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 .
Election/Restrictions
Applicant's election with traverse of Group I, claims 1 and 4-7 in the reply filed on December 9, 2025 is acknowledged. The traversal is on the ground(s) that all groups may be searched and examined without burden. This is not found persuasive because the current application has been filed under 35 USC 371, in which the standard for requiring a restriction requirement is governed by 37 CFR 1.475. As indicated in the Restriction Requirement dated October 22,2025, a national stage application must be related to one invention only or there must be unity of invention in which the presented inventions must be linked as to form a single general inventive concept. To have unity of invention, there must be a technical relationship among the claims involving one or more of the same or corresponding special technical features.
In this case, the technical feature of claim 1, which is shared by all inventions in Groups I-III, is an obvious modification of a known granular composition of Elbaz et al. (US 20170296523 A1) in view of Diallo et al. (US 20170014340 A1) and Xu et al, as explained below. See Claim Rejections - 35 USC § 103. In view of prior art, the common technical features do not constitute a special technical feature under 37 CFR 1.475; therefore, the requirement for restriction is maintained.
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.
Claims 6 and 7 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.
Regarding claims 6 and 7, the phrase "such as" which appears multiple throughout the claim renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Additionally, claims 6 and 7 contain the trademark/trade name “Avicel PH 101”, “Mannitol Pharma”, etc. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe the product microcrystalline cellulose or mannitol and, accordingly, the identification/description is indefinite.
Also, in claims 6 and 7, the term “cellulose MK GR” is vague and infinite as one of ordinary skill in the art would not immediately apprehend the meaning and there is no explanation in the specification.
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.
Claims 1 and 4-7 are rejected under 35 U.S.C. 103 as being unpatentable over Elbaz et al. (US 20170296523 A1, published October 19, 2017) (“Elbaz” hereunder) in view of Diallo et al. (US 20170014340 A1, January 10, 2017) (“Diallo” hereunder) in view of Xu et al. (US 20210060020 A1, published on March 4, 2021) (“Xu” hereunder).
The present claim 1 is directed to a free-flowing granular formulation comprising an internal phase in the form of granules including alpelisib, or a pharmaceutically acceptable salt thereof, as active pharmaceutical ingredient and at least one pharmaceutically acceptable carrier material, and in addition an external granular phase without said active pharmaceutical ingredient comprising at least one pharmaceutically acceptable carrier material.
Elbaz teaches dispersible tablets comprising alpelisib ((S)-pyrrolidine-1,2- dicarboxylic acid 2-amide l-(4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4- yl]-thiazol-2-yl)-amide, or a pharmaceutically acceptable salt thereof. See abstract. The reference teaches that alpelisib is used as a targeted inhibitor of a PI3K-alpha to treat patients with advanced cancer associated with PIK3CA mutation. See [0043, 0142-0143]. The reference teaches that alpelisib is being evaluated in combination with cetuximab for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma. See [0005]. The reference teaches that the dispersible tablets comprises granulates having an inner phase and outer phase, wherein the inner phase comprises alpelisib, at least one disintegrant, at least one binder, and optionally any additional excipients, wherein the outer phase comprises at least one disintegrant, at least one lubricant and optionally any additional excipients, with the proviso that the additional pharmaceutically acceptable excipient in either phases is not calcium phosphate tribasic, calcium phosphate dibasic anhydrous, calcium phosphate dibasic hydrate or sucralose. See [0009].
Elbaz explains the need for alternative dosage forms other than traditional tablets:
[F]or certain groups of patients, oral administration of medicaments in solid tablet form is either undesirable or impractical. In particular, children, elderly patients and patients suffering from head and neck cancers may be unable to swallow such tablets conveniently. For these patients, it is typically desirable or necessary to provide alternative dosage forms or alternative methods for administering a medicament.
See [0006]. The reference goes on to teach that the dispersible tablet is useful for conveniently and safely administer to patients including children and elderly patients with swallowing difficulties. See [0007]. The dispersible tablets here refer to rapid disintegration in an aqueous medium with a disintegration time of 5 minutes or less, preferably 90 seconds or less, when measured according to the test in water at a temperature of 15-20C. See [0087-0088].
Elbaz fails to disclose a granular formulation.
Diallo teaches orally disintegrating medicaments comprising nabilone for improved treatment of nausea arising from chemo therapy for cancer. The reference teaches the granules comprising (i) an intra-granular fraction comprising nablone or a pharmaceutically acceptable salt thereof, at least one filler, and at least one binder; and (ii) an extra-granular fraction comprising at least one disintegrant, at least one lubricant and at least one other pharmaceutically acceptable excipient. See [0009]. While the reference teaches that a preferred embodiment is in the form of an orally disintegrating tablet comprising granules containing the medicament, the reference also teaches and suggests a granular formulation contained in a sachet. See reference claim 19.
Xu teaches pharmaceutical compositions comprising granules comprising micronized drug granules of adenosine A2A receptor antagonists and a pharmaceutically acceptable excipient. See translation, [0005]. The antagonist is used treating central nervous system disorders and cancer. The reference further teaches that the granules can be compressed into a tablet, placed within a capsule shell or placed within a sachet or stick pack. See Id. The reference teaches that a sachet or stick pack comprising granule formulations is useful where the contents are intended to be sprinkled in food or added to a liquid. See [0198-0199].
It would have been obvious to one of ordinary skill in the art before the effective filing date of the present application to modify the teachings of Elbaz and make a granular formulations as motivated by Diallo and Xu. The skilled artisan would have been motivated to do so, as 1) both Elbaz and Diallo teach orally disintegrating tablets useful in cancer treatments, which are formed from inner phase granules comprising an active ingredients and excipients and extra phase granules comprising excipients which stabilize the formulation; 2) Diallo teaches and suggests that the tablet formulations can be modified to a granular formulation; and 3) Xu teaches that granular formulations are useful in sprinkling the medicament over food or adding to a liquid. Since 1) Diallo teaches a composition comprising internal and external phase granules that can be used to make a dispersible tablet or a granular formulation, and 2) Xu also teaches that granules comprising pharmaceutical actives and excipients can be made into tablets, capsules or granular formulations in a sachet or a stick pack, the skilled artisan would have had a reasonable expectation of successfully combining the teachings of the references and producing a stable granular formulation comprising alpelisib which can be sprinkled over food or mixed in a drink. See present claim 1.
Regarding claims 4 and 5, with respect to the amount of alpelisib, Elbaz teaches that an effective daily dose for adults and children is about 1-6.5 mg/kg; the suggested daily dosage to a 70 kg body weight human adult is about 70-455 mg/day, which can be divided up to four times a day. Thus, each dosage form can contain up to 100 mg of alpelisib. One of ordinary skill in the art who combine the teachings of the references would have obviously used such amount of the active ingredient in the inner phase of the granular formulation.
The Elbaz Example 1 discloses a dispersible tablet formulation comprising an inner phase, which contains 50 mg of alpelisib, 18 wt % microcrystalline cellulose as a diluent and 18.1 wt % of mannitol and 2.4 wt % of low-substituted hydroxypropyl cellulose as a binder. Also shown is an external phase which contains 12. 5 wt % of microcrystalline cellulose as a diluent and 4 wt % of sodium stearyl fumarate as a lubricant. The disclosed concentrations of the constituents in the inner and outer phase granules are expressed as a weight percentage relative to the total weight of the tablet. It is obvious that the same or similar proportional formulation can be applied to other single-dosage forms, such as a granular formulation in a sachet or a stick pack.
Although the disclosed formulation in Example 1 does not contain a disintegrant, Elbaz suggests that the inner phase can contain at least one disintegrant such as sodium croscarmellose, calcium croscarmellose, crospovidone, etc. can be used in an amount from about 1-25% based on the total weight of the tablet. See [00025, 0046]. Incorporating the disintegrant as suggested by the reference to manipulate the release of alpelisib from the granules would have been prima facie obvious.
Although the amounts of microcrystalline cellulose and mannitol of the inner phase in the Example 1 is lower than the presently claimed range, it is well settled in patent law that combining or substituting art-recognized functional equivalents is prima facie obvious. See MPEP 2144.06, II. In this case, Elbaz establishes that microcrystalline cellulose and mannitol are art-recognized diluents that can be combined or substituted for the same known purpose. Thus, a similar formulation comprising the combined amount of 32.6 wt % of microcrystalline or mannitol would have been prima facie obvious.
Regarding claims 6 and 7, Elbaz fails to teach sodium carboxymethyl starch.
Xu teaches that carboxymethyl cellulose and sodium starch glycolate are well known disintegrants and used in making pharmaceutical granules. Since Xu establishes that carboxymethyl cellulose and sodium starch glycolate, the disintegrant used in the Elbaz Composition 1, are art-recognized functional equivalents, substituting one for the other to make a similar inner phase granules comprising alpelisib would have been prima facie obvious.
Conclusion
No claims are allowed.
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/GINA C JUSTICE/Primary Examiner, Art Unit 1617