DETAILED ACTION
Notice of 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 .
Status of the Claims
The amendments filed 11/21/2025 have been entered.
Election/Restrictions
Newly amended claims 9 and 19 are directed to an invention that is independent or distinct from the invention originally elected for the following reasons: The claims are drawn to a formulation comprising an immediate release portion wherein the immediate release portion comprises ethyl cellulose and one or more excipients selected from a binder, filler, disintegrant, and lubricant. Yet, as elected by Applicant, the immediate release portion only comprises ethyl cellulose and does not further comprise a binder, filler, disintegrant, and/or lubricant (see Response to Election/Restriction filed 6/17/2025, Page 4).
Accordingly, claims 9 and 19 are withdrawn from consideration as being directed to a non-elected species.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Response to Arguments
Applicant’s arguments, filed 11/21/2025, have been fully considered.
Applicant first argues that “a person of ordinary skill in the art has no motivation to develop the technical solution encompassed by currently amended claim 1 based on the teachings of Turkyimaz et al., which pertains to formulations with thiocolchicose as the active ingredient” (Applicant Arguments, Page 9). As further argued by Applicant, “thiocolchicose... has a completely different molecular structure and therapeutic use from... tofacitinib” (Applicant Arguments, Page 9).
The argument is not found persuasive. It is maintained that one of ordinary skill in the art could incorporate a different active agent in the “pharmaceutical formulation comprising [an] immediate release phase and a sustained release phase” taught by Turkyilmaz et al to provide a modified pharmaceutical formulation comprising an immediate release phase and a sustained release phase with a reasonable expectation of success.
Applicant next argues that “Turkyilmaz et al... provide no data to demonstrate that they have achieved” a reduction in adverse effects, improved patient compliance, and the like (Applicant Arguments, Page 9).
The argument is not found persuasive. Applicant is advised that the arguments of counsel cannot take the place of evidence in the record (see In re Shulze, 346 F.2d 600 (CCPA 1965)). Assertions of inoperability of the prior art must be supported by an appropriate affidavit or declaration.
Applicant next argues that “the technical problem addressed by the present invention does not relate to compliance, but rather to achieving superior in vivo absorption (e.g., higher AUC) and enhanced therapeutic efficacy (e.g., longer Ta)” (Applicant Arguments, Page 10). And, as argued by Applicant, “a person of ordinary skill in the art would not have conceived of dividing the active ingredient into two portions: an immediate-release portion and a sustained-release portion. This is because such a person could not reasonably expect that such a division would result in a higher AUC” (Applicant Arguments, Page 10), further providing an example of a dual-release formulation having “a lower AUC than” a comparative sustained-release formulation thereof (Applicant Arguments, Page 11).
At the outset, it is not found persuasive that “a person of ordinary skill in the art would not have conceived of dividing the active ingredient into two portions: an immediate-release portion and a sustained-release portion”. Dual-release formulations are well-known in the art and specifically taught by Turkyilmaz et al. And, given the low adherence to therapeutic regimens for rheumatoid arthritis treatments and, in particular, tofacitinib, it is maintained that it would have been obvious to formulate tofacitinib in the instantly claimed dual-release formulation as discussed in the basis of the rejection.
As to Applicant’s arguments regarding therapeutic efficacy and AUC, while it is noted that Applicant argues “superior in vivo absorption... and enhanced therapeutic efficacy” of the dual-release formulation, it is not clear what the in vivo absorption and/or therapeutic efficacy is superior and/or enhanced relative to. Additionally, it is not necessary that the prior art suggest the combination of references to achieve the same advantage or result discovered by Applicant (e.g., superior in vivo absorption and enhanced therapeutic efficacy). Rather, the reason or motivation to modify a reference to arrive at the claimed invention can be for a different purpose or to solve a different problem (e.g., to improve patient adherence and health outcomes). The fact that Applicant 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 (see Ex parte Obiaya, 227 USPQ 58 (Bd. Pat. App. & Inter. 1985; see also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446 (Fed. Cir. 1989), “The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention”).
Furthermore, it is noted that none of the claims require or define a specific therapeutic efficacy and only claim 7 requires achieving a specific blood concentration of 17 ng/ml in about 10-60 minutes. And, regarding claim 7, as discussed in the basis of the rejection, Lambda et al teach that a “single-dose... [of] tofacitinib IR 5 mg twice daily” results in a blood concentration of 17 ng/ml in about 15 minutes.
Accordingly, it is evident that the prima facie obvious dual-release solid formulation in the form of a coated tablet would similarly provide a blood concentration of 17 ng/ml in about 10 – 60 minutes (i.e., by virtue of the immediate release portion thereof). Moreover, it would have been obvious to formulate the dual release solid formulation in the form of a coated tablet so as to provide a blood concentration of 17 ng/ml in about 10 – 60 minutes. It would have been obvious to do so in order to deliver a therapeutically effective amount of tofacitinib to a patient in need thereof.
Applicant, however, further argues that “even if a person of ordinary skill in the art would have conceived of dividing the active ingredient into an immediate-release portion and a sustained-release portion, there is no reasonable expectation of success to identify which combination... of those two portions would form the specific structure required to achieve a higher AUC and a longer Ta” (Applicant Arguments, Page 11) and “[n]or would such person have necessarily expected that this specific structure could achieve superior in vivo absorption and therapeutic efficacy, such as a higher AUC and a longer Ta” (Applicant Arguments, Page 12).
Again, it is unclear what the “higher AUC and... longer Ta” is higher and/or longer relative to. Additionally, as discussed above, is it not necessary that the prior art suggest the combination of references to achieve the same advantage or result discovered by Applicant.
Applicant next argues that “only by forming the specific structure as presently claimed, namely a layer of immediate-release coating film containing the active ingredient, and film-forming materials that covers the surface of the sustained-release portion, can it be ensured that... the release profile of the present application’s solid formulations... enables the achievement of a higher AUC and a longer Ta” whereas “any other combination mode of the sustained-release portion and the immediate-release portion fails to achieve” this (Applicant Arguments, Page 12).
Considering that, as noted by Applicant, Turkyilmaz et al disclose multiple dual release formulations (Applicant Arguments, Page 12), it is possible that the AUC and/or Ta of the instantly claimed dual release formulation when compared to those other dual release formulations disclosed in Turkyilmaz et al could entail an unexpected result. However, Applicant has not made this argument nor has Applicant provided evidence to support this conclusion.
Next, Applicant argues that “the specific ratio of the active ingredient... in the sustained-release portion and the immediate-release portion is non-obvious to a person of ordinary skill in the art” (Applicant Arguments, Page 13).
Applicant first argues that “[s]ection 2144.05 of the MPEP... addresses rejection precedents for technical solutions involving ratios (or ranges, quantities) that overlap with, are close to, or are similar to those in the prior art” and, as such, “cannot properly serve as a basis for rejection” since the prior art does not disclose any ratios, ranges, or quantities, let alone those which overlap with, are close to, or are similar to the instantly claimed ratios.
The argument is not found persuasive. Applicant’s arguments are in reference to MPEP 2144.05(I) whereas the reasoning in the rejection is based on MPEP 2144.05(II).
Applicant further argues that, since the prior art “do not explicitly disclose the relationship between the weight ratio of the active ingredient in the sustained-release portion to that in the immediate-release portion, [or] the relationship between said weight ratio and either AUC or Ta... the weight ratio... does not qualify as... ‘results of optimizing a variable’ as specified in Section 2144.05 of the MPEP” (Applicant Arguments, Page 14).
The argument is not found persuasive. It is maintained that it would have been prima facie obvious to determine the amount of tofacitinib to include in the sustained-release portion and the immediate-release portion of the dual release formulation. As indicated by the court in Ariosa Diagnostics, Inc. v. Sequenom, Inc., 809 F.3d 1282, 1293 (Fed. Cir. 2015), every ordinary artisan in medicine performs “merely routine optimization of drug dosage to maximize therapeutic effect.” And, in making this determination (i.e., in optimizing this result-effective parameter) it is necessarily the case that a weight ratio is obtained. As stated by the court in In re Peterson, 315 F.3d at 1325 (Fed. Cir. 2005), “[o]nly if the ‘results of optimizing a variable’ are ‘unexpectedly good’ can a patent be obtained for the claimed critical range” (quoting In re Antonie (559 F.2d 618 (CCPA 1977))).
Applicant, however, points to Table 11 as evidence that “when compared with T3 (where the weight ratio of tofacitinib in the sustained-release portion to that in the immediate-release portion is 1:1), the present application’s solid formulations (e.g., T1 and T2, with... weight ratios of 9:1 and 4:1, respectively) can achieve higher in vivo exposure (AUC), specifically 404 ng*h/mL for T1 and 406 ng*h/mL for T2, and a longer Ta, specifically 8.6 h for T1 and 9.7 h for T2” (Applicant Arguments, Page 14).
Yet, Table 11 does not appear to show any statistically significant difference in Cmax, AUC or Tmax between T1, T2, and T3. Additionally, each of T1, T2, and T3 are limited to formulations comprising:
(a) a coated tablet core comprising a sustained release portion comprising:
(i) tofacitinib; and
(ii) a sustained release matrix material comprising:
microcrystalline cellulose;
lactose;
glyceryl behenate in an amount of 50% based on the weight of the sustained release portion; and
magnesium stearate; and
(b) a coating film comprising an immediate release portion comprising:
(i) tofacitinib;
(ii) ethyl cellulose in an amount of about 50% based on the weight of the immediate release portion;
(iii) mannitol; and
(iv) isopropanol.
As such, even assuming arguendo that Figures 1-2 and Table 11 demonstrate an unexpectedly good result of optimizing the amount of tofacitinib to include in the sustained-release portion and the immediate-release portion of the dual release formulation (and, by definition, the ratio thereof), the claims are not drafted commensurate in scope with these results. As discussed by the court in In re Clemens, 622 F.2d 1029 (CCPA 1980), “the objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support”.
For all the foregoing reasons, Applicant’s arguments are not persuasive.
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.
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 1, 6, 12 and 18 are rejected under 35 U.S.C. 103(a) as being unpatentable over Turkyilmaz et al (ES 2 577 130, based on the attached English translation; of record) in view of Marengo et al (Int J Clin Rheumtol 10:345-356, 2015; of record), Tanaka et al (Rheumatology 58:70-79, published 8/17/2018; of record), Machado et al (Arthritis Research and Therapy 20:60, 2018; of record) and Yaligod et al (J Clin and Diagnostic Res 8:LC11-LC15, 2014; of record).
As amended, claim 1 is drawn to a solid formulation (more specifically, in the form of a coated tablet), comprising:
(a) a coated tablet core comprising a sustained release portion comprising:
(i) tofacitinib; and
(ii) a sustained release matrix material which is glyceryl behenate in an amount of about 40% to 60% based on the weight of the sustained release portion; and
(b) a coating film comprising an immediate release portion comprising:
(i) tofacitinib; and
(ii) a film-forming material which is ethyl cellulose in an amount of about 40% to 60% based on the weight of the immediate release portion;
wherein the weight ratio of Tofacitinib in the sustained release portion to Tofacitinib in the immediate release portion is about 4:1 – 9:1.
Turkyilmaz et al teach a “pharmaceutical formulation comprising [an] immediate release phase and a sustained release phase comprising glyceryl behenate as a speed control polymer” (Abstract), in particular “a formulation tablet [having] a core comprising the sustained release [agent] and… coating layer comprising the drug that is released immediately” (Page 4, Description of the Figures, Figure 3; see also Page 6, Paragraph: “the pharmaceutical formulation is... a tablet, bilayer tablet, multilayer tablet or multi-coated tablet”) wherein, as further taught by Turkyilmaz et al, “the immediate release phase… further comprise[s] at least one pharmaceutically acceptable excipient selected from… binding agents” wherein “[s]uitable binding agents are selected from… ethyl cellulose” (Page 9, 3rd Paragraph).
As further taught by Turkyilmaz et al, the amount of glyceryl behenate in said sustained release phase is between 1% and 50% (Page 7, 3rd Paragraph) and Turkyilmaz et al specifically disclose a composition comprising binding agents in an amount of 6% to 40% (Pages 9-10, i.e., 5.0% to 30.0% corn starch + 0.5% to 5.0% gelatin + 0.5% to 5.0% sugar).
As such, Turkyilmaz et al teach a solid formulation in the form of a coated tablet comprising:
(a) a coated tablet core comprising a sustained release portion comprising glyceryl behenate in an amount of about 40% to 60% based on the weight of the sustained release portion; and
(b) a coating film comprising an immediate release portion comprising ethyl cellulose in an amount of about 40% to 60% based on the weight of the immediate release portion.
The formulation of Turkyilmaz et al thus differs from the instantly claimed formulation in that Turkyilmaz et al do not teach the inclusion of tofacitinib wherein the weight ratio of tofacitinib in the sustained release portion to tofacitinib in the immediate release portion is about 4:1 – 9:1
Yet, as taught by Marengo et al, “[l]ow adherence to therapeutic regimens is a prevalent and persistent healthcare problem, particular for patients with chronic disorders. Many patients with rheumatoid arthritis (RA) show inadequate therapeutic adherence resulting in poor health outcomes” (Abstract). Specifically, in rheumatoid arthritis, “[r]eports of patients’ adherence to their medications range from 14 to 80%” and “[l]ow adherence has been shown to negatively impact RA outcomes” (Page 4). As further taught by Marengo et al, “frequence of dosing” as well as “number of pills” are “all factors that can determine adherence to therapy” (Page 5).
As taught by Tanaka et al, the “immediate-release (IR) formulation of tofacitinib… requires a twice-daily (BID) dosing regimen” (Page 70, Column 2) and is associated with problems with “treatment compliance” (Page 71, Column 1). As further taught by Tanaka et al, “[t]here is evidence that drug adherence decreases over time” and once daily “dosing may result in greater adherence compared with BID dosing” (Page 78, Column 1).
Indeed, as demonstrated by Machado et al, only 27.7% of patients treated with tofacitib for rheumatoid arthritis are considered “highly adherent” (Page 3, Table 1; Page 3, Column 2; and Page 5, Table 3; see also Page 4, Column 2: “high adherence… was especially low for… tofacitinib”).
However, as taught by Yaligod et al, noting that “[t]he main problem associated with management of osteoarthritis is long term patient compliance to paracetamol due to its frequent dosing” (Abstract), “[a]… dual release paracetamol formulation (325 mg IR + 325 mg ER) with reduced frequency of administration may improve compliance” (Page 13, Column 2). Indeed, as further taught by Yaligod et al, “[p]atient’s and physician’s global evaluation of treatments… favored… dual release” and “dual release… was statistically and therapeutically more effective, safe and convenient than… IR”, concluding that the dual release formulation “could be a better alternative treatment option… as it decreases dosing frequency which may improve patient compliance with better long-term efficacy and safety” (Page 14, Column 2).
Accordingly, it would have been prima facie obvious to formulate a dual release solid formulation in the form of a coated tablet (as taught by Turkyilmaz et al) wherein the formulation comprises tofacitinib in the sustained and immediate release portions, as claimed. Considering that, in general, patient adherence to therapeutic regimens for the treatment of rheumatoid arthritis is low (as taught by Marengo et al) and, in particular, patient adherence to tofacitinib for the treatment of rheumatoid arthritis is low (as taught by Tanaka et al and Machado et al), it would have been obvious to formulate tofacitinib as a dual release formulation. It would have been obvious to do so to improve patient adherence and health outcomes based further on Yaligod et al which demonstrate that related dual release formulations are “statistically and therapeutically more effective, safe and convenient than… IR” and “could be a better alternative treatment option… as it decreases dosing frequency which may improve patient compliance with better long-term efficacy and safety”.
And, in doing so, it would have been prima facie obvious to determine the amount of tofacitinib to include in the sustained and immediate release portions of the dual release formulation (and, therefore, the weight ratio of said amounts). As stated by MPEP 2144.05, “[g]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical” (see also In re Aller (220 F.2d 454 (CCPA): “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation…” Indeed, as further discussed by the court, “[s]uch experimentation is no more than the application of the expected skill of the [ordinarily skilled artisan] and failure to perform such experiments would, in our opinion, show a want of the expected skill”; see also In re Peterson, 315 F.3d at 1325 (Fed. Cir. 2005): “[t]he normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages” and “[o]nly if the ‘results of optimizing a variable’ are ‘unexpectedly good’ can a patent be obtained for the claimed critical range” (quoting In re Antonie (559 F.2d 618 (CCPA 1977))).
In the instant case, the concentration of active ingredient in the sustained and immediate release portions of a dual release pharmaceutical formulation is clearly a result-effective variable. As indicated by the court in Ariosa Diagnostics, Inc. v. Sequenom, Inc., 809 F.3d 1282, 1293 (Fed. Cir. 2015), every ordinary artisan in medicine performs “merely routine optimization of drug dosage to maximize therapeutic effect.” As such, it would have been prima facie obvious to determine the optimal amount of said active agent (i.e., tofacitinib) to include therein in order to best achieve the desired results.
Accordingly, in view of all of the foregoing, claim 1 is rejected as prima facie obvious.
Claim 6 is drawn to the solid formulation of claim 1, wherein the active ingredient in the solid formulation has a total dissolution within 15 minutes of from 5-50%, within 1 hour of about 20-60%, within 3 hours of about 55-95%, and/or within 5 hours of at least 80%.
For largely the same reasons as discussed above regarding the amount of tofacitinib in the formulation, it would have also been obvious to determine the total dissolution rate of tofacitinib in said formulation which, as taught by Turkyilmaz et al, is influenced by glyceryl behenate (Page 6, 7th Paragraph and Page 7, 1st Paragraph).
Nevertheless, as further taught by Turkyilmaz et al, “1% - 25% of the [active ingredient] content of the pharmaceutical formulation is in the immediate release phase” (Page 8, 1st Paragraph) which would result in a total dissolution within 15 minutes of from 5-50%.
As such, claim 6 is also rejected as prima facie obvious.
Claim 12 is drawn to a pharmaceutical composition, comprising the solid formulation according to claim 1.
The solid formulation in the form of a coated tablet as taught by the prior art entails a pharmaceutical composition.
As such, claim 12 is also rejected as prima facie obvious.
Claim 18 is drawn to the solid formulation of claim 1, wherein the coated tablet optionally comprises a sustained coating.
As such, claim 18 (which does not require any additional components not already addressed in the rejection of the coated tablet of claim 1) is also rejected as prima facie obvious.
Claim 7 is rejected under 35 U.S.C. 103(a) as being unpatentable over Turkyilmaz et al (ES 2 577 130, based on the attached English translation; of record) in view of Marengo et al (Int J Clin Rheumtol 10:345-356, 2015; of record), Tanaka et al (Rheumatology 58:70-79, published 8/17/2018; of record), Machado et al (Arthritis Research and Therapy 20:60, 2018; of record) and Yaligod et al (J Clin and Diagnostic Res 8:LC11-LC15, 2014; of record) as applied to claims 1, 6, 12 and 18 above, in further view of Lambda et al (J Clin Pharmacol 56:1362-1371, 2016; of record).
Claim 7 is drawn to the solid formulation of claim 1, wherein after a single administration, the time required to achieve a blood concentration of 17 ng/ml is about 10 – 60 minutes.
As taught by Lambda et al, evaluating “single-dose and steady-state conditions [of] tofacitinib IR 5 mg twice daily” (Abstract), a blood concentration of 17 ng/ml was achieved in about 15 minutes (Page 1366, Figure 2 (note that the IR and XR lines appear to be mislabeled)).
Accordingly, it is evident that the prima facie obvious dual release solid formulation in the form of a coated tablet would provide a blood concentration of 17 ng/ml in about 10 – 60 minutes and, at minimum, it would have been obvious to formulate the dual release solid formulation in the form of a coated tablet so as to provide a blood concentration of 17 ng/ml in about 10 – 60 minutes. It would have been obvious to do so in order to deliver a therapeutically effective amount of tofacitinib to a patient in need thereof.
As such, claim 7 is also rejected as prima facie obvious.
Conclusion
Any new ground(s) of rejection presented in this Office action are necessitated by Applicant’s amendments to the claims. 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CRAIG D RICCI whose telephone number is (571) 270-5864. The examiner can normally be reached on Monday through Thursday, and every other Friday, 7:30 am - 5:00 pm ET.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached on (571) 272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CRAIG D RICCI/Primary Examiner, Art Unit 1611