, “prodrug”.
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.
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 1-6, 8-11, and 13-17 are rejected under 35 U.S.C. 103 as being unpatentable over Evotec AG (WO 2016/091776 A1, cited in the IDS of 3/28/2023, herein after “Evotec”), and further in view of Gillis (Gillis, E. P. et. al. J. Med. Chem. 2015, 58, 8315-8359., cited in the IDS of 11/22/2023).
Determining the scope and contents of the prior art
The reference Evotec teaches 1,3-thiazol-2-yl substituted benzamides as compounds active against P2X3 (abstract and Table, starting on page 646). Specifically, Evotec teaches Example 163 (page 489, lines 13-22):
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Which was found to have a 5 nm IC50 against hP2X3, in addition to selectivity for the hP2X3 receptor over the hP2X2/3 receptor (Table, page 653). Example 163 maps to the elected species and instant Formula I:
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When R1 is unsubstituted C1 alkyl, L is –(CH2)n-, where n is 0, R2 is a Ra-substituted C4 alkyl, wherein the Ra substitution is an -OH, R3 is C1 alkyl, and A is a six-membered heteroaryl, wherein the heteroaryl is substituted with Re and Re is a C1 alkyl substituted with three identical halogen atoms. With respect to claim 17, Evotec teaches the addition of the compound to buffer, which indicates a pharmaceutical composition (page 645, lines 30-32).
The reference Gillis teaches that the addition of fluorine on molecules in medicinal chemistry can positively influence physical and pharmacokinetic properties, and specifically productively influence conformation, pKa, intrinsic potency, membrane permeability, and metabolic pathways (abstract). Further, Gillis teaches that the substitution of fluorine on aromatic rings, and electron-withdrawing groups in general, can provide insight into structure-activity relationships, modulate the physical properties of other substituents, and potentially interfere with oxidative metabolic processes (pages 8326-8327).
Ascertaining the differences between the prior art and the claims at issue
Evotec fails to teach a fluorine substitution at the ortho site of the internal aryl adjacent to the amide and thiazole of the elected species. Stated differently, Evotec fails to teach an anticipatory species where m is 1 and X is F of Formula I.
Gillis fails to teach the elected species.
Resolving the level of ordinary skill in the pertinent art
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of benzamide compounds as P2X3 antagonists. An artisan possess the technical knowledge necessary to make adjustments to the benzamide compounds to enhance their effectiveness. Said artisan has also reviewed the problems in the art as regards to use of said benzamide compounds as P2X3 antagonists and understands the solutions that are widely known in the art.
Considering objective evidence present in the application indicating obviousness or nonobviousness
Applying KSR prong (A), it would have been prima facie obvious to one of ordinary skill to combine Example 163 of Evotec with the teachings of Gillis because one skilled in the art would expect the resulting compound, a fluorine-substituted Example 163, to have similar properties to Example 163. The artisan would be motivated before the effective filing date of the claimed invention to test substituents on the internal aryl ring of Evotec and would have specifically been directed to a fluorine substituent based on the teachings of Gillis. A skilled artisan would be motivated before the effective filing date to improve the overall activity of Example 163, a P2X3 antagonist, of Evotec, to identify additional P2X3 antagonists, and would have readily predicted that the combination of the two references would improve known P2X3 antagonists. The Examiner notes this argument can be expanded to additional compounds of the instant claims.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6, 8-11, and 13-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 15 of copending Application No. 18/850,218 (herein after the “‘218 Application”). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘218 Application teach a crystalline form of the elected species. Further, claim 15 of the ‘218 Application additionally teaches a pharmaceutical composition of the crystalline form.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 1-6, 8-11, and 13-17 are rejected. Claims 7, 12, and 18-20 are withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kendall Heitmeier whose telephone number is (703)756-1555. The examiner can normally be reached Monday-Friday 8:30AM-5:00PM ET.
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/K.N.H./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621