DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status
Claims 1-2, 4-6, and 8-27 are pending. Claims 2 and 10-27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species (Claim 2) and invention (Claims 10-27). Therefore, Claims 1, 4-6, 8, and 9 are presented for examination.
Election/Restrictions
Applicant elected without traverse Group I (microcapsule pharmaceutical preparation),
everolimus as the rapamycin analog species,
methyl-methacrylate acid copolymer as the composition coating species and
non-steroidal inflammatory drug as the composition core species
in the reply filed on 5/26/2023.
Claim 2 is now withdrawn because Claim 1 has been amended to recite methyl-methacrylate acid copolymer as the elected coating species. Claim 2 attempts to include additional coating species beyond what Applicant elected in the 5/26/2023 response to the restriction requirement.
Claims 2 and 10-27 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species (Claim 2) and invention (Claims 10-27).
Priority
This application is a continuation of U.S. Application No. 16/552,380, filed on August 27, 2019, which is a continuation of U.S. Application No. 13/128,800 filed on May 11, 2011, which is a national phase application under 35 U.S.C. § 371 of International Application No. PCT/US2009/064044 filed on November 11, 2009, which claims priority to U.S. Application No. 61/113,481 filed on November 11, 2008.
Information Disclosure Statement
No Information Disclosure Statement was filed with Applicant’s remarks.
Specification
The substitute specification filed 10/29/2025 is entered.
Withdrawn Claim Rejections
Claim 2 was rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite. Applicant’s amendment and corresponding reply pertaining to the newly added limitation have overcome the indefiniteness rejection made of record in the previous Office Action, specifically, the removal of the Eudragit limitation from Claim 2.
Claim Rejections - 35 USC § 103
Maintained, slightly modified to address amendments
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 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.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1, 4-6, 8, and 9 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Patel (US 2003/0215496 – 12/8/2021 IDS) in view of SANDOZ (WO 96/13273).
Claimed invention
The claims are drawn to a microcapsule pharmaceutical preparation, comprising:
a core component comprising a rapamycin analog such as everolimus; and
a solid excipient matrix comprising an enteric coating material, wherein said rapamycin is microencapsulated by said enteric coating material, and
wherein said enteric coating material remains intact at a pH level of about or less than 7, and
wherein said enteric coating material comprises a methyl methacrylate-methacrylic acid copolymer, wherein the microcapsule pharmaceutical preparation comprises at least about 0.1% by weight to 5% by weight of the inhibitor of mTOR.
Prior art
Patel teaches solid pharmaceutical compositions for improved delivery of a wide variety of pharmaceutical active ingredients. See abstract; see also Claim 53. The compositions of the invention can be used for improved delivery of hydrophilic or hydrophobic pharmaceutical active ingredients, such as drugs, nutritional agents, cosmeceuticals and diagnostic agents. See abstract. The solid includes a substrate that may contain the active ingredient (see 0116-0117) in an encapsulating coat for enteric delivery. See abstract; Claim 53; see also 0169, 0173. Most preferred hydrophobic active ingredients include, inter alia, rapamycin, tacrolimus and sirolimus and pharmaceutically acceptable salts, isomers, and derivatives thereof. See 0039.
Patel further teaches a specific composition comprising about 8% rapamycin. See 0039, Claim 27; see also Example 21 at 0302. Any coatings should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above. See 0182. One example is Shellac, also called purified lac, a refined product obtained from the resinous secretion of an insect and dissolves in media of pH >7, i.e., remains intact at pH level of about or less than 7.
While Patel teaches a pharmaceutically composition comprising an active agent and a solid substrate core encapsulated for enteric delivery, Patel does not expressly teach
1) the claimed rapamycin analog (e.g., everolimus) as the active, or
2) the rapamycin analog encapsulated in the core inside of an enteric coating that remains intact at a pH of about or less than 7.
Regarding 1), the rapamycin analog encapsulated in the core inside of an enteric coating that remains intact at a pH of about or less than 7, however, Patel further states that the compositions of the invention are coated. Cellulose acetate phthalate is disclosed as a suitable coating. See 0185. The coatings comprising acrylic polymers are preferred. See 0184. They include EUDRAGIT (i.e., methyl methacrylate methacrylic acid copolymer) including series S (EUDRAGIT-S), which is insoluble in the stomach but dissolves in the intestine to release the drug for enteric delivery and is soluble at pH 7.0 and above, i.e., the pH generally found in the colon. See 0182, 0184, 0192. One of ordinary skill in the art would have found it obvious to coat a core containing the active ingredient such as rapamycin or a derivative thereof in a composition with cellulose acetate phthalate or EUDRAGIT-S because Patel teaches the compositions contain a substrate that contain an active ingredient (e.g., rapamycin or a derivative thereof), wherein the substrate is further encapsulated with a coating containing the cellulose acetate phthalate or EUDRAGIT copolymer that delivers the active enterically such as EUDRAGIT-S. The artisan would have reasonably understood that the delivery of the active composition can be tailored for delivery through the colon by coating the active composition with EUDRAGIT-S.
Regarding 2), the claimed rapamycin analog (e.g., everolimus) as the active. Further given that the compositions of Patel are for improved delivery of a wide variety of active ingredients or their derivatives including hydrophobic active ingredients like rapamycin, one of ordinary skill in the art would have found it obvious to incorporate other rapamycin derivatives in order to deliver the derivative using known techniques. SANDOZ discovered O-alkylated rapamycin derivatives and their use as immunosuppressants similar to rapamycin. See title; abstract; see also paragraph bridging pages 1 and 2. SANDOZ teaches rapamycin has a macrolide structure and is highly insoluble, making it difficult to formulate stable galenic compositions. See SANDOZ, p. 2. SANDOZ teaches 40-O-(-hydroxy)ethyl-rapamycin (i.e., everolimus) as an example of the macrolide rapamycin derivative. See SANDOZ, p.3. The macrolide may be present in an amount of 1 to 15 % by weight of the composition. SANDOV, p. 16. One of ordinary skill in the art would have found it obvious to incorporate the macrolide, everolimus, as a derivative of rapamycin into a core encapsulated by EUDRAGIT-S. The artisan would have added it as a derivative with a reasonable expectation of success that the composition would deliver everolimus through the colon because Patel teaches that the formulation is used for a wide variety of drugs including hydrophilic and hydrophobic compounds. The artisan would have found the claimed 0.1-5% concentration obvious because both references teach the presence of the macrolide active in defined weight percentages within pharmaceutical compositions and SANDOV particularly discloses a range (1-15%) of everolimus that overlaps the claimed range (0.1-5%). In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. MPEP 2144.05 [R5]. Note, while the prior art does not disclose the exact claimed values, but does overlap, in such instances even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
Claim 4 limits Claim 1, wherein said microcapsule pharmaceutical preparation further comprises at least one additional compound, wherein the at least one additional compound is vitamin E, vitamin A, an antibacterial antibiotic, an antioxidant, L-carnitine, lipoic acid, metformin, resveratrol, leptin, a non-steroid anti- inflammatory drug, or a COX inhibitor. COX inhibitors, celecoxib, rofecoxib are all examples of active ingredients that can be added to the composition. See 0035-037. This meets the limitations of Claims 8 and 9.
Claim 5 is drawn to a pharmaceutical or nutraceutical composition comprising the microcapsule pharmaceutical preparation of claim 1 for treating or preventing a malady in a mammalian subject, wherein the lifespan expectancy of said mammalian subject is prolonged. Patel teaches the pharmaceutical composition comprising the microcapsule pharmaceutical preparation as outlined above. It is further noted that the limitation for treating or preventing a malady in a mammalian subject, wherein the lifespan expectancy of said mammalian is considered to be an intended use that does not add any patentable weight to the product claimed. In this regard, Claim 6, which limits Claim 5, wherein said malady is selected from the Markush group of options do not add patentable weight to the claimed invention.
Response to argument
Applicant's arguments have been fully considered but have not been found to be persuasive.
Applicant argues that Patel does not teach rapamycin analogs and there is no motivation to substitute everolimus. However, Patel teaches microencapsulated rapamycin and enteric coatings comprising EUDGRAGIT®. SANDOZ teaches macrolides including rapamycin derivatives (e.g., everolimus) as immunosuppressants similar to rapamycin. Given that their similar purpose constitutes a predictable use, a POSA would have found it obvious to substitute everolimus for the rapamycin present in the composition disclosed by Patel.
Applicant contends that Patel discloses numerous formulation options and provides no guidance toward the claimed embodiment. However, Patel does not merely list unrelated elements. It teaches rapamycin as an active agent and microencapsulation of a core containing the active with an enteric coating that dissolves at or above a pH of 7, particularly, EUDRAGIT-S. Thus, Patel teaches the same product structure recited in the claims. The rejection does not rely on selecting isolated elements from unrelated lists, but on combining expressly taught formulation components for their disclosed purpose of controlled intestinal release.
Regarding Applicant’s arguments that the prior art does not teach the newly recited concentration range of ~1% to 5% by weight, SANDOZ teaches that macrolides including everolimus may be present at about 1-15% by weight in the composition. Because the disclosed concentration range of the reference overlaps the claimed range, the claimed range is prima facie obvious.
Applicant references a 2015 declaration as support for arguments that the claimed invention obtains unexpected results including increasing lifespan and increased blood levels of encapsulated rapamycin. However, there is no declaration on the record of the current application. When any claim of an application or a patent under reexamination is rejected or objected to, any evidence submitted to traverse the rejection or objection on a basis not otherwise provided for must be by way of an oath or declaration under this section. See MPEP § 716. Because no declaration has been filed in response to the 35 U.S.C. 103 rejection made in the previous Office action, Applicant’s arguments of obtaining unexpected results are not persuasive.
Applicant argues that Sandoz teaches away from everolimus because it is unstable and undesirable with low bioavailability. This is not persuasive because everolimus is used as an active by Sandoz and Patel teaches formulations that aid in bioavailability of active ingredients.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached on (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622