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 .
Assignment of Examiner
Applicant is being made aware that the previous office action (i.e., restriction) was entered by a different examiner. This case has been transferred to Examiner Ketcham.
Claim Status
Claims 1, and 3-20 are pending.
Claims 1 and 4 are currently amended.
Claims 2 and 21 have been canceled.
Claims 1, 3, and 15-20 are withdrawn as they are drawn to a non-elected group.
Claims 4-14 are currently under consideration.
Claims 4-14 are rejected.
Acknowledgement of Receipt
Applicants’ election without traverse of Group II., claims 4-14 which are drawn to a particle in the reply filed 04/18/2025 is acknowledged. Claims 1 and 15-20 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention. In order to obtain a complete response to the election of species requirement in the previous office action filed 02/27/2025 for A) a single embodiment of the at least two dispersants (claims 1, and 3-20) and B) a single physiologically active substance (claims 1 and 3-20) calls were made to the attorney of record. During a telephone conversation with Dr. Kirsten Grueneberg on 11/21/2025, in response to the election of species, Applicants elected with traverse hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl cellulose (HPC), and diclofenac. Affirmation of this election must be made by applicant in replying to this Office action.
Election/Restrictions
The traversal is on the ground(s) that there is no serious search and/or examination burden on the Examiner (see Remarks, bridging pages 2 and 3). Applicants argue that since claim 1 is limited to wherein a contact angle of the first dispersant is 10 or greater than that of the second dispersant, and the second dispersant has a higher affinity than the first dispersant to the physiologically active substance, the at least two dispersants of claim already contain single embodiments of each. Applicants argue that because the "at least two dispersants" are already tied to the "physiologically active substance."
These arguments are not found to be persuasive because as per PCT Rule 13.1, the international application shall relate to a group of inventions so linked as to form a single general inventive concept or a “unity of invention” (see MPEP §1850). PCT Rule 13.2 states that said “unity of invention” is fulfilled by defining a special technical feature that is shared amidst the claimed inventions. The Rule further specifies that “[t]he expression “special technical features” shall mean those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art.” The recitation of generic subject matter in the base claims (i.e., particle composition comprising a physiologically active substance and at least two dispersants) is sufficient enough to demonstrate a lack of unity amidst the groups set forth in the previous office action, in view of Isojima (US 2011/0177306 A1; pub. 07/21/2011). As such, the instantly alleged special technical feature, is respectfully NOT considered to provide a contribution over the prior art as required above.
The requirement is still deemed proper and is therefore made FINAL.
To summarize, claims 1, 3 and 15-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected Groups (I), there being no allowable generic or linking claim. Applicants’ timely traversed the restriction (election) requirement in the reply filed on 04/18/2025 and the election via phone as mentioned above on 11/21/2025. This Office Action is in response to Applicants’ said elections, amendments and remarks.
Priority
This application is a 371 which is a National Stage Entry of PCT/JP2019/029606 filed 07/29/2019 which claims priority to Japanese patent applications 2019-111757 filed on 06/17/2019 and 2018-142550 filed on 07/30/2018 are acknowledged.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 01/28/2021 is in compliance with the provisions of 37 CFR 1.97. Accordingly, this IDS has been considered by the Examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 4 and all dependent claims thereof are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “higher” in line 13 of claim 4 is a relative term which renders the claim indefinite. The term “higher” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The affinity of a dispersant to another dispersant has been rendered indefinite by the use of the term "higher." Thus, claim 4 and all dependent claims thereof are also rejected for being indefinite as they are dependent on an indefinite claim. For the purposes of this office action, prior art teaching a dispersant having an affinity to an active substance will be considered to have met the limitation of the claims.
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 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:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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. Applicants are 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 4-14 are rejected under 35 U.S.C. 103 as being unpatentable over Walker (US 2005/0170000, pub. 08/04/2005) in view of Beyerinck (US 2005/0031692, pub. 02/10/2005), Zecevic (European Journal of Pharmaceutics and Biopharmaceutics 87 (2014) pg. 264–270), and Talukder (AAPS Pharm Sci Tech, Vol. 12, No. 4, (2011) pg. 1227-1233).
Walker discloses a particulate coformulation, each particle comprising a core of an active substance surrounded by an excipient coating that is preferably continuous. It may take the form of a discrete layer around the active substance core with a distinct physical boundary between the coating and core, as is typically achieved for instance when a coating material is applied to previously formed core particles or when a coating is precipitated from solution around suspended core particles (abstract, [0010], claims 1, 14).
The active substance may be a pharmaceutical ([0018-0019]) and may be diclofenac ([0025], [0087], claims 8, 19) to read on the elected physiological active substance. The excipients may be one or more, polymeric, hydrophobic ([0031]); celluloses and cellulose derivatives (e.g., hydroxypropyl cellulose) ([0033], claim 10, 11). Walker teaches that the excipient may be a mixture of two substances ([0031]) to read on the “at least two dispersants” limitation. Examples 1-4 with diclofenac and ethyl cellulose are found in paragraph [0098].
Regarding the “locally present at the surface side of the particle” limitation, Walker discloses that the coformulation is a solid dispersion of one component in the other (i.e., an intimate, molecular level mixture of the two components) having a finite gradient in the relative excipient concentration in which the concentration increases radially outwards from the core to the surface of each particle ([0011], claims 1, 3).
Regarding span factor of the particle (i.e., ≥ 0 but ≤ 1.20), looking to the instant specification, Applicants describe span factor as particle size distribution and disclose the formula for particle size distribution (PSD) (D90 -D10)/D50) (see Spec., [0106]) with PSD values ranging from 0.39 to 0.63 in Table 2 (see Spec., [0176]). As Walker provides uniform particle sizes, i.e., these particles have a narrow particle size distribution ([0052]).
Walker does not expressly teach the instantly claimed span factor.
Beyerinck discloses a pharmaceutical composition comprising a solid amorphous dispersion comprising a low-solubility drug and a polymer e.g., hydroxypropyl cellulose (HPC) ([0145]) and hydroxypropyl methylcellulose-acetate succinate (HPMCAS) ([0148]) to read on the elected dispersants. The solid amorphous dispersions have a relatively narrow size distribution so as to minimize the fraction of particles that are very small (less than 1 μm) ([0046]). Beyerinck teaches that Span, sometimes referred to in the art as the Relative Span Factor or RSF, is a dimensionless parameter indicative of the uniformity of the drop size distribution ([0103]). Beyerinck goes on to teach that generally, the lower the Span, the more narrow the droplet size distribution produced by the atomizing means, which in turn generally leads to a narrower particle size distribution for the dried particles, resulting in improved flow characteristics ([0103]). Beyerinck teaches that the Span of the droplets produced by the atomizer is most preferably less than about 1.5 ([0103]) and provides embodiments thereof ([0164] Table 1; [0167] Table 3). MPEP 2144.05 states that a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). Accordingly, the prior art renders the claimed range, i.e., 0 – 1.20, obvious.
Regarding the micrometer limitation (i.e., 1 µm - 100 µm), Walker teaches primary particles with a volume mean diameter of 5 µm or less ([0006], [0041], [0044], claims 14, 15). MPEP 2144.05 states that a prima facie case of obviousness exists in the case where the claimed ranges overlap or lie inside ranges disclosed by the prior art.
Regarding line 10 of claim 4 and line 3 of claim 6 (i.e., core-shell structure), Walker teaches that each particle comprising a core of the active substance is surrounded by a coating of the excipient ([0006]). Walker teaches and suggests the core-shell structure by describing the excipient coating forming a discrete layer around the active substance core with a distinct physical boundary between the coating and core ([0010]).
Walker does not teach HPMCAS.
Zecevic discloses solid dispersions of an active pharmaceutical ingredient (API), and enteric polymer hydroxypropyl methylcellulose - acetate succinate (HPMC-AS) and hydrophilic water-soluble low-viscosity hydroxypropyl cellulose (HPC-SSL) (abstract). Results of dissolution tests of binary and ternary solid dispersions of an API, e.g., dipyridamole (DPD) and griseofulvin (GRI) were compared (pg. 267, Fig. 1 Dissolution tests). Zecevic teaches that the use of HPMC-AS facilitated increased solubility and supersaturation at pH-controlled release of the preserved amorphous state of the dispersed drug which might be of benefit for site specific absorption (pg. 269, Conclusion). In combination with HPC-SSL and HPMC-AS, API ternary dispersions achieved tailored release profiles and showed favorable stability properties (pg. 269, see Conclusion).
It would have been prima facie obvious to a person of ordinary skill in the art, ahead of the effective filing date of the claimed invention, to incorporate the HPC and HPMCAS of Zecevic in the composition of Walker in view of Beyerinck with expected results. One would be motivated to do so with a reasonable expectation of success as all of the references focus on overcoming high in vivo variability and bioavailability issues with drug candidates that are pH-dependent or poorly soluble (Walker [0020], Beyerinck [0132], Zecevic (abstract)). Zecevic teaches and suggests that HPMC-AS in combination with the hydrophilic HPC-SSL can be used as a gastro protective matrix for weak polar drugs, e.g, GRI (Zecevic pg. 269, see Discussion) which complements Walker’s teaching of diclofenac and other water insoluble (or low aqueous solubility), poorly tasting active substances, in particular, drugs (Walker [0025]). It is prima facie obvious to combine the diclofenac, HPC and HPMC-AS as taught by the prior art to be useful for the same purpose, in order to form a composition which is to be used for the very same purpose.
Regarding claim 4 and claim 5 (i.e., contact angle 10° or greater), Applicants disclose HPMCAS as having a 10° greater contact angle greater than HPC (see Spec. [0147]). Notably Walker teaches that the active substance in the coformulations may be present in an easily wetted (as indicated by a low contact angle) crystalline form ([0036]) to suggest (water) contact angle measures a surface's wetting property. The prior art teaching of the same elected dispersants, HPC and HPMCAS, would have been expected to one of ordinary skill in the art, to obtain a result that necessarily flows with the intended purpose and properties, i.e., dispersant with a 10° greater contact angle greater than the other, without evidence to the contrary. Thus, the claimed properties are presumed to be a direct result of the form of the composition as claimed. As stated above, Walker in view of Beyerinck, in combination with Zecevic, renders obvious the exact property claimed.
Regarding the higher affinity to the active substance limitation of claim 4, and considering the 112 issue discussed above, while Walker provides coformulations with improved dissolution and bioavailability of the drug to be administered ([0020], [0036]), one dispersant having a higher affinity is not expressly taught.
Talukder discloses a study to investigate the effects of a hydrophilic carrier on the solid-state and dissolution characteristics of poorly water-soluble drugs in the combination with HPC (abstract). Talukder provides the contact angles of 0.5% HPC aqueous solution on non-steroidal anti-inflammatory (NSAID) i.e., ibuprofen (pg. 1232, see Table III). HPC solutions rapidly wet the drug as indicated by the fast rate of adsorption (pg. 1232, see Wetting studies) to suggest a higher affinity to the active.
It would have been prima facie obvious to a person of ordinary skill in the art, ahead of the effective filing date of the claimed invention, to apply the teaching of HPC of Talukder to Walker in view of Beyerinck and Zecevic with expected results. One would be motivated to do so with a reasonable expectation of success for at least two reasons. Talukder teaches that apart from the intimate mixture of HPC and drug particles and enlarged surface area due to particle size reduction, a decrease in the degree of crystallinity is also a likely contributor to dissolution rate enhancement on co-grinding mixture (pg. 1233, col. 1, para. 2). Talukder demonstrates that the presence of HPC improves the wettability of hydrophobic surfaces because of the relatively non-polar nature of HPC which allows a significant reduction in surface tension of aqueous media and also allows contact between the polymer and the low energy surfaces resulting in enhanced dissolution rates of poorly water-soluble drugs (pg. 1233, see Conclusion).
Regarding claim 6 (i.e., core-shell structure), in addition to the rejection discussed above, the recitation of “formed with the first dispersant locally present at the surface side of the particle,” does not impose any other structure not otherwise recited in the claim and does not afford any patentable weight.
Regarding claims 7-10, as discussed above, Beyerinck teaches HPMCAS while Zecevic discloses solid dispersions of an API, HPMC-AS and HPC-SSL.
Regarding claim 11 (i.e., pharmaceutical), Walker discloses that the active substance is a non-steroidal anti-inflammatory drug, wherein the active substance is diclofenac ([0018-0019], claims 4, 25-27).
Regarding claim 12 (i.e., 1 µm – 50 µm) and claim 13 (i.e., 1 µm – 10 µm), Walker discloses volume mean diameter of the particles of 5 µm or less, which falls within or overlaps with the claimed ranges and a prima facie case of obviousness exists where prior art and claimed ranges overlap per MPEP 2144.05(1).
Regarding claim 14 (i.e., medicament), Walker discloses a pharmaceutical or nutraceutical product incorporating the coformulation in the form of a solid tablet intended for oral consumption ([0120], claims 27-28).
It would have been prima facie obvious to a person of ordinary skill in the art, ahead of the effective filing date of the claimed invention, to apply the coformulation of more than one dispersants and diclofenac taught by Walker in view of Beyerinck, Zecevic, and Talukder with expected results. One would be motivated to do so with a reasonable expectation of success because Walker discloses coformulations that improve bioavailability thereby allowing lower doses of a pharmaceutically active substance to be administered to a patient ([0020]). In addition, Walker teaches that cellulosic polymers as excipients, are particularly suitable as taste masking agents ([0032], [0144], claim 5). Beyerinck provides a dispersion that enhances dissolved drug concentration in a use environment and bioavailability thereby reducing the amount of inactive material to be dosed ([0038]). Zecevic specifically teaches HPC and HPMCAS can address the challenge to deliver reliable drug therapies over the entire gastro-intestinal pH-range (abstract). Talukder further provides improvement of oral bioavailability specific to poorly water-soluble drugs by showing that the presence of HPC increases drug wettability (pg. 1228, col. 1, para. 2).
Conclusion
Claims 4-14 are rejected; no claims are currently allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Karen Ketcham whose telephone number is (571)270-5896. The examiner can normally be reached 900-500 ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at 571-272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Karen Ketcham/Examiner, Art Unit 1614
/ALI SOROUSH/Supervisory Patent Examiner, Art Unit 1614