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 .
Current Status of 18/573,074
This Office Action is responsive to the amended claims and Applicant remarks of 06/18/2026. Claims 1, 4, 6-7, 9-15, 19-22, 24, 26 and 29-30 are pending and have been examined on the merits.
Priority
The instant application is national entry of PCT/CN2022/100435, filed 06/22/2022, which claims priority to Chinese patent applications CN202110694497.1, filed 06/22/2021, CN202210002094.0, filed 01/04/2022, and CN202210665753.9, filed 06/13/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/07/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Response to Arguments
Rejections Under 35 U.S.C. §112(a):
Applicants allege that the amendment of claim 1, limiting ring A to either pyrazine or pyrimidine provides a reasonable generalization of compounds 1-35 for the method of treatment of claim 30. Applicants reason that TYK2 is implicated in the pathogenesis of specific diseases and that various Tyk2 JH2 drugs have entered clinical trials and therefore would be understood as capable therapeutic agents for the treatment of Tyk2 JH2-related diseases.
These arguments have been considered but are not persuasive. The amendment to claim 1 narrowing ring A reduces the structural breath of the compounds encompassed by claim 30 and has been considered in evaluating enablement. However, claim 30 remains directed to the treatment of any disease related to Tyk2 JH2 using any compound encompassed by claim 1. This is not merely whether the exemplified compounds may reasonably support additional structurally related Tyk2 JH2 inhibitors, but whether the disclosure enables the use of the full scope of the claimed genus for the full scope of diseases encompassed by claim 30 without undue experimentation.
The specification provides Tyk2 JH2 enzymatic inhibitory activity for exemplary compounds 1-35 and a cellular inhibition of IFNa-stimulated phosphorylated STAT1 for a substantially smaller subset of compounds (Table 2, pg. 96). The biological assays of the disclosure provide evidence that certain disclosed compounds are capable of inhibiting Tyk2 JH2 and Tyk2-dependent signaling and identifies certain diseases which Tyk2 signaling was known to be implicated. However, establishing Tyk2 JH2 inhibitory activity does not establish that every compound encompassed by claim 1 can be administered at an effective does to therapeutically treat every disease encompassed by the phrase “a disease related to Tyk2 JH2.” The disclosure provides insufficient guidance for the artisan to determine which compounds encompassed by claim 1 would be capable of affording the desired therapeutic activity. The artisan would be required to screen the claimed compounds across the encompassed disease indications to determine whether the requisite therapeutic activity is achieved, which would amount to undue experimentation.
Rejections under 35 U.S.C. §103:
Applicants allege that reference Liu fails to teach or suggest compounds containing a sulfoximine group, and further contend that reference Han fails to cure this deficiency because Han fails to provide a synthetic route, SAR data, or direct guidance for incorporating the sulfoximine into the scaffold of Liu’s compound 111. Applicants support this position by emphasizing the historical limitations of the sulfoximine group in medicinal chemistry. Applicants further argue that Han teaches that the substitution would require the replacement of the sulfone with a sulfoximine through the same point of attachment at the sulfur atom and therefore do not suggest the N-linked sulfoximine connectivity required by the instant claims.
Applicants’ arguments have been fully considered but are not persuasive. Although Han does not provide a synthetic scheme specifically directed to the modification of Liu’s compound 111, Han expressly identifies sulfoximines as bioisosteres and aza analogues of sulfones, describes multiple methods for their preparation, and provides examples of sulfone-containing biologically active compounds that were converted to the corresponding sulfoximine analogues while retaining biological activity (Table 2). Han therefore provides a reason to investigate the sulfoximine replacement of sulphones and evidence supporting a reasonable expectation that biological activity could be retained.
Applicants’ reliance on Han’s discussion of the historical limitations of sulfoximines is similarly unpersuasive. Han acknowledges limitations in commercial availability, synthetic accessibility, and medicinal chemistry experience, but explains that newer synthetic methods had become available, interest in sulfoximines was increasing, and multiple sulfoximine-containing compounds had entered clinical development. Han concludes that sulfoximines possess no intrinsic flaw and supports their inclusion in the medicinal chemist’s toolbox (pg. 13, left col., second para.).
Finally, Han is not limited to sulfoximines attached to the parent scaffolds through the sulfur atoms as alleged by Applicants. Han expressly teaches that the sulfoximine nitrogen provides an additional site for substitution, and Table 10 exemplifies biologically active kinase inhibitors containing N-linked sulfoximine groups. Thus, when Liu and Han are considered together, the references provide both motivation to replace the sulfone of Liu with a sulfoximine and a teaching that N-linked sulfoximines were known, viable motifs.
Claim Rejections - 35 USC § 112
Claim 30 is 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 treating psoriasis comprising administering to a subject an effective amount of a compound selected from compounds 1-35, does not reasonably provide enablement for a method of treating any disease related to Tyk2 JH2 using any compound encompassed by formula (II). 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 any disease related to Tyk2 JH2 through administering a compound of claim 1 to a subject in need thereof. Thus, the claims taken together with the specification imply that the method can treat any disease related to Tyk2 JH2 using any compound of the Markush group of claim 1. Thus, the claim is extremely broad.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
Wrobleski teaches that the discovery of the Tyk2 JH2 inhibitor BMS-986165 was a formidable challenge achieved only through late stage optimization using structure guided design and water displacement strategy (Abstract). This compound was shown to have unprecedented selectivity for Tyk2 JH2, underpinning the unpredictability in the art to design compounds that are selective for Tyk2 JH2 (Abstract).
The prior art further demonstrates the unpredictability associated with extrapolating Tyk2 JH2 inhibitory activity to treatment of the full scope of the diseases encompassed by claim 30. The specification identifies psoriasis as an indication which a selective Tyk2 JH2 inhibitor had advanced to Phase III clinical trials with demonstrated clinical efficacy and safety (see [0006]). However, the other identified disease indications of [0005] identifies these treatments at substantially earlier clinical evaluations or merely as diseases with known Tyk2-associated signaling implications. This disparity indicates that, at the time of filing, the therapeutic efficacy of Tyk2 JH2 inhibition had not been established with comparable predictability across the claimed disease scope. Accordingly, the artisan could not extrapolate the demonstrated in-vivo Tyk2 JH2 inhibitory activity of the disclosed compounds and conclude that those compounds would successfully treat every disease encompassed by the phrase “a disease related to Tyk2 JH2.”
(5) The relative skill of those in the art:
The artisan would have experience in organic chemistry, medicinal chemistry, pharmaceutical sciences, or a related field. The artisan would have experience in the design, synthesis, and evaluation of small-molecule kinase inhibitors. The artisan would be familiar with biochemical kinase assays, cellular signaling assays, and pharmacokinetic evaluation of small-molecule drug candidates. The technical expertise of the artisan would not overcome the unpredictability in the art regarding the development of Tyk2 JH2 inhibitors and their therapeutic effects. Based on the limited biochemical and cellular assay data provided in the instant application, the artisan would be unable to determine which compounds encompassed by the broad Markush genus of claim 1 would be capable of treating diseases as claimed without empirical testing.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification has provided guidance for Tyk2 JH2 inhibition for compounds 1-35 (Assay Example 1, [00551-00554]); in vitro cellular activity in hPBMC for compound 1-4, 8, and 9 (Assay Example 2, [00555-00558]); and a pharmacokinetic profile in Balb/c mice for compound 1 (Assay Example 3, [00559-00565]).
However, the specification does not provide any examples demonstrating treatment of any disease related to Tyk2 JH2 using any compound encompassed by the Markush group of claim 1. The experimental data discussed above demonstrates biochemical Tyk2 JH2 inhibition and cellular pathway inhibition, but do not demonstrate therapeutic treatment of disease.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references above, particularly the unpredictability in designing Tyk2 JH2 selective inhibitors, the lack of a predictable basis in the art for extrapolating the disclosed in vitro Tyk2 JH2 inhibitory activity to in vivo therapeutic efficacy across the full scope of the claimed disease, 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.
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.
Claims 1, 4, 6, 7, 9-15, 19-22, 24, 26, 29, and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (WO 2021/222153 A1, found in IDS filed 04/01/2024) in view of Han (Han, Yu, et al. "Application of sulfoximines in medicinal chemistry from 2013 to 2020." European Journal of Medicinal Chemistry 209 (2021): 112885.).
Liu teaches compounds of formula I
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that are useful in modulation of IL-2, IL23 and/or IFNa by inhibiting Tyk2 (Abstract, pg. 6, lines 2-4). The reference teaches that Y is N or CH (pg. 7, line 7). Liu discloses example compound 111
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(pg. 105) which reads on the instantly claimed compounds of formula (II) with the following substitutions: X1 is CH; N2 is N; R3 is H, n is 3; R4 is -C(=O)R41, R41 is a C3 cycloalkyl (cyclopropyl); R5 is H; R6 is -NH-C1 alkyl optionally substituted with 3 Rd, each Rd is deuterium; and ring A is
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. Liu teaches that R3 is a 5-14 membered mono or bicycle heterocycle containing 1-4 heteroatoms selected from N, O, and S (pg. 7, lines 14-15), and discloses compound 17
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(pg. 49) which has an alternative structure of R3 in comparison to compound 111. The reference also teaches a method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of the claimed compounds (Claim 10). These diseases are specified as being inflammatory or autoimmune disease is multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn’s Disease, Sjogren’s syndrome or scleroderma (Claim 11) and identifies these diseases as being associated with disfunction of Tyk2 (pg. 4, line 29 – pg. 6, line 29). Lui does not teach the sulfoximine functionality attached to ring A.
Han teaches that sulfoximines are isosteres of sulfones which have advantageous physiochemical and medicinal chemistry properties (pg. 2, left Col, first para; pg. 3, bottom paragraphs). The reference further teaches that the sulfoximine nitrogen provides an additional site for substitution where functional groups may be introduced. Table 10 (pg. 7, left Col) exemplifies biologically active N-linked sulfoximines, including compounds bearing N-linked dimethylsulfoximine functionalities and cyclic sulfoximine functionalities, and demonstrates that these N-linked structures were known for use as kinase inhibitors. These teachings establish that sulfoximines were recognized in the art as bioisosteric replacements for sulfones and that attachment through the sulfoximine nitrogen was a known, viable mode of incorporating sulfoximine moieties into medicinal compounds.
The artisan would have experience in organic chemistry, medicinal chemistry, pharmaceutical sciences, or a related field. The artisan would have experience in the design, synthesis, and evaluation of small-molecule kinase inhibitors. The artisan would be familiar with biochemical kinase assays, cellular signaling assays, and pharmacokinetic evaluation of small-molecule drug candidates. The artisan would be familiar with isosteric replacement strategies.
The artisan, seeking to further optimize the compounds of Liu, would have been motivated to investigate replacement of the sulfone group with a sulfoximine as part of routine medicinal chemistry optimization. Han expressly identifies sulfoximines as know isosteres of sulfones and describes their use as replacements for sulfones to explore changes in biological and physiochemical properties. The artisan would have recognized preparation and evaluation of the corresponding sulfoximine analogues of Liu as a known, reasonable avenue of lead optimization rather than an arbitrary structural modification.
Han further teaches that the sulfoximine nitrogen provides an additional site for substitution and would have been recognized by the artisan as a known structural option available when preparing the sulfoximine analogues.
In view of Han’s teaching that sulfoximines were established medicinal chemistry replacements for sulfones, together with the known synthetic methods for their preparation, the artisan would have reasonably expected that the corresponding sulfoximine analogues could be prepared and subjected to routine biological screening to determine their activity and medicinal chemistry properties.
Regarding the compounds of instant claim 29, these compounds are obvious derivatives of the known Tyk2 inhibitor compounds disclosed in Liu. Consider the following compound of instant claim 29
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. This compound is identical to Liu’s 111 with the exception of ring A being a pyrazine as opposed to a pyrimidine in 111. However, Liu expressly teaches pyrazine as a suitable R3 group and provides examples incorporating this ring system (see compound 17 above). Liu further indicates that these ring systems are interchangeable embodiments of the invention. The artisan would have been motivated to substitute they pyrimidine ring of compound 111 with a pyrazine ring because both are taught as being suitable embodiments of the same scaffold. The artisan would have reasonably expected that either ring structure would provide a compound retaining the desired Tyk2 inhibitory activity.
Conclusion
Claims 1, 4, 6, 7, 9-15, 19-22, 24, 26, 29, and 30 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/C.K.E./Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625
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