Patent Application 15021384 - MODIFIED RELEASE PHARMACEUTICAL FORMULATIONS

Title: MODIFIED RELEASE PHARMACEUTICAL FORMULATIONS

Application Information

Invention Title: MODIFIED RELEASE PHARMACEUTICAL FORMULATIONS
Application Number: 15021384
Submission Date: 2025-05-21T00:00:00.000Z
Effective Filing Date: 2016-03-11T00:00:00.000Z
Filing Date: 2016-03-11T00:00:00.000Z
National Class: 424
National Sub-Class: 490000
Examiner Employee Number: 83496
Art Unit: 1614
Tech Center: 1600

Rejection Summary

102 Rejections: 0
103 Rejections: 1

Cited Patents

The following patents were cited in the rejection:

US 0215740🔗

Office Action Text

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 .

Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8/15/2024 has been entered.

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 1 ,3-5, 7, 9-11, 13-15, 17, and 18 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.
Claim 1, recites, inter alia, “wherein the only drug in the suspension is an anti-Alzheimer’s agent.” In apparent conflict with this limitation, dependent claim 17 (construed as within the scope of claim 1, because claim 17 depends from claim 1), states the “modified release suspension further comprises an additional anti-Alzheimer’s agent”, Claim 18, with depends from claim 17, requires “the additional anti-Alzheimer’s agent” to be “delivered in an immediate or sustained release manner”. The additional agent language of claims 17-18 introduces confusion into claim 1, which recites the only drug to be an anti-Alzheimer’s agent
claim 1 as currently recited requires the only drug in the suspension to be an (i.e., one?) anti-Alzheimer’s agent, but dependent claims 17 and 18 recite language regarding an additional anti-Alzheimer’s agent. The Examiner’s review of the specification failed to identify any limitation limiting the only drug in the suspension to be an (i.e., one?) anti-Alzheimer’s agent.
In fact, locations such as 6:5 use language such as “at least one Anti-Alzheimer’s agent” (i.e., one or more than one drug/agent). In discussing the phrase “anti-Alzheimer’s agent” (6:18-8:20), there are listings of many unique drugs by name (e.g., donepezil) or by function (e.g., inhibitor of cholinesterase or aβ inhibitor). However, in the middle of this passage, the specification uses the language “and/or combinations thereof” (6:33) or “and combinations thereof” (7:13). The skilled artisan would have construed the meaning of anti-Alzheimer’s agent to be a single drug from this listing or a combination of two or more of these disclosed drugs to satisfy this language.
The claim requires an “only” drug to be “an anti-Alzheimer’s agent”, but since the specification permits a combination of two drugs in certain embodiments of “an anti-Alzheimer’s agent”, the number of drugs permitted in the claim 1 suspension is confusing. Further contributing to this confusion, dependent claims 17 and 18 render this further ambiguous, by explicitly requiring an additional anti-Alzheimer’s drug.

The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.

The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.

Claims 1 ,3-5, 7, 9-11, 13-15, 17, and 18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. As discussed in the above rejection, claim 1 as currently recited requires the only drug in the suspension to be an (i.e., one?) anti-Alzheimer’s agent, but dependent claims 17 and 18 recite language regarding an additional anti-Alzheimer’s agent. The Examiner’s review of the specification failed to identify any limitation limiting the only drug in the suspension to be an (i.e., one) anti-Alzheimer’s agent; in contrast the specification has embodiments that permit anti-Alzheimer’s agent to be combinations of drugs.
In fact, locations such as 6:5 use language such as “at least one Anti-Alzheimer’s agent” (i.e., one or more than one drug/agent). In discussing the phrase “anti-Alzheimer’s agent” (6:18-8:20), there are listings of many unique drugs by name (e.g., donepezil) or by function (e.g., inhibitor of cholinesterase or aβ inhibitor). However, in the middle of this passage, the specification uses the language “and/or combinations thereof” (6:33) or “and combinations thereof” (7:13). The skilled artisan would have construed the meaning of anti-Alzheimer’s agent to be a single drug from this listing or a combination of two or more of these disclosed drugs to satisfy this language.
The claim requires an “only” drug to be “an anti-Alzheimer’s agent”, but since the specification permits a combination of two drugs in certain embodiments of “an anti-Alzheimer’s agent”, the number of drugs permitted in the claims suspension is confusing. Further contributing to this confusion, dependent claims 17 and 18 render this further ambiguous.
Review of the specification failed to identify written description permitting resolution of whether only one drug is permitted or whether two or more are permitted by the language (of course two agents is clearly required by dependent claims 17-18, which conflicts with the “only” limitation of claim 1). Because the broadest reasonable construction of claim 1 permits two drugs, either one or two or more are construed as permitted.

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 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.
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.
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 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.

Claims 1 ,3-5, 7, 9-11, 13-15, 17, and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Coulter (WO 2008/132712 A2; 2008; cited in a prior Office action) in view of Pilgaonkar et al. (US 2010/0215740 A1; 2010; cited in a prior Office action).
The claims are directed to a modified release liquid suspension comprising a plurality of modified release units comprising coated drug resin complexes comprising a drug-resin complex comprising memantine and a cation exchange resin and the coating comprising a modified release coating comprising a cellulose derivative such as ethyl cellulose, wherein the suspension provides release of the memantine for more than about 4 hours. The modified release unit further comprises an excipient such as a disintegrant/release modifier. The modified release suspension further comprises an additional anti-Alzheimer’s agent and is delivered in a sustained release manner.
Coulter teaches a modified release dosage product comprising a plurality of minicapsules or minispheres containing calcium channel blocker such as nimodipine and/or a plurality of minicapsules or minispheres containing calcineurin inhibitor such as tacrolimus (prior art claim 18). The modified release dosage product can further comprise a plurality of minicapsules or minispheres containing a NMDA receptor antagonist such as memantine hydrochloride (prior art claims 47 and 48). The minicapsules of the modified dosage product can further contain a taste-masking entity (prior art claim 73). The modified release dosage product is used for the treatment/prevention of Alzheimer’s disease (prior art claim 25). “The minicapsules may be modified to provide the release profile. A modified release may be attributable to a polymer coating. The polymeric material may, for example, be a methacrylate, or ethylcellulose. The polymeric material may be a composite of methacrylate and ethylcellulose.” (page 13, lines 16-21). The minicapsules may contain a disintegrant (page 19, line 2- which reads on release modifier of instant claim 13). The modified release dosage product has a dissolution profile wherein the API is released for at least 4 hours (Figure 2). Nimodipine has activity in preventing or treating Alzheimer’s disease (page 2, lines 4-10). Tacrolimus has benefit to prevent the progression of Alzheimer’s disease (page 3, lines 2-6). “In another embodiment either single product or the combined products is used to treat or prevent Alzheimer's disease and other dementias … In another case either single product or the combined products is combined with a NMDA receptor antagonist such as memantine hydrochloride” (page 16, lines 4-8). The product comprises at least one minicapsule population filled into a sachet (page 10, 16-17). In one easy to administer format, the present invention permits that the minicapsules or minispheres may be filled into sachets, the contents of which maybe sprinkled onto … drinks and administered to patients by … drinking (page 59, lines 17-24 – which reads on the limitation that the composition is a suspension/liquid suspension). “Surelease®, an aqueous ethylcellulose dispersion, is a unique combination of film- forming polymer; plasticizer and stabilizers. Designed for sustained release and taste masking applications, Surelease® is an easy-to-use, totally aqueous coating system using ethylcellulose as the release rate controlling polymer. The dispersion provides the flexibility to adjust drug release rates with reproducible profiles that are relatively insensitive to pH. The principal means of drug release is by diffusion through the Surelease® dispersion membrane and is directly controlled by film thickness. Increasing or decreasing the quantity of Surelease® applied can easily modify the rate of release. With Surelease® dispersion, reproducible drug release profiles are consistent right through from development to scale-up and production processes … Additionally, alternative controlled release enabling polymers or other entities may be used alone or in combination with polymers such as those mentioned above” (page 55, lines 25-28 and page 56, lines 1-16).
Coulter lacks a teaching or suggestion of the suspension comprising a resin in particular a cation exchange resin that is complexed to memantine.
Pilgaonkar et al. teach the bitter taste of memantine of the composition of the present invention is masked by coating (such as using water insoluble coatings), complexation (such as with ion exchange resins), salt formation (such as with sodium saccharin), use sweeteners or flavors and the like, or any combination thereof (paragraph 0016). “Memantine hydrochloride is positively charged and displaces the cationic groups, typically becoming bonded to the resin by ionic bonds. Various ion exchange resins that can be employed for taste masking of memantine include Amberlite IRP 64, IRP-69 and IRP-70 (copolymer of methacrylic acid crosslinked with divinylbenzene which differ in particle size) and Dowex (based on polystyrenesulfonic acid crosslinked with divinylbenzene). These resins are employed in weight ratio of 1:0.1 to 1:20 with respect to memantine” (paragraph 0029). The active ingredient may be incorporated in the formulation in the powder form, granules, pellets, beads or any other suitable form (paragraph 0033).
It would have been prima facie obvious to one of ordinary skill in the art at the time of the instant invention to complex the memantine hydrochloride of Coulter with the cation exchange resin of Pilgaonkar et al. and have a reasonable expectation of success. One would have been motivated to do so in order to provide a taste-masking entity as suggested by Coulter to mask the bitter taste of memantine hydrochloride as taught by Pilgaonkar et al.
Examiner notes that the language of claim 1 has been construed to permit two or more anti-Alzheimer drugs (e.g., nimodipine + memantine, where “only” this “anti-Alzheimer’s agent” combination is present) to be encompassed by the claim 1 language, which is clearly clarified by the additional agent limitations of claim 17-18. However, in the interest of compact prosecution, even if the language is clarified to limit claims 1, 17 & 18 to a single drug (memantine HCl, claim 5) being present in the claimed modified release suspension, 9:8-10 of Coulter clearly teaches the modified release dosage containing (not further containing) a NMDA receptor antagonist, and memantine HCl is clearly embodied. This is construed as a single drug embodiment of the product of Coulter, which would read on a single drug embodiment, if this construction were required by claim 1.

Response to Applicant’s Arguments
Applicant argues:

The skilled artisan would allegedly not look to Coulter in order to formulate a memantine formulation. Coulter is directed to nimodipine formulations, per abstract and claim 1.
This is not persuasive.
Memantine including the HCl salt, is clearly taught by Coulter. The mention of p. 9 is construed to require memantine, but not any other drug. While drug combination, including with nimodipine are taught by Coulter, these embodiments are not considered excluded by the “only” an anti-Alzheimer’s agent language (see discussion above about construction of claim 1) the two-drug embodiment is clearly embraced by claims 17 and 18, which each recite an additionally anti-Alzheimer’s agent. Applicant cannot have it both ways, arguing that Coulter does not teach embodiments of the claims, but then claiming an additional anti-Alzheimer’s agent. Nonetheless, even if claims are amended (by a future amendment) to only permit memantine HCl, and to exclude nimodipine, the teaching at p. 9 of the memantine HCl containing embodiment does not include nimodipine.
Applicant further argues about the 4 hour release limitation. The teachings of Coulter include less than 60% of the tacrolimus being released within 4 hours (13, 1-3) and less than 65% of the tacrolimus being released within 12 hours. Clearly delayed release is the topic of Coulter, and renders obvious the at least 4 hour release criterion when memantine HCl is utilized as anti-Alzheimer’s agent. Coating on the minicapsules is utilized as an engineering variable, and would have been obvious to apply for the memantine embodiments to achieve similar extended release as figure 1 depicts. The Surelease coating achieves 50% release in about 13 hours, and would have reasonably been expected to have similar release characteristics for the memantine alternative agent.
Applicant argues that looking to Pilgaonkar to formulate memantine would have been more likely. Examiner notes that Pilgaonkar would have been taken into account. Pilgaonkar clearly establishes that taste issues with memantine are clearly relevant, and would have motivated addressing these issues, as set forth in the rejection. While there may have been alternative obvious embodiments when considering these two references, the rejection relies on the basis set forth. Colter clearly teaches modified release suspensions.
Applicant argues that reliance on In re Kerkhoven is somehow improper.
The point is that Pilgaonkar is clear about the need for formulations to mitigate bitter taste of memantine:
[0022]. The bitter taste of memantine poses a great chal-
lenge for the development of orally disintegrating tablet for
mulations. The present invention employs a number of
approaches including, but not limited to, using coating, com-
plexation, Salt formation, Sweeteners, flavours and the like for
masking of the unpleasant taste of memantine.

[0023] Coating is the most widely used technique for taste
masking of pharmaceuticals. This can be achieved using
polymers or lipids to mask the unpleasant taste. In an embody-
ment of the present invention, memantine is taste masked by
coating with water insoluble excipients. The term “water-
insoluble excipient’ as used herein includes polymeric or
non-polymeric materials that are not completely soluble in
water across pH range of 1-8 commonly encountered in gas-
trointestinal tract or are only partially soluble at, at least a
particular pH.

[0024] Polymeric water-insoluble excipients for taste
masking memantine as employed in the present invention
include, but are not limited to, vinyl acetate, vinyl chloride,
vinyl carbonate, methacrylic acid, a polymethacrylic acid
copolymer, other polymethylmethacrylates, ethyl cellulose,
nitrocellulose, vinylidene chloride-acrylonitrile copolymer,
acrylonitrile-styrene copolymer, polyethylene, polyethylene
oxide, polystyrene, ethylene vinyl acetate, cellulose acetate,
cellulose acetate phthalate, cellulose acetate butyrate,
copolymers of vinyl pyrrolidone, and hydroxypropylmethyl
cellulose phthalate or any mixtures thereof.

Thus, to address the bitter taste of memantine, there are many approaches taught, and Pilgaonkar explicitly teaches mixtures of excipients (several paragraphs mention mixtures, indicating combinations of approaches are contemplated) are used to mask taste. Teachings include the cationic ion exchange resins, with negatively charges or anionic, binding sites, which bond to memantine hydrochloride [0029]. This is relevant to suspensions intended for oral ingestion. The skilled artisan would have been motivated to utilize the cationic ion exchange resins, to mitigate the bitter taste problem clearly taught by Pilgaonkar.
Clearly an obvious combination rationale is relevant here, and In re Kerkhoven (MPEP 2144.06 (I)) is also applicable for a finding of obviousness.
The Examiner fails to appreciate the language used by Applicant, relying on an alleged “random” taste masking agent. The rejection relies on teachings cited.
With respect to the allegation that Pilgaonkar teaches away from the modified release suspension of Coulter, Pilgaonkar does discuss solid compositions, but these dissolve/disintegrate in the oral cavity; i.e. giving a solution/suspension in the mouth. Thus, the Examiner does not rely on Pilgaonkar to teach away from the approach of Coulter. In contrast, Pilgaonkar clearly teaches the bitter taste of mematine, which is mitigated by following the excipient approach taught, including the cationic ion exchange resins.
Regarding the argument about Sriwongjanya (cited in a prior Office action), the record establishes that this reference also documents prevention of drugs leaching during storage, and this is applicable to drugs with cationic nature (which Pilgaonkar establishes is present for memantine HCl). Certainly, the skilled artisan would have optimized conditions (concentrations, etc.) to achieve what this reference documents. The Examiner notes this reference reasonably suggests what Applicant has argued was unexpected about the claimed resin, to mitigate leaching of cationic drugs, reasonably expected for memantine HCl.
Applicant argues that the release is different for 3 different drugs. The Examiner notes that each of the referenced figures corresponds to extended release, and general approaches to release within 4 to 12 to 24 hours are discussed. A skilled artisan would have recognized these modified release suspensions provide a benefit of the need for less frequent dosing of memantine HCl. For instance, the discussion of Figure 1 (19:18-23) makes clear that a dissolution profile shown is suited to once-daily administration of nimodipine. Similar approaches with memantine HCl would have permitted similar outcomes for dosing. Figure 2 corresponds to a twice-daily dosage form. The skilled artisan is clearly capable of applying modified release forms based on release profile characteristics. The skilled artisan is not an automaton, but is capable of modifications based on teachings such as those of the cited references.

Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIMOTHY P THOMAS whose telephone number is (571)272-8994. The examiner can normally be reached M-Th 6:30-5:00.
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TIMOTHY P. THOMAS
Primary Examiner
Art Unit 1614

/TIMOTHY P THOMAS/Primary Examiner, Art Unit 1614