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 .1
Status of the Claims
Claims 1, 2 and 16-21 are pending in this application. Examination is based on Applicant’s previous election without traverse of Group I, claims 1-13 in the reply filed on Jan. 31, 2024 is acknowledged.
Applicants election of a species, drawn to a pharmaceutical composition for administration to a body orifice, comprising a compound of formula (I), also known as Indomethacin.
Information Disclosure Statement
At this time an IDS has NOT been filed by Applicant.
Response to Arguments
Applicant’s arguments and amendments, filed September 25, 2025, with respect to Claims 16, 17 and 19 were rejected under 35 U.S.C. § 112(b), as being indefinite have been fully considered and are persuasive. The rejection of Claims 16, 17 and 19 has been withdrawn.
Applicant’s arguments, filed September 25, 2025, with respect to the rejection of Claims 1 and 2 under 35 U.S.C. § 103, unpatentable over Zhang et al. Acta Pharmacol. Sin. 2006 Aug; 27 (8): 1097-1102) in view of USP lndomethacin Suppositories 2019 and US Pub 20040092498 Al (US Pub '498) have been fully considered but not persuasive. See below response to Attorney arguments.
Applicant’s arguments, filed September 25, 2025, with respect to the rejection of Claims 1, 2 and 19 under § 35 U.S.C. 103 as being unpatentable over Zhang et al. Acta Pharmacol. Sin. 2006 Aug; 27 (8): 1097-1102) in view of USP lndomethacin Suppositories 2019, and US Pub 20040092498 A1 (US Pub '498) in further view of US Patent 4,681,858 ('858 patent) have been fully considered and are persuasive. However, see below, the new rejections in view of Zhang, USP Indomethacin Suppository 2019, and US Pub ‘498, as evidenced by SciFinder substance pages CAS Reg. No. 85665-33-4 or 67701-26-2.
Applicant’s arguments, filed September 25, 2025, with respect to the rejection of Claims 1, 2, 16-18 and 20-21 are rejected under§ 35 U.S.C. 103 as being unpatentable over Zhang et al. Acta Pharmacol. Sin. 2006 Aug; 27 (8): 1097-1102) in view of USP lndomethacin Suppositories 2019, and US Pub 20040092498 A1 (US Pub '498) in further view of US Patent 4,681,858 ('858 patent) have been fully considered but are not persuasive. See below response to Attorney arguments.
New Claim Rejections Necessitated by Amendment - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1 and 2 remain rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. “Biotransformation of indomethacin by the fungus Cunninghamella blakesleeana,” Acta Pharmacol. Sin. 2006 Aug; 27 (8): 1097–1102) in view of USP Indomethacin Suppositories 2019 and US Pub 20040092498 A1 (US Pub 498). Zhang, USP Indomethacin Suppositories 2019 and US Pub 498 were previously cited by the Examiner.
Examined claim 1 is directed to a pharmaceutical composition for administration to a body orifice as a suppository, consisting of a compound of formula (I), also known as Indomethacin, or a pharmaceutically acceptable salt thereof having a purity of about 99.5% or more as measured by HPLC, and a base material, acceptable salt thereof having a purity of about 99.5% or more as measured by HPLC, and a base material, wherein the base material is a hard fat which is a mixture of triglycerides C10-C18 and/or triglycerides C12-18.
Regarding claim 1 and the indomethacin impurity limitation of about 99.5% or more and less than 0.3 %, Zhang 2006 discloses its indomethacin was 99.5% pure and purchased from Dongyu Pharmaceutical (Shenyang China). See page 1098, column 1, reproduced below.
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Zhang 2006 teaches that indomethacin is a NSAID agent with anti-pyretic and analgesic properties “extensively used because of its pharmaceutical properties.” See page 1097, column 1.
While Zhang 2006 teaches the suitability of indomethacin for use in pharmaceutical compositions, it does not teach the limitation where the pharmaceutical composition suitable for administration to body orifice, for example a suppository, where purity would be measure by HP Liquid Chromatography (HPLC), as per USP Indomethacin Suppos. 2019 below.
USP Indomethacin Suppositories 2019 teaches the claimed indomethacin as suppositories which are known to be administered to a body orifice. See page 1. A person having ordinary skill in the art (PHOSITA) would formulate such suppositories, based off the teachings of Zhang 2006 which teaches bulk indomethacin with a known pharmaceutical utility that is 99.5% pure and USP Indomethacin Suppositories 2019 teach pharmaceutical compositions suitable for administration to a body orifice. Further, USP Indomethacin Suppositories 2019 teaches evaluating Indomethacin suppositories by liquid chromatography (LC) assay procedures, as per USP Chapter <621> Chromatography. See page 2, column 1 reproduced below.
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Further, with regard to the limitation that that the claimed suppository consist of indomethacin and the hard fat suppository base, the formulation of suppositories consisting only of an active ingredient and a hard fat suppository base is well known to a PHOSITA as taught by US Pub 498, where a suppository formulation consisting only of active ingredient and a hard fat base is taught. See between paragraphs 305-306 reproduced below of US Pub ‘498.
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Furthermore US Pub ‘498 teaches an active ingredient of choice is indomethacin. See paragraph 96 that discloses NSAID drugs as active ingredients, including indomethacin.
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of the primary reference Zhang 2006 regarding nearly pure indomethacin (99.5% pure as identified by liquid chromatography, LC) to modify with the secondary and tertiary references to be formulated into indomethacin suppositories as per USP Indomethacin Suppositories 2019 and US Pub ‘498, where saponified triglycerides (i.e. hard fats) are known in the prior art are known, and hard fats, are known to be used in suppositories.
The PHOSITA would have had a reasonable expectation of success because the rationale to do so combining prior art elements according to known methods to yield predictable results, i.e., pure indomethacin, known to be combined by prior art methods to formulate hard fat suppositories.
Claim 2 recites an indomethacin purity of about 99.9% as measured by HPLC. Zhang 2006 discloses its indomethacin was 99.5% pure and purchased from Dongyu Pharmaceutical (Shenyang China), (page 1098, column 1) and a pharmaceutical composition for administration to a body orifice (as per USP Indomethacin Suppositories 2019) as detailed above. With regard to the functional descriptive limitation where purity of 99.5% is determined by HPLC, it would be routine for a PHOSITA to optimize via known methods of HPLC to arrive at claimed purity or 99.5% or more of indomethacin. The general condition of purity of 99.5% or more are known in the prior art so as it would be routine to arrive at such claimed purity range via routine optimization2 by known methods such as HPLC times as per RRT as per USP Indomethacin suppositories 2019.
Claims 1, 2 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. “Biotransformation of indomethacin by the fungus Cunninghamella blakesleeana,” Acta Pharmacol. Sin. 2006 Aug; 27 (8): 1097–1102) in view of USP Indomethacin Suppositories 2019, and US Pub 20040092498 A1 (US Pub 498) as evidenced by SciFinder substance pages CAS Reg. No. 85665-33-4 or 67701-26-2.
Zhang, USP Indomethacin Suppositories 2019 and US Pub ‘498 were previously cited by the Examiner. The SciFinder substances pages are cited on the PTO-892 form.
As discussed above, the combination of cited prior art (Zhang ,USP Indomethacin Suppositories 2019, and US Pub 498) provides a PHOSITA a reasonable expectation of success to arrive at the claimed invention, a suppository consisting of indomethacin and a hard fat with the claimed 99.5% purity as determined by HPLC. Thus claims 1 and 2 are rendered obvious by these references as discussed above.
The particular species of claim 19, is not taught by the teachings of Zhang, USP Suppository and US Pub ‘498. This species of claim 19 is noted to be taught by the previously cited references in further view of the ‘858 patent as detailed below.
Claim 19 is directed to a pharmaceutical composition wherein the composition comprises a hard fat having a melting point in the range of 33.5°C and 37.0° C, an hydroxyl value less than equal to 10mg KOH/g, a free fatty acid content (as oleic acid) less than equal to 0.1 % and a saponification value comprised between 236 and 248mg KOH/g.
In terms of claim interpretation, an embodiment of the formulation claimed, indomethacin with hard fat NF at paragraphs Example 1, Table 1 at page 9 of the specification. In fact, the specification describes hard fat having the limitations of claim 1 with regard to the melting point and so forth, along with the claimed CAS Reg. Nos. See page 6, lines 10-15 as detailed below.
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Further, with regard to the limitation that that the claimed suppository consist of indomethacin and the hard fat suppository base, the formulation of suppositories consisting only of an active ingredient and a hard fat suppository base is well known to a PHOSITA as taught by US Pub 498, where a suppository formulation consisting only of active ingredient and a hard fat base is taught. See between paragraphs 305-306 reproduced below of US Pub ‘498.
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Furthermore US Pub ‘498 teaches an active ingredient of choice is indomethacin. See paragraph 96 that discloses NSAID drugs as active ingredients, including indomethacin.
With regard to the particular limitations of claim 19 and the identification of the hard fat, that such limitations of melting point, hydroxyl value, free fatty acid content and saponification value are associated with mixtures of triglycerides with CAS Reg. No. 85665-33-4 OR CAS Reg. No. 67701-26-2 and known in the prior art as reproduced below. Both saponified triglycerides are known in the art, prior to the invention of the claimed invention, as commercially available EUTECTOL M® pellets as admitted in the specification as reproduced above. See page 6. Accordingly, prior at disclosing the saponified triglycerides (CAS Reg. No. 85665-33-4 or 67701-26-2) into suppositories, will be relevant in the prior art obviousness analysis.
Note that both saponified triglycerides are known in the art as evidenced by SciFinder substance pages for both CAS Reg. No. 85665-33-4 or 67701-26-2, where both were registered with the European Union EINECS (Eur. Inventory of Existing Commercial Chemical Substances) as far back as June 1990. See page 3 of both SciFinder substance data pages.
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of the primary reference Zhang 2006 regarding nearly pure indomethacin (99.5% pure as identified by liquid chromatography, LC) to modify with the secondary and tertiary references to be formulated into indomethacin suppositories as per USP Indomethacin Suppositories 2019 and US Pub ‘498, where saponified triglycerides (i.e. hard fats) are known in the prior art are known, and hard fats, are known to be used in suppositories, where the particular hard fat species per claim 19 is known in the art.
The PHOSITA would have had a reasonable expectation of success because the rationale to do so combining prior art elements according to known methods to yield predictable results, i.e., pure indomethacin, known to be combined by prior art methods to formulate hard fat suppositories, with the particular species of claim 19.
Claims 1, 2, 16-18 and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. “Biotransformation of indomethacin by the fungus Cunninghamella blakesleeana,” Acta Pharmacol. Sin. 2006 Aug; 27 (8): 1097–1102) in view of USP Indomethacin Suppositories 2019 and US Pub 20040092498 A1 (US Pub 498) in further view of US 3644630 A (‘630 patent).
Zhang, USP Indomethacin Suppositories 2019, US Pub 498 and the 630 patent were previously cited by the Examiner.
As discussed above, the combination of cited prior art (Zhang ,USP Indomethacin Suppositories 2019, and US Pub 498) provides a PHOSITA a reasonable expectation of success to arrive at the claimed invention, a suppository consisting of indomethacin and a hard fat with the claimed 99.5% purity as determined by HPLC. Thus claims 1 and 2 are rendered obvious by these references as discussed above.
However, it is noted that certain species of claim 1, where such species are defined by claims 16-18 and 20-21 are not taught by the teachings of Zhang, USP Indomethacin Suppositories 2019 and the US Pub 498. These species of claims 16-18 and 20-21 are noted to be taught by the previously cited art in further view of the ‘630 patent as detailed below.
Claims 16-17 recites the limitations wherein the composition comprises
about 1 % to about 10% by weight of indomethacin (formula (I)) and about 90% to about 99% by weight of a base material (claim 16)
about 1 % to about 5% by weight of indomethacin (formula (I)) and about 95% to about 99% by weight of a base material (claim 17).
The ‘630 patent discloses indomethacin suppositories, where 6.8% to 7.0 % indomethacin (approximating the about limitations of claim 7) is found in a suppository, see Table of column 2.
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As per the Table of column 2 above, noting indomethacin concentrations in values of 6.8 to 7.0 %, it would be routine for one of ordinary skill in the art adjust amounts of indomethacin in suppositories to approximate about 1-10% and about 1-5% by weight as claimed. Per MPEP 2144.05 II, the routine optimization of ranges through routine experimentation supports a prima face case of obviousness, citing to In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The 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.")
Regarding claim 18 and the ranges of indomethacin to hard fat claimed about to pharmaceutical compositions where they contain about 3.125% indomethacin (about 50 mg/about 1600 mg) in the suppository to about 6.25% indomethacin (about 100 mg/about 1600 mg) in the suppository. As per the Table of column 2 above, noting indomethacin concentrations in values of 6.8 to 7.0 %, it would be routine for one of ordinary skill in the art adjust amounts (via routine optimization, note MPEP 2144.05 II.) of indomethacin in suppositories to approximate about 100 mg/ about 1600 mg (about 6.25%).
Claim 20 is directed to a pharmaceutical composition consisting of about 1 to about 10% of indomethacin (or a pharmaceutically acceptable salt), having a purity of about 99.5% or more as measured by HPLC, and about 90% to about 99% by weight of a base material, wherein the base material is a mixture of triglycerides C10-C18 and/or triglycerides C12-C18; wherein the composition releases at least about 70% or more of the compound (I) within 90 minutes when analyzed with USP apparatus II, adopting a dissolution media comprising a buffered 0.1M phosphate solution having a pH in the range of about 7.0 to about 7.4 and maintained at 40°C.
As discussed above, the combination of cited prior art (Zhang ,USP Indomethacin Suppositories 2019 and US Pub 498) provides a PHOSITA a reasonable expectation of success to arrive at the claimed invention of claim 20, a suppository consisting of indomethacin and a hard fat with the claimed 99.5% purity as determined by HPLC.
The limitation of about 1-10% indomethacin is taught by the ‘630 as discussed above.
With regard to the functional descriptive limitation of composition release when analyzed with USP apparatus II of claim 20, this limitation is necessarily present in the composition as taught by the cited prior art.
Claim 21 discloses a pharmaceutical composition for administration to a body orifice as a suppository, comprises consisting of a compound of formula (I), also known as Indomethacin, or a pharmaceutically acceptable salt thereof having a purity of about 99.5% or more as measured by HPLC, wherein the composition comprises from about 50 mg to about 100 mg of compound (I) and about 1600 mg of EUTECTOL grade hard fat NF hard fat, which is a mixture of triglycerides C10-C18 and/or triglycerides C12-C18.
As discussed above, the combination of cited prior art (Zhang ,USP Indomethacin Suppositories 2019 and US Pub 498) provides a PHOSITA a reasonable expectation of success to arrive at the claimed invention of claim 21, a suppository consisting of indomethacin and a hard fat with the claimed 99.5% purity as determined by HPLC.
The limitation of about 50 mg to about 100 mg of indomethacin and about 1600 mg hard fat is taught by the ‘630 as discussed above. As per the Table of column 2 above, noting indomethacin concentrations in values of 6.8 to 7.0 %, it would be routine for one of ordinary skill in the art adjust amounts (via routine optimization)3 of indomethacin in suppositories to approximate about 100 mg/ about 1600 mg (about 6.25%).
With regard to the functional descriptive limitation of composition release when analyzed with USP apparatus II of claim 21, this composition release limitation is necessarily present in the composition as taught by the cited prior art.
Prior to the filing of the present patent application, it would have been prima facie obvious to a PHOSITA following the teachings of the primary reference Zhang 2006 regarding nearly pure indomethacin (99.5% pure as identified by liquid chromatography, LC) to modify with the secondary and tertiary references to be formulated into indomethacin suppositories as per USP Indomethacin Suppositories 2019 and US Pub ‘498, where saponified triglycerides (i.e. hard fats) are known in the prior art are known, and hard fats, are known to be used in suppositories, where the particular concentrations and amounts of indomethacin and hard fat are known in the prior art, per ‘630 patent.
The PHOSITA would have had a reasonable expectation of success because the rationale to do so combining prior art elements according to known methods to yield predictable results, i.e., pure indomethacin, known to be combined by prior art methods to formulate hard fat suppositories, where the particular concentrations and amounts of indomethacin and hard fat are known in the prior art, per ‘630 patent.
RESPONSE TO ATTORNEY ARGUMENTS:
The Attorney response states use of the transitional phrase "consisting of' excludes any other ingredients that would materially affect the basic and novel characteristics of the composition.
The Attorney response states prior art, as discussed below, teaches away from such a simple formulation, suggesting that additional components are necessary to create a stable and effective product, particularly when using a highly pure active pharmaceutical ingredient (API).
In response, it is noted that even with the use of the transition phrase “consisting of” a PHOSITA would routinely optimize the teachings of US Pub 498 where a suppository formulation consists only of an active ingredient and a hard fat base, as reproduced below. See paragraphs 305-306.
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The Attorney response argues Zhang is from a non-analogous field of art, where the invention is a pharmaceutical formulation, and Zhang is microbial biochemistry and drug metabolism, (the prevention of degradation and ensuring long term stability of the API in a dosage form vs. induction and study of degradation of the API). See between paragraphs 305-306 of US Pub ‘498.
In response, despite the statements regarding Zhang being from a non-analogous field of art, its teachings can be relied upon a PHOSITA in the formulation of indomethacin dosage forms, as Zhang establishes the suitability of indomethacin for use in pharmaceutical compositions (99.5% pure), where USP Indomethacin Suppositories teach the use of indomethacin suppositories and US Pub 498 teaches a suppository consisting only of an API and a hard fat base.
The Attorney response states there is no motivation to combine the cited prior art with a reasonable expectation of success. The Attorney response states the Office action pieces together the claimed composition by taking the purity value from Zhang, a general concept of indomethacin suppositories from USP Monograph and a two-component base from US Pub 498. The Attorney response argues that there is teaching or suggestion of combining a highly pure (99.5% or 99.9%) indomethacin with only a hard fast base would result in a stable and effective product.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
A PHOSITA would have a reasonable expectation in looking towards pure indomethacin (99.5% or 99.9%), into indomethacin suppositories, where it would be obvious to formulate indomethacin as the sole API into hard fat suppositories, with no other excipients, as these are all spelled out in the prior art in the rejection detailed above.
The Attorney response rebuts the rejection of claims 1, 2, 16-18 and 20-21 (sic 1, 2 and 19) over Zhang, USP Indomethacin Suppos. 2019, US Pub ‘497 and ‘630 patent.
The Attorney response states the ‘630 patent teaches a fundamentally and non-interchangeable technology, i.e. PEG 4000 and PEG 6000 bases, not hard fat bases, where the skilled artisan would not be motivated to apply the ‘630 patent concentrations ranges to a hard fat based suppository.
In response to applicant's argument that the ‘630 patent is nonanalogous art, it has been held that a prior art reference must either be in the field of applicant’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the applicant was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, the ‘630 patent is in the field of Applicant’s endeavor, to form indomethacin suppositories, which are physically and chemically stable. See Applicant’s specification, page 2, first full paragraph; and ‘630 patent, column 1 lines 44-46. While choice of the particular suppository carrier varies, both the claimed invention and the teachings of the ‘630 patent both are directed to form physically and chemically stable indomethacin suppositories.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, as detailed above, both the ‘630 patent and claimed invention are both directed to physically and chemically stable indomethacin suppositories.
Conclusion and Correspondence
In summary, no claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/ Supervisory Patent Examiner, Art Unit 1623
1 This application is a Continuation of U.S. Patent Application No. 17/869,346, filed July 20, 2022, which is hereby incorporated by reference in its entirety.
2 MPEP 2144.05 II. A. Optimization Within Prior Art Conditions or Through Routine Experimentation
“[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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955
3 Per MPEP 2144.05 II, the routine optimization of ranges through routine experimentation supports a prima face case of obviousness, citing to In re Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The 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.")