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
This office action is in reply to the Applicant’s Remarks/Arguments field 15 April 2026 for application 18/263,434 filed 28 July 2023. Claims 1, 31-33, 39, 43, 47 and 49 are amended. Claims 17-30, 34-37, 40-42, 44-46, 48, 50, 53-55, 57-59, and 61 are canceled. Claims 1-16, 31-33, 38-39, 43, 47, 49, 51-52, 56, 60, and 62 are pending.
REJECTIONS WITHDRAWN
The status for each rejection and/or objection the previous office action is set out below.
35 U.S.C. 102, 103 and Double Patenting
Applicant’s amendments to claim 1 were sufficient to overcome the prior 103 rejection. However, the amendments, as a condensation of limitations from other claims, required reworking the interpretation from the given prior art, rather than the introduction of new prior art, resulting in the sections below.
REJECTIONS – MAINTAINED & NEW
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(New) Claims 1-16, 31-33, 39, 43, 47, 49, and 62 are rejected under 35 U.S.C. 103 as being unpatentable over Mao et al. ((1,2,4)triazolo(1,5-a)pyridine compound as JAK inhibitor and application thereof, AU2019326647B2, 2020) in view of Rowe et al. (Handbook of pharmaceutical excipients, 6th edition, Pharmaceutical Press, 2009), Beelen et al. (G1T38 superior dosage regimes, US 2020/0405721 A1, 2020), Roslan et al. (Comparison of various fillers on the physical properties of compounded tablets, J. Pharma. Neg. Results 2022, 13, 7), PharmaState Academy (Excipients used in tablets, pharmastate.academy/excipients-used-in-tablets/, 2017), PharmaExcipients (Lubricants - pharmaceutical excipients, pharmaexcipients.com/lubricants/, 2023) and European Medicines Agency (Sodium laurilsulfate used as an excipient, EMA/CHMP/606830/2017, 2017).
Mao discloses a [1,2,4]triazolo(1,5-a)pyridine Markush structure with several exemplifications and described as a JAK inhibitor with the implication of treating JAK1 or TYK2 related diseases utilizing a compound represented by the illustrated Markush formula I or a pharmaceutically acceptable salt of that compound.
This is further expanded upon where Mao specifies that the substitution pattern includes: E1 and E2 are independently selected from single bond, -CH2 or -(CH2)2-; L1 is selected from single bond, -(CH2)g-, -C(=O)- or -C(=O)-(CH2)h-; m is 1 or 2; n is 1 or 2; g is 1, 2 or 3; h is 1, 2 or 3; RI is selected from H, CN, Cl-6 alkyl group or 3~6-membered cycloalkyl group, wherein the above Cl- 6 alkyl group and 3~6-membered cycloalkyl group are optionally substituted by 1, 2 or 3 Ra; R2 is selected from H, F, CI, Br, / or CI-3 alkyl groups, wherein the above CI-3 alkyl group is optionally substituted by 1, 2 or 3 Rb; R3, R4 and R5 are independently selected from H, F, Cl, Br, / or CI-3 alkyl group, wherein the above CI-3 alkyl group is optionally substituted by 1, 2 or 3 Rc; R6, R7 and R8 are independently selected from H, F, CI, Br, / or CI-3 alkyl group, wherein the above CI-3 alkyl group is optionally substituted by 1, 2 or 3 Rd; Each Ra is independently selected from H, F, CI, Br, I, CN or CI-3 alkyl group, wherein the above CI-3 alkyl group is optionally substituted by 1, 2 or 3 R; Each Rb is independently selected from F, CI, Br or I; Each Rc is independently selected from F, Cl, Br or I; Each Rd is independently selected from F, Cl, Br or I; Each R is independently selected from F, CI, Br or I; the isomers are selected from geometrical isomers, stereoisomers or tautomers, in comparison to claim 1.
Mao further specifies that in some embodiments of the present application, each of the above Ra is independently selected from H, F, Cl, Br, I or CN, and other variables are as defined in the present application, in comparison to claim 2.
Mao further specifies that in some embodiments of the present application, the above Ri is selected from H, CN, C1.3 alkyl group or 3~5-membered cycloalkyl group, in which the C1.3 and 3~5-membered cycloalkyl group are optionally substituted by one, two or three Ra, and other variables are as defined in the present application, in comparison to claim 3.
Mao further specifies that in some embodiments of the present application, the above Ri is selected from H, CN, CH3, or in which CH3, and are optionally substituted by one, two or three Ra, and other variables are as defined in the present application, in comparison to claim 4.
Mao further specifies that in some embodiments of the present application, the above Ri is selected from H, CN, CF3, CHF2, cyano-dimethyl, fluoro-cyclopropyl, fluoro-cyclobutyl, 6,4-azospiro, in comparison to claim 5.
Mao further specifies that in some embodiments of the present application, the above R2 is selected from H, F, Cl, Br or I, and other variables are as defined in the present application, in comparison to claim 6.
Mao further specifies that in some embodiments of the present application, the above R3, R4 and Rs are independently selected from H, F, CI, Br or I, and other variables are as defined in the present application, in comparison to claim 7.
Mao further specifies that in some embodiments of the present application, the above Re, R7 and Rs are independently selected from H, F, CI, Br or I, and other variables are as defined in the present application, in comparison to claim 8.
Mao further specifies that in some embodiments of the present application, the above Li is selected from single bond, -CH2-, -(012)2-, -C(=O)- or -C(=O)-(CH2)-, and other variables are as defined in the present application, in comparison to claim 9.
Mao further specifies that in some embodiments of the present application, the 6,4-azospiro structural unit is selected from several structures as show in the prior office action, in comparison to claim 10.
Mao further specifies that in some embodiments of the present application, the 6,4-azospiro structural unit is selected from several structures as shown in the prior office action, in comparison to claim 11.
Mao further specifies that in some embodiments of the present application, the 6,4-azospiro structural unit is selected from several structures as shown in the prior office action, in comparison to claim 12.
Mao further specifies that in some embodiments of the present application, the above compound of formula (I), isomers thereof, or pharmaceutically acceptable salt thereof, are selected from several structures as shown in the prior office action, in comparison to claim 13.
Mao further specifies that in some embodiments of the present application, the above compounds of formula (I), isomers thereof, or pharmaceutically acceptable salts thereof, are selected from I-1A, shown in the prior office action, in comparison to claim 14.
Mao also provides the following compounds as examples, as shown in the prior office action, in comparison to claim 15.
Mao also provides the following compounds as examples, as shown in the prior office action, in comparison to claims 16 and 31.
Mao also discloses exploration of in vivo efficacy study in collagen-induced arthritis in mice as an exploration into rheumatoid arthritis. Rheumatoid arthritis is described a type of multiple autoimmune diseases with a global incidence rate of 1%, leading to inflammation, damage, and malformation of arthrosis, and systemic inflammation reactions. In the collagen- induced mice arthritis model, type II collagen was used to induce arthritis in DBA/1 mice via tail injections. The regimen was conducted over 28 days, dexamethasone was used as a reference drug, with dosing done at 0.3 mg/kg and 15 mg/kg, with experimental cohorts dosed BID for 14 days. The mice were evaluated via clinical scores with certain experimental compounds at 15 mg/kg demonstratively reducing collagen-induced arthritis in a statistically significant number of the experimental population, in comparison to claim 62.
Mao does not, however, teach an oral preparation comprising the JAK inhibitors of a compound of formula I and a pharmaceutical excipient wherein the pharmaceutical excipients comprise a filler, a disintegrant, an adhesive, a lubricant or a surfactant, or a combination of two or more thereof; and the content of the JAK inhibitor is 1% to 50% of the total weight of the oral preparation; the content of the fillers is 0% to 78.5% of the total weight of the oral preparation; wherein the filler is selected from a group consisting of microcrystalline cellulose, lactose, pre-gelatinized starch or anhydrous dicalcium phosphate, or a combination of two or more of them; the content of the disintegrants is 2%~16% of the total weight of the composition; wherein the disintegrant is selected from a group consisting of cross-linked carboxymethyl cellulose sodium, carboxymethyl starch sodium, cross-linked povidone or dry starch, or a combination of two or more of them: . the content of the adhesives is 0.1%~5% of the total weight of the composition; wherein the adhesive is selected from a group consisting of Hypromellose, hydroxypropyl cellulose, povidone, methyl cellulose, or ethyl cellulose, or a combination of two or more of them; the content of the lubricant is 0.1% to 5% of the total weight of the composition; wherein the lubricant is selected from a group consisting of magnesium stearate, micronized silica gel, talc powder, hydrogenated vegetable oil, polyethylene glycol or sodium dodecyl sulfate, or a combination of two or more of them; and the content of the surfactant is 0.1% to 5% of the total weight; wherein the surfactant is sodium dodecyl sulfate.
This deficiency is rectified by Rowe who extensively covers many topics within the field of drug formulation, including, but not limited to, typical properties of select excipients, incompatibilities, safety, related substances, along with numerous other examples in the categories of fillers, disintegrants, adhesives, lubricants, and surfactants, such as microcrystalline cellulose for fillers, carboxymethyl starch sodium for disintegrants, methyl cellulose for adhesives, magnesium stearate for lubricants, and sodium dodecyl sulfate for surfactants.
In regards to the limitations of claims 1 and 32, Beelen & Strum teaches that pharmaceutical compositions can be formulated for oral administration and can contain any amount of active compound that achieves the desired result, e.g. between 0.1% and 99% weight % of the compounds and usually at least about 5 wt. % though some embodiments contain at least about 10%, 15%, 25%, 25 wt. % to about 50 wt. % or from about 5 wt. % to about 75 wt. % of the active compound (para. 135). A prima facie case of obviousness necessarily exists when the prior art range overlaps or touches a claimed range, such as in the instant rejection. MPEP § 2144.05.
With concern to the limitations of claims 1 and 33, Roslan teaches that fillers are pharmaceutical ingredients that are not pharmaceutically active but essential in tablet preparation, consisting of heterogeneous groups of substances intended to generate the necessary amount when the drug dosage itself is sufficient to generate the required bulk and that the range of fillers in a pharmaceutical formulation may differ from 5% to 80%.
With respect to the limitations of claims 1, 39 and 43, PharmaState Academy teaches that the use of disintegrants, excipients that are incorporated into the formulation of tablets or capsules to promote their disintegration when they come into contact with liquid or fluid matter, including cross-linked carboxymethyl cellulose and polyplasonde (cross-linked povidone) being 10% to 20 wt. % and 2 wt.%, respectively. Cellulose is described as highly hydrophilic and water-soluble compounds with controllable cross-linking, capable of rapid swelling and wicking, whereas cross-linked povidone is described as swelling very little, water insoluble and spongy. Both ingredients are described as super disintegrants, designed to have greater effectiveness at low concentrations when compared to other traditional disintegrants. PharmaState Academy also teaches that binders and adhesives are materials added in wet or dry form to form granules or cohesive compacts for directly compressed tablets, with examples including cellulose derivatives such as methyl cellulose, hydroxy propyl cellulose, hydroxy propyl cellulose, gelatin, glucose, povidone (2%) or starch paste.
Regarding the limitations of claims 1 and 47, PharmaExcipients teaches that lubricant excipients are substances added to formulations to aid in the tableting process and to improve flow of powders during manufacturing, reducing friction and preventing the sticking of the tablet material. This is further expanded to include factors such as compatibility on the active ingredient, stability and bioavailability, effect on physical properties, and compatibility with equipment and the manufacturing process. Several commonly used lubricants were listed including the optimal concentration in solid dosage forms including sodium stearate (0.25% to 2%) and talc (1% to 5%).
Concerning the limitations of claims 1 and 49, European Medicines Agency teaches that sodium laurilsulfate (sodium dodecyl sulfate) is an alkaline, anionic surfactant with a number of uses including as an emulsifying agent, modified-release agent, penetration enhancer, solubilizing agent, lubricant, and as a surfactant. In medicinal products, sodium laurilsulfate , has several listed uses along with associated concentrations including tablet lubricant (0.5% to 2 wt. %) and dissolution/wetting agent in solid oral dosage forms (0.2% to 1.5 wt. %). It is generally regarded as a safe excipient and included in the FDA inactive ingredients data base.
As such, it would have been prima facie obvious, to a person of ordinary skill in the art, to explore well known and documented excipients to develop an oral preparation involving a pharmaceutical composition appropriate for a compound that inhibits JAK utilizing well established literature that is exemplified by the teachings of Rowe, Beelen, Roslan, PharmaState Academy, PharmaExcipients, and the European Medicines Agency.
(New) Claim 38 is rejected under 35 U.S.C. 103 as being unpatentable over Mao, Rowe, Beelen, Roslan, PharmaState Academy, PharmaExcipients and European Medicines Agency, as applied to claims 1-16, 31-33, 39, 43, 47, 49 and 62 above, and further in view of Meggle (Meggle technical brochure MicroceLac100, Meggle 2019).
Mao teaches triazolopyridines as JAK inhibitors while the other sources teach separate roles in different excipients for the purpose of an oral preparation.
They do not, however, teach the use of a filling agent that is a mixture of lactose and microcrystalline cellulose, with a weight ratio of 0:1, 5:3, 3:1, 1:1, 1:0 for lactose and microcrystalline cellulose.
Meggle overcomes this by teaching MicroceLac100, co-processed lactose and microcrystalline cellulose designed for direct compression, comprising 75% lactose and 25% microcrystalline cellulose, for the optimal synergistic functional performance, such as increased compactibility and powder flow, that creates a monoparticulate system with two compaction mechanisms, brittle fracture and plastic deformation, giving the desirable properties for direct compression while maintaining their individual chemical identities. A prima facie case of obviousness necessarily exists when the prior art range overlaps or touches a claimed range, such as in the instant rejection. MPEP § 2144.05.
As such, it would have been prima facie obvious, to a person of ordinary skill in the art, to consider the use of a combination of lactose and microcrystalline cellulose as fillers for an oral administration composition due to the advertised relevant and superior properties by Meggle.
(New) Claim 60 is rejected under 35 U.S.C. 103 as being unpatentable over Mao, Rowe, Beelen, Roslan, PharmaState Academy, PharmaExcipients and European Medicines Agency, as applied to claims 1-16, 31-33, 39, 43, 47, 49 and 62 above, and further in view of Shi et al. (Pharmaceutical application of multivariate modelling techniques: a review on the manufacturing of tablets, RSC Adv. 2021, 11, 8323).
Mao teaches triazolopyridines as JAK inhibitors while the other sources teach separate roles in different excipients for the purpose of an oral preparation.
They do not, however, teach a preparation method selected from wet granulation, dry granulation process, and powder direct pressing process, and where the filler, disintegrant, adhesive, lubricant, or surfactant is added internally or externally.
Shi rectifies this by teaching an overviewed and nuanced look into continuous tablet manufacturing, exploring the multiple unit operation including mixing of excipients and active pharmaceutical ingredients, granulation and tableting, and applying a mathematical model to improve product quality and enhancing product and process understanding. Shi applies multivariate modeling techniques in tablet manufacturing to more thoroughly understand the three pathways, direction compaction, dry granulation, and wet granulation, to actively monitor the different processes, and quantify the model prediction against empirical parameters such as tablet quality. They utilize several techniques including transmission near infrared spectroscopy and Raman spectroscopy to study the manufacturing processes. As such, it would be prima facie obvious, to a person of ordinary skill in the art, to incorporate these different aspects of tablet manufacturing, including the use of listed categories of excipients, and the various operations including the blending process, granulation, and tablet compaction, to be able to produce a formulated JAK inhibitor tablet, for the development of an oral composition appropriate for the delivery in oral administration.
Allowable Subject Matter
Claims 51-52 and 56 objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Reasons for Indication of Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: the crystal form of structure II as illustrated below, recited in claim 51, specified as forms A, B, C, D were not taught in the prior art in a 100% embodiment.
Claim 52, disclosing the XRPD characteristic peaks of crystal forms A, B, C, D of structure II were not taught in the prior art in a 100% embodiment.
Claim 56, disclosing the XRPD diagrams of crystal forms A, B, C, D, of structure II were not taught in the prior art in a 100% embodiment.
Response to Arguments
The office kindly thanks the Applicant for their consideration and arguments to the previous office action. Responses are detailed below.
Applicant’s arguments, see pg. 18 – Rejection Under 35 USC § 103, filed 15 April 2026, with respect to the rejection of claim 1 under 35 U.S.C. 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of a reworking and incorporation of references from claims 32-33, 39, 43, 47, and 49.
Applicant’s arguments filed 15 April 2026 have been fully considered but they are not persuasive.
On pgs. 18-19, – Rejection Under 35 USC § 103, filed 15 April 2026, the Applicant argues:
… the technical features in original claims 26, 32-33, 39, 43, 47, 49 are added to amended claim 1 and the amended claim 1 further defines the types of excipients… the amended claim 1 further defines that the content of JAK and various pharmaceutical excipients… which is not disclosed by references… present invention also offered large number of tests and proved that the oral preparation is more effective… technical solution in the amended claim 1 is not disclosed or taught by Mao et al. and Rowe et al. in combination with A. Beelen & J. C. Strum, Roslan et al. Meggle, Pharmastate academy, Pharmaexcipients, European Medicines Agency and/or Shi et al. … the amended claim 1 is not obvious, and a person skilled in the art cannot achieve the present invention without creative labor…
The Applicant’s argument that, since the limitations of the dependent claims are incorporated into claim 1 and render it non-obvious, has been considered but is regarded as unconvincing. The selection of excipients is still taught by the references. Furthermore, as stated previously, the ranges of use of excipients falls within the rejection of obviousness. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range."). See also In re Bergen, 120 F.2d 329, 332, 49 USPQ 749, 751-52 (CCPA 1941) (The court found that the overlapping endpoint of the prior art and claimed range was sufficient to support an obviousness rejection, particularly when there was no showing of criticality of the claimed range). "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003).
Applicant’s argument that a large number of tests and proved that the oral preparation is more effective is unclear to the Examiner. The instant specification appears to primarily compare two crystal forms of the same compound against each other, though only the data for the “standard” crystal form B is provided. Additionally, the initial formulation examples utilize a compound labeled TUL01101 whose identity isn’t made clear in the specification. This renders a comparison of effectiveness difficult.
Furthermore, the specification itself states that “the oral preparation of the present application can be prepared using commonly used preparation methods in the field” (pg. 17, para. 00109). As stated in MPEP § 2145(III), combining the teachings of references does not involve an ability to combine their specific structures. Furthermore, a person of ordinary skill is also a person of ordinary creativity, not an automaton, and in many cases will be able to fit teachings of multiple patents together like pieces of a puzzle (See MPEP § 2141.03). That is, a person of ordinary skill in the art would be able to combine the teaching of Mao et al. and Rowe et al. in combination with A. Beelen & J. C. Strum, Roslan et al. Meggle, Pharmastate academy, Pharmaexcipients, European Medicines Agency and/or Shi et al with a reasonable expectation of success, especially given that, as stated prior, these are commonly used preparation methods in the field.
Given this creativity the ability to fit teachings of multiple patents together like the pieces of a puzzle, one of ordinary skill in the art would be able to combine the teachings in such a way that it would not render the prior art devices inoperable for their intended purpose, as there are more ways than those proposed by Applicant to combine the references. Indeed, Applicant’s assertion that this application can be prepared using commonly used preparation methods in the field undermines the argument that the teachings of these references would not be obvious to the person of ordinary skill in the art.
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Allen Chao whose telephone number is (571)272-7001. The examiner can normally be reached Monday - Friday 0700-1300.
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/ALLEN CHAO/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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