DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This is the second Office action on the merits of the claims.
All citations to the Manual of Patent Examining Procedure (MPEP) refer to Revision 01.2024, which was released in November 2024.
Status of the Claims
In the Reply filed 07 July 2026, Applicant amended claims 2, 6-7, 12-19, 25, and 29. Additionally, Applicant cancelled claims 4, 9-10, 20, and 22-23. Claim 1 was previously cancelled by Applicant. Claims 2-3, 5-8, 11-19, 21, and 24-31 are pending.
Status of the Rejections and Objections
The objection to the specification is withdrawn in view of Applicant’s amendment to the title of the application.
The rejection of claims 2-31 under 35 U.S.C. 112(b) is withdrawn as to all claims except claim 3, in view of Applicant’s (i) clarifying amendments to claims 2 and 6; and (ii) cancellation of claim 4.
The rejection of claims 2-31 under 35 U.S.C. 103 as being unpatentable over Fellstrom (“Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial.” The Lancet 389.10084 (2017): 2117-2127) in view of Calliditas Therapeutics (“Pharmalink’s core patents for Nefecon® treatment for renal disease granted in United States, Europe, China and Hong Kong.” 2014 July 10. [Press Release]) and Watts (US 8,491,932 B2) has been modified in view of Applicant’s amendment to claim 2 adding the following product-by-process limitation: “wherein the polymeric blend is cured by heating at about 55°C to about 75°C for at least about 1 hour to form a single polymeric phase coating.” The following three additional optional references are newly cited and apply if and only if the step of curing results in a significant structural difference over Watts: (1) Surelease: Ethylcellulose Dispersion Type B NF [Technical Information Sheet]. Colorcon (2013 June); (2) SURELEASE* [Technical Brochure]. Colorcon (1990 October); and (3) US 5,472,712 to Oshlack.
All seven rejections on the ground of non-statutory double patenting set forth in the previous Office action (07 January 2026) are withdrawn in view of the Terminal Disclaimer filed by Applicant, which has been approved by the Patent Office. The examiner appreciates Applicant's effort to advance prosecution.
Claim Rejections - 35 U.S.C. 112(b)
The following is a quotation of 35 U.S.C. 112(b):
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claim 3 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter that the inventor regards as the invention.
Regarding claim 3, the following limitation remains unclear: “wherein the release is predicted by an in vitro/in vivo correlation (IVIVC).” How does the prediction concerning the release profile further define the actual compositional or structural profile of the pharmaceutical composition? Isn’t a prediction essentially a mental step?
Response to Applicant’s Argument
The remarks made by Applicant on pages 7-8 of the recent Reply are insufficient to clarify claim 3 because the following salient question still has not been answered: How does the prediction, itself, further define the actual compositional or structural profile of the pharmaceutical composition? More broadly, it is unclear whether (and, if so, how) a prediction can even further limit the pharmaceutical composition, as presently claimed. The examiner notes that claim 3 already requires: “the composition begins releasing budesonide only once the ileum is reached and at least 90% of budesonide is released throughout the entire ileum.” Applicant’s assertion of Example 25 and Figure 23 is unavailing because (i) the release of budesonide is occurring in vivo (following oral administration to the subject), not in vitro; and/or (ii) the protocol for determining IVIVC described in Example 25 is too poorly defined to allow a person having ordinary skill in the art to reliably practice it and achieve reproducible results. For example, it is unclear what the following entails: “After introducing gut wall metabolism to the PBPK model a good fit of the data was achieved.” Specification, page 94, at para. [0465].
The §112(b) rejection of claim 3 is maintained.
* * *
Claim Rejections - 35 U.S.C. 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 2-3, 5-8, 11-19, 21, and 24-31 are rejected under 35 U.S.C. 103 as being unpatentable over Fellstrom (“Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial.” The Lancet 389.10084 (2017): 2117-2127) in view of Calliditas Therapeutics (“Pharmalink’s core patents for Nefecon® treatment for renal disease granted in United States, Europe, China and Hong Kong.” 2014 July 10. [Press Release]) and Watts (US 8,491,932 B2) and, optionally, Colorcon-2013 (Surelease: Ethylcellulose Dispersion Type B NF [Technical Information Sheet]), Colorcon-2009 (SURELEASE* [Technical Brochure]), and Oshlack (US 5,472,712).
Fellstrom is directed to: “Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial.” Title.
Fellstrom discloses that “[p]rimary IgA nephropathy is the most prevalent chronic glomerular disease worldwide, with patients often diagnosed as young adults.” Page 2117, left column.
Fellstrom discloses: “A novel, oral, targeted-release formulation of the glucocorticosteroid budesonide (TRF-budesonide; Nefecon [Pharmalink AB, Stockholm, Sweden]) was developed to release the drug in the distal ileum, which has a high density of Peyer’s patches.” Page 2118, left column.
Fellstrom discloses: “Trial medication was an oral capsule formulation of TRF-budesonide (Nefecon) or placebo, designed to provide sustained release of active compound that was delayed until the capsule reached the distal ileum, targeting the site with a high density of Peyer’s patches.” (Emphasis added) Page 2119, right column. “The safety profile of TRF-budesonide was anticipated to be superior to high dose systemic corticosteroids because of its extensive first-pass metabolism—less than 10% of budesonide enters systemic circulation.” (Emphasis added) Page 2118 at sentence bridging left/right columns.
Fellstrom discloses: “Patients were stratified according to their baseline UPCR (≤0·9 g/g and >0·9 g/g) at month 0 (baseline). We randomly allocated patients to treatment groups using a computer algorithm method of permuted blocks. Within each block, patients were allocated in a 1:1:1 ratio to 16 mg/day TRF-budesonide, 8 mg/day TRF-budesonide, or placebo.” (Emphasis added) Page 2119, left column.
Fellstrom discloses: “To ensure masking, placebo capsules provided by the sponsor had the same appearance and route of administration as the active capsules. Patients self-administered masked capsules, once daily, 1 h before breakfast during the treatment phase. During follow-up (months 9–12), patients who received 16 mg/day TRF-budesonide during months 0–9 were tapered to 8 mg/day for 2 weeks while all other patients (ie, those who received TRF-budesonide 8 mg/day or placebo during months 0–9) received placebo to maintain masking. No further trial medication was administered after tapering.” (Emphasis added) Page 2119 at paragraph bridging left/right columns.
Fellstrom discloses: “This trial showed that 9 months’ treatment with TRF-budesonide resulted in reduced proteinuria and stabilised eGFR in patients with IgA nephropathy at risk of progression to end-stage renal disease. The observed effect was additive to optimised RAS blockade and supports the use of TRF-budesonide as adjunct therapy in patients with IgA nephropathy with persistent proteinuria. TRF-budesonide has the potential to become the first disease-specific treatment for IgA nephropathy, with a risk-benefit profile supportive of its use early in the course of disease.” Page 2126, right column. “At 9 months, mean UPCR [urine protein creatinine ratio] had decreased by 27.3% in 48 patients who received 16 mg/day (0.71; 0.53–0.94; p=0.0092) and 21.5% in the 51 patients who received 8 mg/day (0.76; 0.58–1.01; p=0.0290); 50 patients who received placebo had an increase in mean UPCR of 2.7%.” (Emphasis added) Abstract.
Although Fellstrom discloses that TRF-budesonide (Nefecon®) provides sustained release of active compound that is delayed until the capsule reaches the distal ileum (page 2118), Fellstrom is silent as to whether Nefecon includes (i) a blend of a water-soluble polymer and a water-insoluble polymer that is cured to form a single polymeric phase coating and (ii) an enteric coating. Consequently, Fellstrom does not satisfy claim 2 of the present application. As explained below, the following two references — in combination — compensate for this deficiency: Calliditas Therapeutics and Watts.
Calliditas Therapeutics is a press release directed to the core patents for Nefecon®.
Calliditas Therapeutics teaches: “Nefecon is a potential disease-modifying treatment for patients with primary lgA nephropathy at risk of developing end-stage renal disease.” Page 1.
Calliditas Therapeutics teaches: “The patents issued in the US (US 8,491,932), Europe (EP 2278958) China (200980127272.5) and Hong Kong (1158510) provide protection around the formulation of Nefecon and its use as a treatment of glomerulonephritis, including IgA nephropathy, the most common form of primary glomerulonephritis and a cause of end-stage renal disease.” (Emphasis added) Page 1.
Watts, which is US 8,491,932, is directed to compositions for the oral delivery of corticosteroids.
Section (iv) of Example 1 of Watts (columns 10-11) teaches budesonide cores that are coated with a controlled-release (extended-release) layer comprising a blend of a water-insoluble polymer (ethylcellulose) and water-soluble polymers (HPMC/PEG). More specifically, Watts teaches:
900 g of Surelease® dispersion (ethylcellulose aqueous dispersion, 25% by weight solids) was transferred to a beaker. 45 g of Opadry® coating material (hydroxypropyl methylcellulose/polyethylene glycol blend) was dissolved in 555 g of water and the resulting solution gently mixed into the Surelease® dispersion.
4 kg of the coated beads (obtained in step (iii)) were transferred into the coating chamber of the MP-1 coater which was set up with the following parameters:
Fluidisation air volume=80 m3/h
Inlet temp=70° C.
Atomisation pressure=29 psi (2 bar)
778 g of coating dispersion was applied to the beads at an approximate rate of 9 g/min. The coated beads were dried while being fluidised for 15 minutes at 60° C. followed by 15 minutes at 30° C.
Column 11, lines 22-38 (emphasis added).
The examiner notes that drying in a fluidized bed for 15 minutes at 60°C (equivalent to 140°F) qualifies as cured to form a single polymeric phase coating. The examiner’s position is supported by page 44 of Applicant’s specification, as originally filed, which states in relevant part: “Spraying at a temperature towards the upper end of this region, such as about 50 to about 65°C may avoid the requirement of a separate curing/coalescing step as outlined below.” Para. [0226]. Applicant is reminded that “[d]uring patent examination, the pending claims must be ‘given their broadest reasonable interpretation consistent with the specification.’” MPEP § 2111, quoting Phillips v. AWH Corp., 415 F.3d 1303, 1316 (Fed. Cir. 2005) (en banc).
Claim 2, as recently amended, now recites the following product-by-process limitation: “wherein the polymeric blend is cured by heating at about 55°C to about 75°C for at least about 1 hour to form a single polymeric phase coating.” Emphasis added. It is well established that product-by-process limitations do not require the manipulations of the recited steps, only the structure implied by the steps. MPEP § 2113(I). As suggested by paragraph [0226] of Applicant’s specification (quoted above), the curing step now recited in claim 2 does not appear to yield an extended-release (XR) coating that differs significantly in structure from the XR coating disclosed in Watts (column 11, lines 22-38). MPEP § 2113(II) (“‘The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature’ than when a product is claimed in the conventional fashion.”), quoting In re Fessmann, 489 F.2d 742, 744 (CCPA 1974). In the alternative, Applicant is referred to paragraphs 34-46 of this Office action, which apply the following three optional references to establish it is prima facie obvious to cure the XR coating of Watts by heating at about 55°C to about 75°C for at least about 1 hour: Colorcon-2013, Colorcon-2009, and Oshlack.
In Example 2 (column 11), Watts teaches an enterically-coated capsule containing the sustained-release budesonide beads of Example 1. More specifically, section (b) of Example 2 teaches that the capsule is coated with a solution comprising Eudragit® L100 copolymer and Eudragit® S100 copolymer (Degussa, Darmstadt, Germany). Column 11, lines 52-56. Those are enteric copolymers. Column 9, lines 20-25; column 8, 62-68; and column 1, lines 41-44. Watts even teaches that the enterically-coated capsules of Example 2 “are suitable for use in the treatment of glomerulonephritis.” Column 12, lines 1-2. The examiner notes that Immunoglobulin A (IgA) nephropathy, commonly referred to as Berger disease, has been widely recognized as the most common form of primary glomerulonephritis worldwide since at least as early as the effective filing date of the present application. Fellstrom at page 2117, left column (quoted above).
Before the effective filing date of the claimed invention, the teachings of Calliditas Therapeutics would have motivated a person having ordinary skill in the art to modify Fellstrom by orally administering the enteric budesonide capsules of Example 2 of Watts to a patient suffering from IgA nephropathy. The foregoing modification would have been made with a reasonable expectation of success in treating IgA nephropathy because Example 2 is essentially identified as Nefecon® (TRF-budesonide) in Calliditas Therapeutics, especially considering no other exemplary budesonide formulation in final form (i.e., ready or otherwise intended for administration to the patient) is disclosed in Watts. Figure 23A of the present application provides additional (but non-critical) evidence that Nefecon® satisfies the release profile now recited in claim 2, i.e., “wherein together the enteric coating and the single polymeric phase coating are sufficient to release at least 90% of the budesonide to the ileum region of the small intestine.” Therefore, claims 2-3, 7-8, 11-13, 21, and 25 are prima facie obvious.
The three references discussed below — i.e., Colorcon-2013, Colorcon-2009, and Oshlack — apply if and only if the product-by-process step of curing now recited in claim 2 actually yields an XR coating structure that differs significantly from Watts.
Colorcon-2013 is a technical information sheet directed to Surelease®.
Colorcon-2013 teaches: “Surelease® Ethylcellulose Dispersion Type B NF, is optimally plasticized for modified release and taste masking applications. Using ethylcellulose as the rate controlling polymer, Surelease delivers dependable and reproducible extended release profiles that are consistent from laboratory to pilot and production scale processes.” Page 1.
Colorcon-2013 teaches: “Need of curing to achieve stable drug release profile during storage must be evaluated on a case by case basis. Curing of the film may not be necessary when processed under recommended conditions.” Page 1 (emphasis added).
Colorcon-2009 is a technical brochure directed to Surelease®.
Colorcon-2009 teaches: “Tests have shown that a curing step is not normally necessary with SURELEASE, however, if the SURELEASE coating has been modified or if the coating process has not been fully optimised, additional film coalescence may occur over time. It is recommended that the effect of curing on film coalescence be investigated during initial studies. One hour in an oven at 60°C is usually sufficient.” Page 5/C/06 (emphasis added); see also page 5/C/03 at Figure (showing how “full coalescence” yields a polymeric film having a single phase).
Oshlack is directed to “[c]ontrolled-release formulations coated with aqueous dispersions of ethylcellulose.” Title.
Oshlack teaches: ‘When coating using aqueous polymeric dispersions to obtain a desired release profile of the active agent(s) over several hours or longer, it is known in the art that the dissolution release profile changes on ageing, e.g. when the final coated product is stored for a period of time, during which time it may be exposed to elevated temperature and/or humidity above ambient conditions.” Column 2, lines 28-35.
Oshlack focuses on commercially-available aqueous dispersions of ethylcellulose, specifically, Aquacoat® (FMC Corp.) and Surelease® (Colorcon, Inc.). Column 8, lines 47-66; see also column 10, lines 2-5.
Oshlack teaches that curing the ethylcellulose coating “provide[s] a stable dissolution profile (e.g., release of the active agent in the environment of use) when stored for extended periods of time at room temperature and ambient humidity (e.g., long term (real time) testing), and when tested under accelerated storage conditions.” Column 6, lines 42-48; see also column 4, lines 51-60 (“said coated substrate being cured to cause individual ethylcellulose particles in said coating to coalesce and to gradually slow the release of said active agent when exposed to an environmental fluid…after exposing the cured, coated substrate to accelerated storage conditions”).
Oshlack teaches that if the coalescence process is not complete, variability in release rates will result. Column 9, lines 11-13.
Oshlack teaches that “the beads which have been overcoated with the aqueous dispersion of plasticized ethylcellulose are stabilized via an oven curing conducted at a temperature of about 60° C. and a relative humidity from about 60% to about 100% for a time period from about 48 to about 72 hours.” Column 10, lines 48-54. “However, one skilled in the art will recognize that necessary curing conditions will be affected by the particular drug incorporated in the formulation, as well as by the thickness of the controlled release coating, the size of the substrate (e.g., beads as compared to tablets).” Column 10, lines 57-61. “It is especially contemplated that the time period needed for curing to an endpoint as described above may actually be longer or shorter than the 48-72 hour time period mentioned above.” Column 10, lines 62-65.
Before the effective filing date of the claimed invention, the collective teachings of Colorcon-2013, Colorcon-2009, and Oshlack would have motivated a person having ordinary skill in the art to cure the Surelease® coating of Watts at a temperature of about 60°C for at least one hour, in an effort to yield a budesonide formulation having a release profile that remains stable when stored for extended periods of time at room temperature and ambient humidity. Therefore, claims 2-3, 7-8, 11-13, 21, and 25 are prima facie obvious, even if the product-by-process step of curing now recited in claim 2 results in a significant structural difference.
Regarding claims 5-6, Watts teaches: “Commercial sources of methacrylic acid-methyl methacrylate copolymer (1:1) and methacrylic acid-methyl methacrylate copolymer (1:2) are Eudragit® L100 copolymer and Eudragit® S100 copolymer respectively (Degussa, Germany).” Column 9, lines 21-25; see also Section (b) of Example 2.
Regarding claims 14-16, the polymer blend of the controlled-release layer of Section (iv) of Example 1 of Watts comprises about 83 wt% ethylcellulose (225/270 grams) and about 17 wt% water-soluble polymers HPMC/PEG (45/270 grams). MPEP § 2144.05(I) (overlapping, approaching, and similar ranges, amounts, and proportions).
Regarding claims 17-19, as established above, Watts discloses that 4 kg of budesonide cores are coated with 778 g of the extended-release polymeric blend (ethylcellulose/HPMC/PEG). The calculation of 778 g / (778 g + 4,000 g) yields a weight percentage of 16.3%, which lies inside — or is close to — the concentration ranges recited respectively in claims 17-19. MPEP § 2144.05(I) (overlapping, approaching, and similar ranges, amounts, and proportions).
Regarding claim 24, Watts teaches: “To provide delayed release of the sustained release component either the sustained release component or the capsule in which it is contained is treated, for example coated, with a material that substantially prevents release of the sustained release component until the composition reaches the intestine, for example the lower small intestine.” (Emphasis added) Column 8, lines 52-57.
Regarding claims 26-28, Watts teaches: “Expressed as mg of coating per cm2 of surface area, the amount of delayed release coating on a capsule or the sustained release component is preferably from about 1 to about 30 mg/cm2, more preferably from about 2 to about 25 mg/cm2 and most preferably from about 3 to about 20 mg/cm2. Thus, a capsule with a surface area of about 5 cm2 most preferably contains from about 15 to about 100 mg of coating.” (Emphasis added) Column 9, lines 39-45; see also column 9, lines 49-51 (“a coating layer of from about 6 to 10 mg/cm2 may be suitable for a dosage form intended for use in the treatment of glomerulonephritis”) and MPEP § 2144.05(I) (“In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.”).
Regarding claim 29, Example 2 of Watts uses size 0 capsules (column 11, lines 46-48), which are close enough to size 1 capsules to support a finding of prima facie obviousness. MPEP § 2144.05(I) (“a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close”).
Regarding claim 30, Watts teaches that each capsule of Example 2 comprises 4 mg of budesonide. Column 11, lines 48-50.
Regarding claim 31, Applicant is referred to Watts at column 3, lines 60-66, where the desired release profile for treatment of glomerulonephritis is set forth.
Conclusion
Claims 2-3, 5-8, 11-19, 21, and 24-31 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PETER ANTHOPOLOS whose telephone number is 571-270-5989. The examiner can normally be reached on Monday – Friday (9:00 am – 5:00 pm). If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany P. Barham, can be reached on Monday – Friday (9:00 am – 5:00 pm) at 571-272-6175. The fax number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.A./
15 September 2026
/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
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