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
Applicant’s preliminary amendment of 26 August 2025, in which claims 1-3, 11-12, 20-21, 26-27, 32-33, 38-39, 44-45, 49, 50 have been amended, claims 4-10, 13-19, 22-25, 28-31, 34-37, 40-43, 46-48 have been cancelled, and new claims 51, 52 have been added, is acknowledged.
Claims 1-3, 11-12, 20-21, 26-27, 32-33, 38-39, 44-45, 49-52 are pending in the instant application.
Claims 1-3, 11-12, 20-21, 26-27, 32-33, 38-39, 44-45, 49-52 are examined herein.
Priority
This application is a 35 U.S.C. 371 National Phase entry of International Application PCT/US2023/021522, filed on 9 May 2023, which claims the benefit of U.S. Provisional Patent Application Number 63/340,348, filed on 10 May 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 26 August 2025 is acknowledged and considered.
Objection to the Specification
`The Specification is objected to because it recites (1s, 3s) as part of the compound name; yet R and S in enantiomer nomenclature are always written as capital letters.
Applicant is required to identify all instances in the Specification where enantiomers R or S are written in lowercase and correct each instance.
Appropriate correction is required.
The Specification is objected to because on page 26 it recites
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.
This is incorrect. The starting material (to which acryloyl chloride is added) is an amine, namely (1S, 3S)-N,3-dimethyl-3-((6-(1-methyl-]H-pyrazol-4-yl)pyrazolo[,5-a]pyrazin-4- yl)oxy)cyclobutan-l-amine, and not acrylamide.
Appropriate correction is required.
The Specification is objected to because of a typographical error: on page 28, Example 2, text line 3 under the Scheme, the text “acroloyl chloride” should read –acryloyl chloride--.
Objection to the claims
Claim 1 is objected to because it recites N- methyl-N-((1 s,3 s)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyrazin-4- yl)oxy)cyclobutyl)acrylamide; yet R and S in enantiomer nomenclature are always written as capital letters.
Appropriate correction is required.
Claim Rejections- 35 USC 112
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, 12, 21, 27, 33, 39, 45 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 pre-AIA the applicant regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 3 recites the broad recitation
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, and the claim also recites
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which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
The same analysis applies to claims 12, 21, 27, 33, 39, and 45.
Appropriate correction is required.
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, 20-21, 26-27, 32-33, 38-39, 44-45, 49-52 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 claim(s) 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. This is a new matter rejection.
Claim 1, as amended, is drawn to
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Yet, the instant Specification (Example 3) and the original claims of 11/08/2024 (claims 19-24) indicate that Crystalline Form I is of N-methyl-N-((1S,3S)-3-methyl-3-((6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide maleate salt.
The instant Specification (Example 4) and the original claims of 11/08/2024 (claims 25-30) indicate that Crystalline Form II is of N-methyl-N-((1S,3S)-3-methyl-3-((6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide tartrate salt.
The instant Specification (Example 5) and the original claims of 11/08/2024 (claims 31-36) indicate that Crystalline Form III is of N-methyl-N-((1S,3S)-3-methyl-3-((6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide tartrate salt.
The instant Specification (Example 6) and the original claims of 11/08/2024 (claims 37-42) indicate that Crystalline Form IV is of N-methyl-N-((1S,3S)-3-methyl-3-((6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide citrate salt.
The instant Specification (Example 7) and the original claims of 11/08/2024 (claims 43-48) indicate that Crystalline Form V is of N-methyl-N-((1S,3S)-3-methyl-3-((6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide proline salt.
As such, the instant Specification contains no information regarding Forms I, II, III, IV or V being crystalline forms of N-methyl-N-((1S,3S)-3-methyl-3-((6-(1-methyl-1H- pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide, as now claimed. This is new matter.
Removal of new matter is required.
Claims 50-51 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 a method of inhibiting BTK, or treating MS with N- methyl-N-((1S, 3S)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyrazin-4- yl)oxy)cyclobutyl)acrylamide or a salt or crystalline form thereof, does not reasonably provide enablement for the treatment of the claimed scope of disorder responsive to inhibition of BTK, or for the treatment of auto-immune disorders, with a crystalline form of N- methyl-N-((1S, 3S)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyrazin-4- yl)oxy)cyclobutyl)acrylamide. 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/or use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir.1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breath of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
Claim 50-51 are drawn to a method of treating a disorder responsive to inhibition of BTK, or to a method of treating an auto-immune disorder, with a crystalline form of N- methyl-N-((1S, 3S)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyrazin-4- yl)oxy)cyclobutyl)acrylamide. Thus, claims 50-51, taken together with the specification, imply that a crystalline form of N- methyl-N-((1S, 3S)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyrazin-4- yl)oxy)cyclobutyl)acrylamide can treat any disorder responsive to inhibition of BTK, or any auto-immune disorder in a patient.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The compound of the instant claims, N- methyl-N-((1S, 3S)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyrazin-4- yl)oxy)cyclobutyl)acrylamide, is an covalent irreversible acrylamide-based inhibitor of BTK.
Zhang et al. (Molecules 2021, 26(16), 4907, cited in PTO-892) summarizes advances in BTK inhibitors for the Treatment of Inflammatory and Autoimmune Diseases.
Zhang teaches (Figure 4) BTK inhibitors and some covalent irreversible inhibitors, including acrylamide-based inhibitors 1, 4, 5, 6, with fused bicyclic heterocycle scaffolds and their progress in the treatment of autoimmune and inflammatory diseases. CIA, collagen-induced arthritis; CAIA , collagen antibody-induced arthritis; ITP, immune thrombocytopenia; RD, IgG4-related disease; RA, rheumatoid arthritis; SS, Sjogren’s syndrome.
Zhang teaches that covalent irreversible inhibitors are one of the two most established small-molecule BTK inhibitors. Covalent inhibitors feature an α,β unsaturated amide as an electrophilic warhead which generally targets Cys481 in the ATP-binding pocket of BTK to form a covalent bond via a Michael addition reaction. Irreversible inhibitors have the advantage of longer-lasting inhibitory activity, but their binding mode is restricted by the need to react with Cys481 residue.
Zhang teaches (Figure 6) a number of acrylamide-based covalent irreversible BTK inhibitors effective to treat EAE, or MS, or SLE.
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Importantly, Zhang teaches (see, for example, discussion on pages 8, 9) that each BTK inhibitor has to be individually evaluated for its selectivity over other kinases, for its PK properties, and for efficacy in relevant animal models of disease, specific for each disease responsive to inhibition of BTK, or for each autoimmune disorder to be treated. For example, ibrutinib, which is the first-in-class covalent irreversible BTK inhibitor (Table 1, Figure 4), is effective to treat mantle cell lymphoma (MCL), CLL, Waldenstrom’s macroglobulinemia (WM) and chronic graft-versus-host disease (cGVHD), and effective in animal models of RA. Zhang teaches that Ibrutinib is highly potent against BTK, with an IC50 of 0.5 nM; however, 0.3- to 4-fold unsatisfactory selectivity ratios over BLK, BMX, TXK and HCK kinases were observed. Ibrutinib also demonstrated moderate to high potency towards hERG, JAK3, EGFR, ERBB4, and TEC. Therefore, side effects have emerged due to the off-target effects of ibrutinib.
Thus, Zhang teaches the need to evaluate each covalent irreversible BTK inhibitor for its selectivity, toxicity (which may be due to off-target effects) and efficacy in relevant animal models, in order to establish efficacy in each BTK mediated disorder or each autoimmune disease.
Zhang teaches (page 16 of 35, point 3.2) that the irreversible acrylamide-based kinase inhibitors have been shown to form permanent covalent adducts with cysteine-containing kinase and non kinase off-target proteins. These irreversible adducts have always been a concern in drug discovery owing to the relationship between covalent drug binding and the potential for idiosyncratic adverse drug reactions.
In view of the teachings of Zhang, and the varying mechanisms of the different autoimmune diseases, a skilled artisan would view that it is unlikely that the claimed method would be useful for treating the full scope of autoimmune diseases encompassed by the instant claim limitations. Furthermore, as the etiology of the different autoimmune diseases is typically multi-factorial, differing from one condition to another, or can be inherited, it is unlikely that a skilled artisan would view that a compound of the instant application could be used to treat the full scope of autoimmune diseases as claimed.
(5) The relative skill of those in the art:
The level of skill in the art is that of the authors of the references cited to support the examiner’s position (MDs, PhDs, or those with advanced degrees and the requisite experience in treatment of autoimmune diseases/inflammation).
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
A disclosure should contain representative examples which provide reasonable assurance to one skilled in the art that the compound is effective in treating the full scope of diseases as claimed.
The specification has provided guidance for preparing crystalline forms of N- methyl-N-((1S,3S)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyrazin-4- yl)oxy)cyclobutyl)acrylamide. The compound is known (Hopkins et al. WO 2022/104079) as a potent BTK inhibitor in vitro (Table 1, compound 79, [00994], IC50 less than 1nM), and known to have IC50 less than 1 mM (Table 2, [00998]) in a whole blood CD69 in vitro T cell activation assay.
However, the Specification has provided no data related to in vivo efficacy in treating any disorder responsive to BTK inhibition, or any autoimmune disorder with this compound, or a salt thereof, or a crystalline form thereof.
The specification does not provide guidance for treatment of broadly claimed disorders responsive to BTK inhibition or auto-immune disorders, with N- methyl-N-((1S,3S)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo [1,5-a]pyrazin-4- yl)oxy)cyclobutyl)acrylamide in a patient in need thereof.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regards to claims 50, 51, and the high unpredictability in the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate in scope with instant claims 50-51.
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 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)(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.
Claims 1-3, 49-52 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Hopkins et al. (WO 2022/104079, published 19 May 2022, cited in IDS).
Hopkins (WO 2022/104079) teaches (Example 79, [00398]-[00401]
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N-methyl-N-((1S,3S)-3-methyl-3-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)oxy)cyclobutyl)acrylamide, which is the very compound of the instant claims, as a crystalline solid, melting point 137.5 °C [00401], which is within the 138.4 0C
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20C range in instant claim 3.
With respect to the XRD peaks in instant claim 2, since Hopkins teaches the very compound as in the instant claims as a crystalline solid, having the same melting point as crystalline Form A of instant claim 3, the examiner's position is that the properties of the compound are inherent to the compound. Therefore, if the prior art teaches the compound, then the properties are also taught or rendered obvious by the prior art. In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990.) See MPEP 2112.01. The burden is shifted to Applicant to show that the prior art product does not possess or render obvious the same properties as the instantly claimed product.
Hopkins teaches pharmaceutical compositions comprising the compounds of the invention and a pharmaceutical excipient, as in instant claim 49.
Hopkins teaches that the compounds of the invention are effective to treat multiple sclerosis [0131], which is an autoimmune disorder responsive to inhibition of BTK, as in instant claims 50-52.
Thus, instant claims 1-3, 49-52 are anticipated by Hopkins.
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, 49-52 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable at least over claims 1, 72-73, 80, 81 of co-pending US patent application 18/036,853 (cited in PTO-892).
Claims 1, 72-73, 80 of co-pending US patent application 18/036,853 are drawn to a genus encompassing the compound of the instant claims, or a pharmaceutical salt thereof, or composition thereof.
The compound of the instant claims is a compound of formula (XV)
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of claims 72, 73 of co-pending US patent application 18/036,853, for which the following definitions apply: R0 is H; X3 is O; R2 is cyclobutylene, substituted with R10 which is methyl and R4 which is N(Me)C(O)CH=CH2.
Claim 81 of co-pending US patent application 18/036,853 is drawn to a method of treating an autoimmune disorder responsive to inhibition of BTK, as in instant claims 50-51.
The Specification of co-pending US patent application 18/036,853 teaches compounds of the invention (Example 79) in crystalline form.
The Specification of co-pending US patent application 18/036,853 teaches [0131] that compounds of the invention effective to treat multiple sclerosis as an autoimmune disorder responsive to inhibition of BTK, as in instant claim 52.
As such, claims 1, 72-73, 80, 81 of co-pending US patent application 18/036,853 render obvious instant claims.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1-3, 11-12, 20-21, 26-27, 32-33, 38-39, 44-45, 49-52 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IRINA NEAGU whose telephone number is (571)270-5908. The examiner can normally be reached Mon-Fri 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY S. LUNDGREN can be reached at (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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/IRINA NEAGU/Primary Examiner, Art Unit 1629
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