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 .
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.
Claims 3 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Brown et al. (previously cited) in view of Stefan et al. (US PGPub No. 2016/0022661 - previously cited) and Karakatsani et al. (previously cited).
Brown et al. teach pyrrolo[2,3-d]pyrimidinyl compounds that are useful as kinase inhibitors to treat a variety of conditions that include autoimmune diseases and cancers (see page 1 lines 4-23, page 2 lines 5-8, and page 5 lines 16-page 6 line 12). Exemplified compounds include 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (see page 38 lines 12-page 39 line 2 and example 5). In addition, Brown et al. teach salt forms of their taught compounds, such as tosylate (toluenesulfonate), as well as their preferred formulation of the compounds in forms for oral administration (see page 44 lines 8-18). While excipients known to those in the art are generally taught, a particular formulation for the oral dosage form is not detailed.
Stefan et al. teach an oral dosage form for delivery of a kinase inhibitor to treat cancer (see paragraph 1-3). The dosage form is provided as an immediate release tablet, where fillers at 12 to 27 wt%, lubricants at 9 to 20 wt%, disintegrants at 2 to 10 wt%, and 2 to 12 wt% binders may be included with 20 to 75 wt% drug (see paragraphs 71-77). Combinations of fillers are suggested (see paragraph 59). Microcrystalline cellulose and lactose are particular fillers that are envisioned (see paragraphs 58-59). An example provides drug at 59.24 wt%, glyceryl dibehenate at 9.48 wt%, microcrystalline cellulose at 22.51 wt%, crosslinked polyvinyl pyrrolidone (crospovidone) at 3.55 wt%, and silicone dioxide (see example 1).
Karakatsani et al. teach the selection of excipients to maintain stability of drugs by avoiding water absorption in tablets (see abstract, column 2 lines 40-43 and column 3 lines 8-16). Amongst envisioned excipients include lactose and its forms such lactose monohydrate (see column 5 lines 38-40).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare an oral tablet of the exemplified compound of Brown et al., where a set of excipients are included as exemplified by Stefan et al. This modification would have been obvious because Stefan et al. provide a carrier known to be suitable for a similar type of drug to treat the same class of pathology. It also would have been obvious as the simple substitution of one known element for another in order to yield a predictable outcome (e.g., specific excipients vs generic excipients). Additionally, it would have been obvious to include microcrystalline cellulose and lactose as two fillers in the excipient blend because Stefan et al. suggest the inclusion of fillers in combination and envisioned both as options. More specifically, it would have been obvious to select lactose monohydrate as the lactose in the tablet of Brown et al. in view of Stefan et al. This choice would have been obvious in light of Karakatsani et al. who teach it was a known form of lactose suitable for tablet applications where water absorption is undesired and as the simple substitution of one known element for another in order to yield a predictable outcome (see instant claim 3). The proportions for the drug, glyceryl dibehenate, and crosslinked polyvinyl pyrrolidone (crospovidone) overlap with those instantly claimed. In addition, the total amount of lactose monohydrate and microcrystalline cellulose as the fillers collectively present at 12 to 27 wt%, imply ranges for each of them (greater than zero to less than 27 wt%) that overlap or embrace the instantly claimed ranges. “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)” (see MPEP 2144.05; instant claim 3). Thus the claimed ranges are obvious in light of these prior art teachings. According to MPEP 2145II, mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). In addition, the fact that an inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). The instantly claimed components and proportions are rendered obvious by the prior art teachings; therefore, absent evidence to the contrary, the degree of occurrence of dimer of 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one at the recited storage conditions would follow. Therefore claims 3 and 12-13 are obvious over Brown et al. in view of Stefan et al. and Karakatsani et al.
Claims 3 and 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Brown et al. in view of Stefan et al. and Karakatsani et al. as applied to claims 3 and 12-13 above, and further in view of Ruiz et al. (WO 2017/064192).
Brown et al. in view of Stefan et al. and Karakatsani et al. render obvious the limitations of instant claims 3 and 12-13. Stefan et al. describe the dosage form as an immediate release formulation, where the drug is provided in particle form with an average size up to 150 mm (see abstract and paragraphs 34-38). The instantly claimed particle size is not explicitly detailed.
Ruiz et al. teach an immediate release dosage for that includes is drug active in particle form having a Dv50 from 100 to 420 mm and a Dv90 from 300 to 850 mm (see abstract and page 4 lines 21-23).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to size the drug particles in the dosage form rendered obvious by Brown et al. in view of Stefan et al. and Karakatsani et al. in light of Ruiz et al. who provide a size distribution known to be suitable for such immediate release dosage forms that also coordinates with the size range detailed by Stefan et al. Since there is no clear evidence of an unexpectedly superior outcome purely due to sizing (e.g., as opposed to surface grinding), the selection of a size distribution within that known to be suitable would have been obvious (see MPEP 2144.05). Therefore claims 3 and 12-14 ae obvious over Brown et al. in view of Stefan et al., Karakatsani et al., and Ruiz et al.
Response to Arguments
Applicant's arguments filed November 21, 2025 have been fully considered. In light of the amendment, the objection to the drawings and specification as well as the rejection under 35 USC 112 and under 35 USC 103 over Thorarensen et al. in view of others are hereby withdrawn. The arguments directed towards the remaining rejection of claim 3 under 35 USC 103 are not persuasive.
The applicant argues that tested formulations in instant tables 11 and 21 had over 10 times the stability of a different formulation in regard to dimer formation upon storage. In order for such an outcome to qualify as a secondary consideration sufficient to overcome the prima facie case of obviousness, the evidence must be commensurate in scope with the claims. The evidence of record falls short of this requirement for multiple reasons.
The claims are drawn to an immediate release formulation comprising 15-67 wt% 1-((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one (henceforth PPAMP) or a pharmaceutically acceptable salt thereof, in combination with particular proportions of crospovidone, lactose monohydrate, glyceryl dibehenate, and microcrystalline cellulose. The tested formulations in table 11 and 21 are composed of a toluenesulfonate salt form of PPAMP. A free base and various salt forms of a compound can have different degrees of stability. For example, another compound prone to dimer degradation product formation upon storage was more stable in hydrochloride salt form than in other salt forms (see US PGPub No. 2015/0110820 paragraph 39). Thus the degree of dimerization for the tested toluenesulfonate salt is not clearly predictive of the free base or other salt form dimerization under the same conditions. Claims 12 and 13 recite that the formulation comprises PPAMP toluenesulfonate salt, but do not require that all of the PPAMP is in toluenesulfonate salt form. While there may be some similarity in function amongst the different forms of PPAMP, the applicant has not provided a nexus between the performance of the tested toluenesulfonate salt and the full scope of the claimed compounds.
Formulations A-C, E, and G in table 11 all fulfill the dimerization formation threshold of the instant claims, yet none of them have the claimed combination of excipients in combination with a PPAMP toluenesulfonate salt. The applicant point to these compositions as demonstrative of the invention; however, they show that the selection of the instantly claimed excipient blend and proportions is not critical and that several other combinations of excipients also have a similar stability profile as that instantly claimed. When the formulations of table 21 are considered, they have the excipient combination and proportions as well as the stability profile as claimed. It remains unclear how these outcomes compare to the expected performance based on the prior art. The applicant provides a comparative formulation, but its importance in reference to the expected storage behavior of an immediate release PPAMP formulation is not clear.
The applicant additionally argues that each reference in the rejection does not teach each aspect of instant claims. These are not persuasive arguments since the combination of references is provided precisely because each reference does not separately teach all of the claimed limitations. These references represent the knowledge the artisan of ordinary skill would have had within their technical grasp at the time of filing. Where one reference omits a pertinent teaching, another reference fills the void. For example, the applicant argues that Stefan et al. do not teach the claimed compound. While true, Brown et al. teach the claimed compound which is a kinase inhibitor, like those of Stefan et al., that is detailed as addressing some of the same conditions. The applicant also notes that Karakatsani et al. teach a glyceryl behenate and not the claimed diglyceryl behenate. Stephen et al. exemplify glyceryl dibehenate in combination with most of the other claimed excipients. Thus the ‘missing’ limitations highlighted by the applicant were already addressed by other references.
The applicant also argues that silicon dioxide is a required component of Stefan et al. but was not deemed suitable by the applicant due to the high ejection force its inclusion induced. The silicon dioxide containing formulations tested by the applicant are not representative of those of Stefan et al., given that they do not include the lubricant glyceryl dibehenate that Stefan et al. employed (see instant tables 2 and 3 formulations A and D). Instantly tested formulations with glyceryl dibehenate had lower ejection forces suggesting that the excipient mixture of Stefan et al. would not be prone to inducing undesired ejection force (see instant table 3 formulation B, C, and F vs. A and D). Moreover, the claimed formulations were not assessed for ejection volume, but instead were filled into capsules as opposed to being tableted, where ejection force can matter.
The applicant references commentary from the International Preliminary Report on Patentability. The current examination is not bound by the conclusions made in the referenced document. In addition, the applicant did not appear to apply the suggestions they highlighted from the report. Thus the relevance of the commentary from the report to the obviousness of the current claims is unclear
Conclusion
No claim is 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.
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/CARALYNNE E HELM/Examiner, Art Unit 1615
/MELISSA S MERCIER/Primary Examiner, Art Unit 1615