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 .
Priority
The instant application is a national stage entry of PCT/CA2022/050674, filed May 2, 2022, which claims priority to U.S. Provisional Application no. 63/182,249, filed April 30, 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on May 14, 2023 and May 1, 2026 were in compliance with the provisions of 37 CFR 1.97 and 37 CFR 1.98. The IDS documents were considered. A signed copy of each form 1449 is enclosed herewith.
Election/Restrictions
Applicant's election with traverse of Group I in the reply filed on February 24, 2026 is acknowledged. The traversal is on the ground(s) that examining all subject matter would not impose a serious burden. This is not found persuasive because the claims lack unity as evidenced by the restriction requirement. It would be a burden on the Examiner to examine all groups as the search for compounds and the search for methods require different searching queries and databases. Therefore there is a search burden on the Examiner.
The requirement is still deemed proper and is therefore made FINAL.
5. In accordance with the 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 (see MPEP 803.02). 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 reexamined. Id. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. Id. In the event prior art is found during reexamination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final. Id.
6. As per MPEP 803.02, the Examiner will determine whether the entire scope of the claims is patentable. Applicants' elected species
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makes a contribution over the prior art of record. Therefore, according to MPEP 803.02: should the elected species appear allowable, the search of the Markush-type claim will be extended. The Markush-type claim shall be rejected and claims to the nonelected invention held withdrawn from further consideration. It has been determined that the entire scope claimed is not patentable.
Status of Claims
7. Claims 1-2, 5, 19, 25-27, 35, 41, 69, 71, 98, 103, 106, 122, 126, 132, 136, 138, and 141 are pending in the instant application. Claims 35, 71, 103, 122, 126, 136, and 138 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a non-elected invention and species. Therefore, claims 1-2, 5, 19, 25-27, 41, 69, 98, 106, 132, and 141 read on an elected invention and species and are therefore under consideration in the instant application.
Claim Rejections - 35 USC § 112
8. 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.
9. Claims 1-2, 5, 19, 25-27, 41, 69, 98, 106, 132, and 141 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.
A. Claim 1 has the limitation of “wherein all available hydrogen atoms are optionally substituted with a fluorine atom”. This statement is indefinite because it is unclear if the hydrogen atoms form a cation by binding to a fluorine atom (forming a -H+-F moiety), or if the limitation should be interpreted as the hydrogens can be replaced by fluorine. Claim 1 and the claims dependent therefrom are indefinite as Examiner cannot ascertain the metes and bounds of the claimed scope.
B. Claim 1 has the limitation of “Q is C1-C4 alkylene optionally interrupted by a heteromoiety selected from O, S, S(O), S(O)2, and NR5 and/or optionally substituted with one or more R5 and/or optionally disubstituted on one carbon with R5a and R5b (emphasis added). It is unclear how the limitations “and/or” modifies the claim, therefore, Claim 1 and the claims dependent therefrom are indefinite as Examiner cannot ascertain the metes and bounds of the claimed scope.
C. Claim 132 is indefinite because it makes express reference to the specification. The claim recites ‘compounds listed in Table 1’ which are not present in the claims. According to MPEP 2173.05(s) “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993).”
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.
10. Claims 1-2, 5, 19, 25-27, 41, 69, 98, 106, and 141 are rejected under 35 U.S.C. 103 as being unpatentable over Augeri (US 2012/0225857; Publication Date: 6 September 2012) in view of Meanwell (Journal of Medicinal Chemistry, 2018, 61, 5822-5880).
Augeri (See IDS, 14 May 2024) discloses compounds which inhibit mammalian Ste20-like kinase 1 (MST1), along with their compositions and methods of use in the treatment of diseases (Abstract). The invention is directed to compounds useful for the inhibition of MST1. One embodiment of the invention encompasses compounds of the formula
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(Paragraph 0004). Another embodiment encompasses a formulation comprising a compound of the invention and a pharmaceutically acceptable excipient (Paragraph 0005). Particular compounds of the invention are of the formulae
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wherein Y1 and Y2 are independently N or CH, r is 1 or 2, and R4 is hydrogen or alkyl (Paragraph 0047). Other compounds are of the formula
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(Paragraph 0056). These compounds, along with many others, are shown in Table 1 to have the ability to inhibit MST1 in vitro (Paragraphs 0236, 0237). The compound 1-(4-(5-amino-6-(1-oxo-1,2, 3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)phenyl) cyclopropanecarbonitrile was tested in vivo (Paragraph 0249, Figure 7B). The compound 4-(5-amino-6-(1-oxo-1,2,3,4- tetrahydroisoquinolin-6-yl)pyrazin-2-yl)-N-cyclo propyl-N-methylbenzenesulfonamide showed significant clinical responses (Paragraphs 0249-0252, Figures 7A, 7B, 8, 9A, 9B, 10A, 10B, 10C, and 10D). These compounds each have X1, X2, and X3 as CH, Q as C2 alkylene, Cy1 as phenyl or heteroaromatic.
Augeri does not teach halogenation, in particular, fluorination, at the position that would be analogous to the claimed R3 location on X4 or X5.
Meanwell teaches the use of fluorine and fluorinated motifs in drug development and their use as bioisosteres. The electronic properties and relatively small size of fluorine endow it with considerable versatility as a bioisostere and it has found application as a substitute for lone pairs of electrons, the hydrogen atom, and the methyl group while also acting as a functional mimetic of the carbonyl, carbinol, and nitrile moieties. Fluorine substitution can influence the potency, conformation, metabolism, membrane permeability, and P-gp recognition of a molecule (Abstract). The use of bioisosteres is a common principle in drug design. Introduction of fluorine can increase the overall lipophilicity of a molecule (Page 5823). The replacement of hydrogen with fluorine can lead to resistance towards oxidative metabolism, and fluorination has developed into a popular approach to address the poor pharmacokinetic performance of drug-like compounds in vitro and in vivo (Page 5824). The judicious replacement of a hydrogen atom in aromatic and heteroaromatic rings by a fluorine atom can exert a significant impact on the properties of a molecule that are beneficial to both drug design and development. An early focus of the introduction of fluorine to aromatic rings was as a tactic to slow metabolism. Fluorine is also introduced in order to improve the membrane permeability of compounds, improving bioavailability. Introduction of fluorine ortho- to an NH influences conformation, which resulted in both improved binding to the protein target, as well as improved pharmacokinetics and solubility (Replacing Hydrogen by Fluorine in Aromatic Rings).
Augeri and Meanwell are considered analogous to the claimed invention as all are involved in drug development and design. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to modify the cited compounds of Augeri by fluorination of the central pyrazine ring as Meanwell teaches that fluorination, in particular, the fluorination of aromatic and heteroaromatic moieties, is commonly employed in drug development to improve the metabolic properties of compounds, enhance permeability, and has been shown to result in improved binding efficacy when placed proximal to an NH group, as is seen in the compounds of the examined application. The fluorination of the kinase inhibitors of Augeri in view of the teachings of Meanwell is prima facie obvious application of a known technique to a known product ready for improvement to yield predictable results (See MPEP § 2143 I (D)); the compounds of Augeri are shown to be effective both in vitro and in vivo, and fluorination is a known method to improve pharmacokinetic and pharmacodynamic properties. The artisan would recognize this, and would be motivated to select one of the cited compounds for improvement as they are shown to have inhibitory activity, predictably resulting in a compound which inhibits MST1. The fluorination of these compounds is also prima facie obvious as the only difference is the presence of a fluorine atom, and the artisan would not expect these compounds to have significantly different properties due to the close chemical structure (See MPEP § 2144.09 I).
11. Claims 1-2, 5, 19, 25-27, 41, 69, 98, 106, and 141 are rejected under 35 U.S.C. 103 as being unpatentable over Gray (WO 2016/161145; Publication Date: 6 October 2016) in view of Meanwell (Journal of Medicinal Chemistry, 2018, 61, 5822-5880).
Gray (See IDS, 14 May 2024) discloses compounds of Formula (I’) which modulate the activity of a kinase (e.g., STK4), a pharmaceutical composition comprising the compound, and a method of treating a disease or disorder associated with the modulation of a kinase such as STK4 (Abstract). The compounds of the invention are of Formula (I’) or (I):
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(Paragraph 0006). In another embodiment, the compounds of Formula (I) have the structure of Formula (Id) (with pyrazine)
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wherein
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(Paragraph 00396). Paragraph 00462 contains a table which lists several compounds which render those of the examined application obvious, such as I-33
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, among others found within the table. These compounds each have X1, X2, and X3 as CH, Q as C2 alkylene, Cy1 as phenyl. Table 1 (Beginning on Page 202) lists the activity of the claimed compounds against various kinases, and shows that these compounds have low nanomolar inhibitory capacity against STK4, with several being highly specific for SKT4 alone. Another aspect of the invention relates to a pharmaceutical composition comprising a compound of any of the formulae described herein and a pharmaceutically acceptable carrier (Paragraph 0007).
Gray does not teach fluorination or halogenation at the position that would be analogous to the claimed R3 location on X4 or X5. Further, several of the cited compounds are positional isomers of compounds of the examined application, having the fluorine in a different location than what is claimed. As these are structural isomers which merely differ by the placement of the fluorine atom, the artisan would not expect these compounds to have significantly different properties from the parent compound.
The teachings of Meanwell are previously described and are fully incorporated into this rejection.
Gray and Meanwell are considered analogous to the claimed invention as in drug development and design. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to modify the cited compounds of Gray by fluorination of the central pyridine ring as Meanwell teaches that fluorination, in particular, the fluorination of aromatic and heteroaromatic moieties, is commonly employed in drug development to improve the metabolic properties of compounds, enhance permeability, and has been shown to result in improved binding efficacy when placed proximal to an NH group, as is seen in the compounds of the examined application. The fluorination of the kinase inhibitors of Gray in view of the teachings of Meanwell is prima facie obvious application of a known technique to a known product ready for improvement to yield predictable results (See MPEP § 2143 I (D)); the compounds of Gray are shown to be effective both in vitro and in vivo, and fluorination is a known method to improve pharmacokinetic and pharmacodynamic properties. The artisan would recognize this, and would be motivated to select one of the cited compounds for improvement as they are shown to have inhibitory activity, predictably resulting in a compound which inhibits STK4. The fluorination of these compounds is also prima facie obvious as the only difference is the presence of a fluorine atom, and the artisan would not expect these compounds to have significantly different properties due to the close chemical structure (See MPEP § 2144.09 I).
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.
12. Claims 1-2, 5, 19, 25-27, 41, 69, 98, 106, 132, and 141 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 19, 26, 27, 41, 42, 45, 48, 58, 98, 103, 106, 121, 130, 132, 136, 138, and 141 of copending Application No. 18/288,213 (Amended Claims of 15 May 2024) (‘213) in view of Thornber (Chemical Society Reviews, Issue 4, 1979).
Claim 1 of ‘213 is directed to a compound of Formula (I)
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which has identical limitations to the compounds of the examined application, save for requiring that the central ring is pyridine versus the claimed pyrazine (wherein one of X4 and X5 is selected from N and CR3). Claim 132 is directed to a compound of Claim 1 found in Table 1, such as I-1
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. This table contains numerous compounds which only differ from those claimed in the examined application by the central ring being pyridine rather than the claimed pyrazine. Claim 141 is directed to a pharmaceutical composition comprising a compound of Claim 1 and a pharmaceutically acceptable excipient.
‘213 does not teach that the central ring is pyrazine.
Thornber teaches the concept of bioisosterism, which is the concept wherein groups or molecules which have chemical and physical similarities produce broadly similar biological properties (Page 563). Table 1 (Page 564) lists the classical isosteres, and includes ring equivalents. Such ring equivalents include -CH=CH-, =CH-, =N-, and S. These atoms have similar electronic properties and as such, their replacement within a ring system is not expected to significantly alter the properties of that ring.
‘213 and Thornber are considered analogous to the claimed invention as all are involved in drug development and design. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to modify the compounds of ‘213 by replacing the central pyridine ring with pyrazine as Thornber teaches that =N- and =CH- function as ring equivalents, and thus the artisan would not expect the properties of these compounds to be significantly altered by performing this substitution as due to the close chemical structure (See MPEP § 2144.09 I). The artisan would expect these compounds to have similar properties, and would not expect there to be significant differences in activity by performing this substitution.
This is a provisional nonstatutory double patenting rejection.
13. Claims 1-2, 5, 19, 25-27, 41, 69, 98, 106, 132, and 141 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 5, 22, 29, 51, 71, 130, 135, and 137of copending Application No. 18/288,219 (Amended Claims of 09 April 2026) (‘219) in view of Meanwell (Journal of Medicinal Chemistry, 2018, 61, 5822-5880).
Claim 1 of ‘219 is directed towards a compound of Formula (I)
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which has identical limitations to the compounds of the examined application. Claim 71 of ‘219 is directed towards a compound of Table 1, such as II-1
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. Claim 130 of ‘219 is directed to a pharmaceutical composition comprising a compound of Claim 1 and a pharmaceutically acceptable carrier or diluent.
‘219 does not teach the fluorination of the pyrazine ring of the present claims.
The teachings of Meanwell are previously described and are fully incorporated into this rejection.
‘219 and Meanwell are considered analogous to the claimed invention as all are involved in drug design and development. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to modify the compounds of ‘219 in view of the teachings Meanwell as Meanwell teaches that fluorination is commonly employed to enhance pharmacokinetic and pharmacodynamics. Fluorination as taught by Meanwell is prima facie obvious application of a known technique to a known product ready for improvement to yield predictable results (See MPEP § 2143 I (D)); the compounds of ‘219 are shown to be effective both in vitro and in vivo, and fluorination is a known method to improve pharmacokinetic and pharmacodynamic properties. Moreover, the artisan would not expect the properties of these compounds to be significantly altered by performing these modifications due to the close chemical structure (See MPEP § 2144.09 I). The artisan would expect these compounds to have similar properties, and would not expect there to be significant differences in activity by performing these changes.
This is a provisional nonstatutory double patenting rejection.
Conclusion
14. No claims allowed.
15. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Samantha Shterengarts whose telephone number is (571)270-5316. The examiner can normally be reached on Monday thru Thursday 9-6pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Mr. Adam Milligan can be reached on 571-270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SAMANTHA L SHTERENGARTS/Primary Examiner, Art Unit 1623
Prosecution Insights