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 action is in response to Applicant’s amendment filed November 12, 2025 in reply to the First Office Action on the Merits mailed August 18, 2025. Claims 1-5, 7-9, 11, 14-17, 19, 22, and 25-28 have been amended, and claims 6, 10, 12, 13, 18, 20, 21, 23, and 24 have been canceled. Claims 22 and 25 have been withdrawn. 1-5, 7-9, 11, 14-17, 19, and 26-28 are under examination
Withdraw of Prior Objection - Abstract
The abstract filed November 12, 2025 has been satisfactorily amended. Therefore, the objection to the abstract presented in the First Office Action on the Merits mailed August 18, 2025 is hereby withdrawn.
Withdrawal of Prior Objection - Drawings
The figure has been satisfactorily amended on corrected drawing sheets in compliance with 37 CFR 1.121(d). Therefore, the objection to the drawing presented in the First Office Action on the Merits mailed August 18, 2025 is hereby withdrawn.
Withdrawal of Prior Claim Objections
Claims 1-5, 7-9, 11, 14-17, 19, and 26-28 have been satisfactorily amended. Claim 10 has been canceled. Therefore, the objections to these claims presented in the First Office Action on the Merits mailed August 18, 2025 are hereby withdrawn.
Withdraw of Prior Claim Rejections - 35 USC § 112(b)
Claims 8 and 16 have been satisfactorily amended. Therefore, the 35 USC 112(b) rejection presented in the First Office Action on the Merits mailed August 18, 2025 is hereby withdrawn.
Withdrawal of Prior Claim Rejections - 35 USC § 112(d)
Claim 10 has been canceled. Therefore, the 35 USC 112(d) rejection presented in the First Office Action on the Merits mailed August 18, 2025 is hereby withdrawn.
NEW GROUNDS OF REJECTION
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 16 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 16, which depends from claim 1, as now amended, stipulates in a wherein clause that “the obizidine fumarate is in amorphous form or crystalline form”. Claim 1, however, already provides for obizidine fumarate, and one of ordinary skill in the art would understand that the obizidine fumarate is in either amorphous or crystalline form. Indeed, one of ordinary skill in the art would generally understand that if the obizidine fumarate is not in crystalline form, then it is in amorphous form. Therefore, claim 16 does not appear to further limit claim 1 from which it depends.
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 (i.e., changing from AIA to pre-AIA ) 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 1-5, 7-9, 11, 14-17, 19, and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (WIPO International Application Pub. No. WO 2010/102513), in view of Chen et al. (Chinese Patent Application Pub. No. 106344519A), Ren et al. (Chinese Patent Application Pub. No. 102579408A), and Kesisoglou et al. (J Pharm Sci. 2019; 108: 2917-2925).
***This rejection addresses the elected subject matter.
Applicant Claims
Applicant’s elected subject matter is directed to a pellet 0.3-1.5 mm in size comprising i) a core containing amorphous obizidine fumarate particles less than or equal to 50 µm, microcrystalline cellulose, low substituted HPC, sodium carboxymethyl starch, polyvinylpyrrolidone (PVP), and TWEEN-20, ii) an isolation layer comprising HPMC, talcum powder, and glyceryl monostearate, and iii) an enteric layer comprising HPMC acetate succinate, triethyl citrate, talcum powder, and glyceryl monostearate; wherein the core, the isolation layer and the enteric layer comprise 60-78%, 10-20% and 12-20% by mass of the pellet; and wherein the pellet comprises, by weight, 10-30 portions of obizidine fumarate, 4-12 portions microcrystalline cellulose, 0-5 portions sodium carboxymethyl starch, 2-8 portions low substituted HPC, 0-4 portions TWEEN, 0-3 portions PVP, 1-5 portions HPMC, 1-5 portions HPMC acetate succinate, 0-3 portions triethyl citrate, 0-5 portions talcum powder, and 0-0.5 portions glyceryl monostearate.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Liu et al. disclose compositions, such as e.g. an enteric-coated granule, which can comprise e.g. amorphous obizidine fumarate particles, microcrystalline cellulose, disintegrants, polyvinylpyrrolidone (PVP), polyoxyethylene sorbitan fatty acid esters (e.g. TWEEN), and lubricants including talcum powder and stearates.
Chen et al. disclose an enteric-coated pellet (i.e. a spherical granule) 0.5-0.8 mm in size comprising i) a core containing e.g. tandospirone (i.e. a piperazine derivative, active agent), microcrystalline cellulose (i.e. filler), low substituted HPC (i.e. disintegrant), sodium carboxymethyl starch (i.e. disintegrant), and povidone (i.e. PVP, a spheroidal accelerator), ii) an isolation layer comprising HPMC and talcum powder, and iii) an enteric layer comprising HPMC acetate succinate, triethyl citrate, and talcum powder; wherein the core, the isolation layer and the enteric layer comprise 50-80%, 4-10% and 10-27% by mass of the pellet; and wherein the pellet comprises, by weight, 1-30 wt% tandospirone (active agent), 10-80 wt% filler (e.g. microcrystalline cellulose), 8-13 wt% disintegrant (e.g. low substituted HPC), and 0-12 wt% HPMC.
Ren et al. disclose a pellet about 0.6 mm in size comprising i) a core containing doxycycline (i.e. active agent), microcrystalline cellulose, HPC, and povidone (i.e. PVP), ii) an isolation layer comprising HPMC and iii) a sustained-release layer comprising HPMC acetate/or succinate; wherein anti-tack lubricants can include talc, metal stearates, and glyceryl stearate; and the solubilizer can be e.g. TWEEN-20 (i.e. a polyoxyethylene sorbitan fatty acid ester).
Kesisoglou et al. disclose that amorphous drug nanoparticles 100 nm or less in size show improved solubility and bioavailability upon oral administration compared to crystalline drug forms and drug particles 200 nm or larger in size.
Ascertainment of the Difference Between the Scope of the Prior Art and the Claims (MPEP §2141.02)
Liu et al. do not explicitly disclose that the enteric-coated granule/pellet has the specific structure claimed including the isolation layer. This deficiency is cured by the teachings of Chen et al., Ren et al., and Kesisoglou et al..
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious for one of ordinary skill in the art at the time the present application was filed to combine the respective teachings of Liu et al., Chen et al., Ren et al., and Kesisoglou et al., outlined supra, to devise Applicant’s presently claimed pellet.
Liu et al. disclose compositions, such as e.g. an enteric-coated granule, which can comprise e.g. amorphous obizidine fumarate particles, and that obizidine fumarate can be formulated with microcrystalline cellulose, disintegrants, polyvinylpyrrolidone (PVP), polyoxyethylene sorbitan fatty acid esters (e.g. TWEEN), and lubricants including talcum powder and stearates, wherein the composition, upon oral administration, successfully treats cancer. As anyone of ordinary skill in the art would immediately recognize, obizidine fumarate is a piperazine derivative. Since Chen et al. disclose that a piperazine derivative, e.g. tandospirone, can be advantageously formulated as an enteric-coated pellet (i.e. a spherical granule) 0.5-0.8 mm in size comprising i) a core containing the piperazine derivative, microcrystalline cellulose (i.e. filler), low substituted HPC (i.e. disintegrant), sodium carboxymethyl starch (i.e. disintegrant), and povidone (i.e. PVP, a spheroidal accelerator), ii) an isolation layer comprising HPMC and talcum powder, and iii) an enteric layer comprising HPMC acetate succinate, triethyl citrate, and talcum powder; wherein the core, the isolation layer and the enteric layer comprise 50-80%, 4-10% and 10-27% by mass of the pellet to thus provide high drug bioavailability in the intestine and minimal side effects; and since Ren et al. disclose that for a pellet about 0.6 mm in size comprising i) a core containing active agent, microcrystalline cellulose, HPC, and povidone (i.e. PVP), ii) an isolation layer comprising HPMC and iii) a sustained-release layer comprising HPMC acetate/or succinate; anti-tack lubricants can advantageously include glyceryl stearate as well as talc and metal stearates; and that TWEEN-20, i.e. a polyoxyethylene sorbitan fatty acid ester, is a suitable solubilizer; and since Kesisoglou et al. disclose that amorphous drug nanoparticles 100 nm or less in size show improved solubility and bioavailability upon oral administration compared to crystalline drug forms and drug particles 200 nm or larger in size; one of ordinary skill in the art would thus be motivated to formulate obizidine fumarate as an enteric-coated pellet (i.e. a spherical granule) 0.5-0.8 mm in size comprising i) a core containing amorphous obizidine fumarate particles 100 nm or less in size, microcrystalline cellulose (i.e. filler), low substituted HPC (i.e. disintegrant), sodium carboxymethyl starch (i.e. disintegrant), polyvinylpyrrolidone, and TWEEN-20, ii) an isolation layer comprising HPMC, talcum powder, and glyceryl stearate, and iii) an enteric layer comprising HPMC acetate succinate, triethyl citrate, talcum powder, and glyceryl stearate; wherein the core, the isolation layer and the enteric layer comprise 50-80%, 4-10% and 10-27% by mass of the pellet, with the reasonable expectation that the resulting enteric coated pellet will exhibit high drug bioavailability in the intestine and minimal side effects, and that upon oral administration, will successfully treat cancer.
Claim 9 requires 10-30 portions of obizidine fumarate, 4-12 portions of microcrystalline cellulose, and 2-8 portions of low substituted HPC; and claim 14 requires 10-30 portions of obizidine fumarate, 4-12 portions of microcrystalline cellulose, and 2-8 portions of low substituted HPC, 1-5 portions of HPMC, and 1-5 portions of HPMC AS. Chen et al. discloses that the pellet comprises, by weight, 1-30 wt% tandospirone (active agent), 10-80 wt% filler (e.g. microcrystalline cellulose), 8-13 wt% disintegrant (e.g. low substituted HPC), and 0-12 wt% HPMC, and further exemplifies that when HPMC is present at 30 pts, HPMC AS is present at 20 pts. Hence, from the express teachings of Chen et al., one of ordinary skill in the art could arrive at a pellet comprising e.g. 30% piperazine derivative active, 10% microcrystalline cellulose, 8% low-substituted HPC, and 2% HPMC. In view of the example in which HPMC and HPMC AS are present in the ratio of 30:20, or 3:2, the amount of HPMC AS would thus be about 1-2%. Hence, based on 100 parts or portions, this would be equivalent to 30 portions obizidine fumarate, 10 portions microcrystalline cellulose, 8 portions low-substituted HPC, 2 portions HPMC, and 1-2 portions of HPMC AS, which is not patentably distinct from 10-30 portions of obizidine fumarate, 4-12 portions of microcrystalline cellulose, and 2-8 portions of low substituted HPC, 1-5 portions of HPMC, and 1-5 portions of HPMC AS.
In light of the foregoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed November 12, 2025 have been fully considered but they are not persuasive.
i) Applicant contends that “Liu discloses that Formula I and Formula II can be used to prepare enteric-coated granules, but does not explicitly disclose that obizidine fumarate can be used to prepare enteric coated pellet”; that “it is well known that the biological activity of a compound is determined by its chemical structure” and that “differences in biological activity between obizidine fumarate and tandospirone…implies…great structural distinction” between the two compounds, and thus that “the Examiner should not classify both compounds as piperazine derivatives”; that “in fact, although nearly all active pharmaceutical ingredients worldwide could be categorized as carbon-containing compounds…these compounds exhibit vast structural diversities and correspondingly diverse biological activities, making it impossible to extrapolate from one structure to another structure”; that “obizidine fumarate contains a seven-membered piperazine ring, whereas tandospirone contains a six-membered piperazine ring” and “this structural distinction significantly impacts biological activity”, and thus “the two compounds act on different cellular receptors” and “their biological activities are entirely different”; and that “Liu’s Formulas I and II are unstable under acidic conditions…however, paragraph [0005] of Chen discloses that tandospirone is easy to be absorbed in the gastric acid environment, that is, tandospirone is stable under acidic conditions”.
The Examiner, however, would like to point out the following:
1. In stark contrast to Applicant’s assertions, the prior art rejection at issue here is simply not based in any way whatsoever on the premise that obizidine fumarate and tandospirone share the same biological activity. The prior art rejection says nothing at all whatsoever about obizidine fumarate being somehow equivalent to tandospirone in activating the same cellular receptor, triggering the same cellular signaling cascade, and/or treating the same disease.
2. It is a simple fact that would be readily recognized by anyone of ordinary skill in the art that obizidine and tandospirone are piperazine derivatives. This is not the Examiner’s own personal classification scheme, and there has been absolutely no attempt, as Applicant asserts, to somehow “extrapolate” from the structure of tandospirone to the structure of obizidine, or vice versa. Moreover, Applicant’s assertion that because obizidine and tandospirone are known to have unique biological functions implies they must therefore “have great structural distinction” is not found persuasive. Indeed, it is well known in the biological arts that even rather large compounds with almost identical structures, differing only in e.g. a single amino acid, or even e.g. a single methyl group, can have drastically different biological functions.
3. Liu has not been cited for anticipating the presently claimed subject matter. Liu need not provide a specific example or a preferred embodiment in which obizidine fumarate in particular is contained in the core of an enteric-coated granule or pellet. It is readily apparent to one of ordinary skill in the art, however, that Liu’s formula I encompasses within its purview obizidine. Liu expressly provides that the compound of formula I, e.g. obizidine, can be in the fumarate salt form. Moreover, Liu provides that the compound of formula I, e.g. obizidine fumarate, can be formulated in the core of an enteric-coated granule. More specifically, Liu teaches an enteric-coated granule comprising e.g. amorphous obizidine fumarate particles, which can also comprise e.g. microcrystalline cellulose, disintegrants, polyvinylpyrrolidone (PVP), polyoxyethylene sorbitan fatty acid esters (e.g. TWEEN), and lubricants including talcum powder and stearates.
4. Chen discloses that a piperazine derivative, e.g. tandospirone, can be advantageously formulated as an enteric-coated pellet (i.e. a spherical granule) 0.5-0.8 mm in size comprising i) a core containing the piperazine derivative, microcrystalline cellulose (i.e. filler), low substituted HPC (i.e. disintegrant), sodium carboxymethyl starch (i.e. disintegrant), and povidone (i.e. PVP, a spheroidal accelerator), ii) an isolation layer comprising HPMC and talcum powder, and iii) an enteric layer comprising HPMC acetate succinate, triethyl citrate, and talcum powder; wherein the core, the isolation layer and the enteric layer comprise 50-80%, 4-10% and 10-27% by mass of the pellet to thus provide high drug bioavailability in the intestine and minimal side effects.
5. Hence, both Liu and Chen teach formulating a piperazine derivative compound into an enteric-coated granule/pellet. Liu provides that their enteric-coated granule can contain many of the same elements employed in Chen’s enteric coated pellet. Chen further informs one of ordinary skill in the art in more specific terms how to thus formulate an active compound, in this case a piperazine derivative, into an enteric-coated granule/pellet for the specific advantages disclosed in Chen. In stark contrast to Applicant’s assertion, it is completely irrelevant that obizidine is acid labile, while tandospirone is a stomach irritant. The common purpose for formulating the active in each case into an enteric-coated granule/pellet is to avoid release of the active into the stomach, and rather to provide a high active bioavailability in the intestine. Indeed, one of ordinary skill in the art would clearly understand that the Chen formulation achieves this purpose successfully because of the manner in which tandospirone is formulated, not because of the biological activity of the tandospirone. Moreover, one of ordinary skill in the art would reasonably expect success in formulating obizidine fumarate in the same manner to achieve the same success of avoiding active release into the stomach and attaining a high active bioavailability in the intestine, even if obizidine fumarate has a different biological activity as tandospirone.
For the foregoing reasons, the 35 USC 103 rejection is hereby maintained.
Conclusion
No claims are 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.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID BROWE whose telephone number is (571)270-1320. The examiner can normally be reached Monday - Friday, 9:30 AM to 6 PM EST.
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/DAVID BROWE/Primary Examiner, Art Unit 1617
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