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 without traverse of Group I in the reply filed on 08/17/2026 is acknowledged. Applicant’s election of Example 6 as a species of formula (I) is acknowledged. A search for the elected species provided to relevant prior art. The search was extended to include compounds of formula (I) where ring A is phenyl. This search did not provide any relevant prior art. The search was extended to the full scope of compounds of formula (I). The previous restriction requirement is withdrawn.
Current Status of 18/709,273
This Office Action is responsive to the amended claims of 11/24/2024 and the Applicant response of 08/17/2026. Claims 1, 4-6, 12, 16, 19, 21, 26-27, 29, 33, 35-36, 38, 41, 43 and 45-48 are pending. Claims 1, 4-6, 12, 16, 19, 21, 26-27, 29, 33, 35-36, 38, 41, 43 and 45-48 have been examined on the merits.
Priority
The instant application is a national stage entry of PCT/US2022/049618, filed 11/10/2022, which claims priority to U.S. Provisional Patent Application No. 63/277,879, filed 11/10/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/30/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 6, 16, 21, and 29 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.
Regarding claims 16 and 21, the phrase "preferably" renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 6, the claim depends from any one of claims 1-5. Claims 2-3 have been cancelled. To the extent claim 6 depends from canceled claims 2 or 3, the claim is incomplete, and the scope of the subject matter encompassed by those dependency paths cannot be determined with reasonable certainty. Therefore, the metes and bounds of claim 6 are indefinite.
Similarly, claim 29 depends from claim 28. Claim 28 has been canceled. Claim 29 is incomplete, and the scope of the subject matter encompassed by claim 29 cannot be determined with reasonable certainty. The metes and bounds of claim 29 are therefore indefinite.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 6 recites that X3 is selected from: (i) phenyl. However, phenyl is not an allowed substitution of X3 according to claim 1. Claim 1 limits the cyclic moieties of X3 to 5- to 6-membered heteroaryl or 4- to 7-membered monocyclic heterocyclyl. The phenyl group of claim 6 does not fall within the allowed alternatives of X3 recited in claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 47 and 48 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 the in vitro inhibition of BTK using certain compounds of formula (I), does not reasonably provide enablement for the full scope of treating all autoimmune diseases responsive to BTK inhibition using the full scope of compounds encompassed by formula (I). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to 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 breadth 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:
The claims are drawn to a method of treating a disorder responsive to inhibition of BTK comprising administering an effective amount of a compound of claim 1 to a subject. Claim 48 further specifies the disorders to be treated are selected from autoimmune disorder, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), atopic dermatitis, leukemia, and lymphoma. Thus, the claims taken together with the specification imply that the administration of an effective amount of any compound of claim 1 is capable of treating any disorder responsive to inhibition of BTK.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The state of the prior art is that in vitro BTK kinase inhibition alone is insufficient to reasonably predict therapeutic efficacy across the full scope of diseases associated with or mediated by BTK signaling. Ringheim et al. teach that the therapeutic efficacy of BTK inhibitors in autoimmune disease was dependent upon the particular disease indication and remained unpredictable (pg. 10, Clinical Study paradigms and Covalent BTK Inhibition). The reference further teaches that available clinical data is insufficient to thoroughly assess correlations between efficacy and inhibitor potency, selectivity, treatment paradigm, and exposure variables (pg. 10, Clinical Study paradigms and Covalent BTK Inhibition). Ringheim et al. additional disclose that it is unclear what threshold of BTK inhibition is required for clinical efficacy in treating autoimmune disease and that the current data has not established the relationship between percentage BTK inhibition attained, the minimum effective dose, and an effective dosing schedule (pg. 11, Clinical Study paradigms and Covalent BTK Inhibition, second para.). Consistent with this uncertainty, the section BTK Clinical Efficacy in Rheumatoid Arthritis reports that nine of thirteen clinical BTK inhibitors were tested in RA, but only one was reported to have positive clinical data. This is despite the fact that nearly all of the inhibitors were previously shown to have positive results in the treatment of RA in animal models. Similarly, in SLE and SJ Clinical Failures of BTK Inhibitors, Ringheim et al. report that BTK inhibition failed to produce therapeutic benefit in SLE despite favorable animal model results. For example, fenebrutinib treatment of SLE over 48 weeks produced the expected reduction in B cells, plasmablasts, IgG levels, and autoantibodies, but these pharmacodynamic changes did not translate into meaningful improvement of clinical measures. The reference highlights the high degree of unpredictability associated with treating disorders using BTK inhibitors. Even favorable animal disease models and expected downstream biological effects were not reliably predictive of clinical therapeutic efficacy. Accordingly, the artisan could not reasonably extrapolate the instant inhibition assays to the treatment of any and all disorders susceptible to BTK inhibition as claimed.
(5) The relative skill of those in the art:
The artisan would have experience in the field of organic chemistry, medicinal chemistry, pharmaceutical sciences or a related field. The artisan would have experience in the design, synthesis, and evaluation of kinase inhibitors for the treatment of disease including BTK inhibitors. The artisan would be familiar with BTK signaling and the development and evaluation of BTK inhibitors.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification has provided guidance for synthetic routes to produce compounds of formula (I) and characterization data of exemplary compounds (pg. 35 line 19 through pg. 240 line 12). The specification also provides in vitro BTK kinase assay data reporting IC50 values for certain exemplary compounds selected from 1-173 (pg. 204, line 13 through pg. 246, line 2, Table 1). The specification also provide in vitro whole blood CD69 assay data for selected exemplary compounds (pg. 246, line 3 through pg. 251, Table 2).
However, the specification does not provide any disease models, treatment or dosing regimens, or other experimental guidance demonstrating the treatment of diseases associated with BTK inhibition.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly with regards to the unpredictability associated with extrapolating in vitro inhibitory activity to therapeutically effective methods of treatment 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 the scope of the claims.
Close Art
The closest prior art of record is WO 2015/089327 (found in IDS filed 12/30/2024). ‘327 discloses BTK inhibitors of formula I
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([0004]) which are structurally distinct from the instantly claimed compounds. The compounds of ‘327 require a nitrogen atom at the indicated position (shown above), corresponding to Ring B of the instant compounds. The instant compounds require carbon at the indicated position. The ‘327 reference further defines positions A1-A4 as being selected from combinations of carbon, nitrogen, sulfur and oxygen. The instant compounds require that A3 is N and further specify that A1, A2, and A4 may only be selected from N or CH. The specific atom arrangements around the bicyclic core of the ‘327 reference’s formula I do not teach the disclosed compound required by the instant claims. The ‘327 reference, alone or in combination with the other prior art of record, does not provide a teaching or suggestion that would have led the artisan to modify the disclosed compounds in the manner required to arrive at the instantly claimed compounds. The compounds of formula (I) are therefore novel and nonobvious over the prior art.
Conclusion
Claims 1, 4-5, 12, 19, 26-27, 33, 35-36, 38, 41, 43 and 45-46 are allowed.
Claims 6, 16, 21, 29, and 47-48 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CONNOR KENNEDY ENGLISH whose telephone number is (571)270-0813. The examiner can normally be reached Monday Friday, 8 a.m. 5 p.m. ET..
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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
