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 responsive to the Response to Election/Restriction filed 09/29/2025. Claims 3-7 and 9-12 are pending.
Priority
This application claims the following priority:
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Election/Restrictions
Applicant’s election without traverse of Group II in the reply filed on 09/29/2025, is acknowledged.
Claims 3-7 and 12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 9-11 are examined on the merits herein.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0193347 to Herbig (published 2018, PTO-892) in view of Wrobleski (Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Allosteric Inhibitor of BMS-986165, J. Chem, published 2019, PTO-892) and Pandi (Amorphous solid dispersions: An update for preparation, characterization, mechanism on bioavailability, stability, regulatory considerations and marketed products, Inter Jn of Pharma, published 08/30/2020, PTO-892).
Herbig teaches tofacitinib oral sustained release dosage forms.
Herbig teaches the sustained release dosage forms as sustained release osmotic systems, wherein the tofacitinib is incorporated into osmotic delivery devices or “osmotic pumps.” The osmotic pumps comprise a core containing an osmotically effective composition surrounded by a semipermeable membrane. Owing to the semipermeable nature of the surrounding membrane, the contents of the device, including tofacitinib and its excipients, cannot pass through the non-porous regions of the membrane and are driven by osmotic pressure to leave the device through an opening or passageway pre-manufactured into the dosage form or, alternatively, formed in situ in the GI tract as by the bursting of intentionally incorporated weak points in the coating under the influence of osmotic pressure. The osmotically effective composition includes water-soluble species, which generate a colloidal osmotic pressure, and water-swellable polymers. Examples of such dosage forms are well known in the art ([0105]).
Herbig teaches that the composition optionally includes osmogens, such as water-soluble salts, sugars, organic acids, and other low-molecular-weight organic compounds that are capable of imbibing water, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium chloride ([0111]).
Herbig teaches that the core is prepared by placing a mixture of the tofacitinib-containing composition into a tablet press and then leveling the mixture by gentle compression. The water-swellable composition is then placed on top of the tofacitinib-containing composition and compressed in order to complete the formation of the core ([0120]). Following formation of the core, the semi-permeable coating is applied ([0122]).
Herbig exemplifies a bilayer osmotic tablet comprising an active layer, a sweller layer, and a coating. The active layer comprises tofacitinib citrate, polyethylene oxide, sodium metabisulfite (osmogen). The sweller layer comprise the osmogens sodium chloride and sodium metabisulfite. The coating comprises cellulose acetate and polyethylene glycol and is 13% of the target bilayer core weight (pgs. 29-30, Example 7).
Herbig teaches the tofacitinib as in a crystalline or amorphous form ([0003], [0039]). Herbig teaches the tofacitinib composition as a solution or dispersion ([0186]).
Regarding claim 9, while Herbig teaches a swellable core dosage form that is a tablet (i.e., a bilayer osmotic tablet) comprising a core, wherein the core comprises a drug layer (i.e. active layer) and a sweller layer, each layer comprising an osmogen (i.e., sodium metabisulfite and sodium chloride), and wherein the drug layer comprises a polymer matrix (polyethylene oxide), it differs from that of instant claim 9 in that it does not teach BMS-986165.
Wrobleski teaches that small molecule JAK inhibitors have emerged as a major therapeutic advancement in treating autoimmune diseases. Wrobleski teaches BMS-986165 as a high affinity JH2 ligand and potent allosteric inhibitor of TYK2. Wrobleski teaches BMS-986165 as having excellent pharmacokinetic properties with minimal profiling liabilities and as efficacious in several murine models of autoimmune disease (abstract). BMS-986165 is differentiated from previous JAK inhibitors due to its unique ability to selectively bind to the pseduokinase domain of TYK2 and inhibit its function through an allosteric mechanism (pg. 8973).
Regarding tofacitinib, Wrobleski teaches that while it is a JAK2, 2 and 3, and TYK2 inhibitor approved for treatment of moderately to severely active rheumatoid arthritis, only the 5mg dose was approved because of an unfavorable risk to benefit ratio observed at the 10mg dosage.
Wrobleski further teaches the difference in JAK family potencies between tofacitinib and BMS-986165, wherein tofacitinib is compound 1 and BMS-986165 is compound 11:
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(Fig. 1; Table 1).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the tofacitinib of Herbig with BMS-986165, to arrive at instant claim 9. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-tofacitinib and BMS-986165 are both JAK and TYK2 inhibitors,
-Herbig teaches tofacitinib for the treatment of immunological disorders (pg. 41, claims 105-107), and Wrobleski teaches BMS-986165 for the treatment of autoimmune diseases (abstract),
-Wrobleski teaches BMS-986165 as having greater selectivity for receptors and as having greater potency than tofacitinib, and
-substituting equivalents known for the same purpose is prima facie obvious, see MPEP 2144.06.
As such, an ordinary skilled artisan would have been motivated to make such a substitution to predictably arrive at a therapeutically more effective method of treating immunological disorders.
Further regarding claim 9, while the combination of Herbig and Wrobleski teaches a swellable core dosage form that is a tablet comprising a core, wherein the core comprises a drug layer and a sweller layer, each layer comprising an osmogen, and wherein the drug layer comprises BMS-986165 and polymer matrix, it differs from that of instant claim 9 in that it does not teach explicitly teach the drug layer as an amorphous dispersion.
Pandi teaches that amorphous solid dispersions (ASD) are employed to improve the bioavailability of poorly soluble molecules by enhancing the rate and extant of dissolution. These systems comprise an amorphous active pharmaceutical ingredient stabilized by a polymer matrix to provide enhanced stability (abstract). In an ASD, the solubility of the drug substance is improved by disarranging its crystalline lattice to produce a higher energy state of amorphous form. The polymer stabilizes the ASD and prevents the drug from crystalizing and provides improved physical stability under a variety of accelerated stability conditions, such as elevated temperature and relative humidity. ASD maintains its supersaturation in the gastrointestinal tract, which is the reason for the improvement of bioavailability (pg. 1, Introduction; 7.1.; 7.2.; 7.3.; 8).
Pandi teaches amorphous solid dispersions as the most emerging area in the pharmaceutical field (abstract).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to select a dispersion of amorphous BMS-986165, as the composition form and drug form, to arrive at instant claim 9. One of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Herbig teaches that the drug can be in an amorphous form, and
-Pandi teaches amorphous solid dispersions as stabilizing the drug and improving the drug’s bioavailability.
As such, an ordinary skilled artisan would have been motivated to make such a selection, to predictably arrive at swellable core dosage tablet that provides greater stability to and bioavailability of BMS-986165, leading to a greater therapeutic effect.
Regarding claim 10, Herbig teaches that following formation of the core, the semi-permeable coating is applied ([0122]). Herbig teaches the coating solutions as comprising cellulose acetate, polyethylene glycol, water and acetone ([0129]; pgs. 29-30, Example 7).
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0193347 to Herbig (published 2018, PTO-892), Wrobleski (Highly Selective Inhibition of Tyrosine Kinase 2 (TYK2) for the Treatment of Autoimmune Diseases: Discovery of the Alloseric Inhibitor of BMS-986165, J. Chem, published 2019, PTO-892) and Pandi (Amorphous solid dispersions: An update for preparation, characterization, mechanism on bioavailability, stability, regulatory considerations and marketed products, Inter Jn of Pharma, published 08/30/2020, PTO-892) as applied to claims 9-10 above, and further in view of Tonglairoum (Effect of Polyethylene Glycol on Cellulose Acetate Films Designed for Controlled Porosity Osmotic Pump Systems, Indian Jn. of Pharma Sciences, published 2019, PTO-892).
The combination of Herbig, Wrobleski, and Pandi is applied as discussed above, and incorporated herein.
While the combination of Herbig, Wrobleski, and Pandi teaches a swellable core dosage form that is a tablet comprising a core coated with the cellulose acetate and polyethylene glycol, wherein the core comprises a drug layer and a sweller layer, each layer comprising an osmogen, and wherein the drug layer comprises BMS-986165 and polymer matrix, it differs from that of instant claim 11 in that it does not teach explicitly teach the instantly claimed % of cellulose acetate and polyethylene glycol.
Herbig teaches that the weight of the coating around the core depends on the composition and porosity of the coating, but generally ranges from 3 to 30 wt. % ([0132]). Herbig exemplifies a biolayer osmotic tablet wherein the coating comprises cellulose acetate and polyethylene glycol and is 13% of the target bilayer core weight (pgs. 29-30, Example 7).
Tonglairoum teaches the properties of films containing cellulose acetate and different amounts of polyethylene glycol (PEG) for controlled porosity osmotic pump systems. Polyethylene glycol is used as a plasticizer and pore-forming agent and is incorporated into the cellulose acetate films at varied concentrations. Film properties, such as polymer interaction, mechanical properties, swelling properties, thickness, porosity, polarity and morphology of the films is investigated. The amount of polyethylene glycol had an effect on the film strength and water permeability. As PEG content is increased, the number of pores in the films increased (abstract).
Osmotic imbibitions of water results in the formation of a saturated solution of drug within the core, which is dispensed at a controlled rate from the delivery orifice in the membrane. Numerous factors affect the drug release from osmotic pumps, such as membrane permeability (pg. 117).
Tonglairoum teaches the PEG level in the coating film affects morphologies. For example, as PEG concentration increases, surface smoothness decreases and the pinholes and their size in the cross sections increase (pg. 118).
The properties of the film or membrane is one of the important factors essential for predicting drug release rate from osmotic pump systems.
Tonglairoum performs a study in which PEG 200 is used as a plasticizer and pore-forming agent and is incorporated into cellulose acetate film. The amount of PEG and the thickness of the cellulose acetate (CA) membranes are varied (pg. 118, Col. 2). CA in acetone films were prepared and PEG 200 at a weight ratio of 0, 5, 10, 20, 30, 40, or 50%, based on the polymer weight, was added into the polymeric solution:
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(pgs. 118-119, “Preparation of the polymer films”).
The semi-permeable membrane/film in osmotic pump systems must be sufficiently rigid to retain its dimensional integrity during the operational lifetime of the device. At higher levels of PEG, the elongation, which indicates the extent to which films can be stretched, was decreased as a result of phase separation of PEG and CA. The tensile strength and elongation at rupture was studied (pg. 120):
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.
The porosity and decrease in thickness was studied:
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; the percent porosity of the films increase as the amount of PEG increases (pgs. 120-121). The polarity and water permeability of the films was also studied (pgs. 120-122).
In summary, the study examined the impacts of PEG 200 concentrations as pore-forming agents in the CA film by systematically evaluating the interaction between a CA film and PEG 200, as well as the mechanical properties, porosity, swelling properties, and water permeability rates of the CA film containing different amounts of PEG 200. The study revealed that the amount of PEG affected the structure and strength of the CA films, and that the amount of PEG has an impact on the water permeation rate. This knowledge can assist in formulating a drug delivery system, such as controlled porosity osmotic pump systems, that employ CA films as a component and contain PEG as a plasticizer or pore-forming agent (paragraph spanning pgs. 122-123).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the amount of cellulose acetate and polyethylene glycol in the coating of Herbig, to arrive at instant claim 11. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Tonglairoum teaches that it is known in the art to modify the amount of polyethylene glycol and cellulose acetate in the coatings of osmotic formulations to affect the polymer interaction, mechanical properties, swelling properties, thickness, porosity, polarity, and morphology of the films, and
- "[W]here 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." MPEP 2144.05(II).
As such, an ordinary skilled artisan would have been motivated to make such a modification, to predictably arrive at a tablet with a coating that is optimized for polarity, water permeability, and controlled drug delivery.
Conclusion
No claims are allowed.
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/LAUREN WELLS/Examiner, Art Unit 1622