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 without traverse of Group I in the reply filed on 04 March 2026 is acknowledged.
Applicant’s election without traverse of certain species in the reply filed on 04 March 2026 is acknowledged. The elected species are as follows:
(+)-TBZ, as a single species of a vesicular monoamine transporter 2 (VMAT2) inhibitor;
sesame oil, as a single species of a pharmaceutically acceptable oil;
cholesterol, as a single species of a lipid; and
tardive dyskinesia, as a single species of hyperkinetic movement disorder.
Status of Claims
Claims 1-18 are pending. Claims 3 and 13-17 are withdrawn from consideration. Of the withdrawn claims, claim 3 is drawn solely to non-elected species, and claims 13-17 are drawn to non-elected invention(s).
Information Disclosure Statement
All references from IDS(s) received 23 May 2024 have been considered unless marked with a strikethrough.
Priority
The instant application claims priority as follows:
This application claims priority to 63/384,008 filed 16 November 2022.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claim Interpretation
The Examiner notes that claim 1 recites, in part, that “the lipid is present in an amount from 0% to about 50% by weight, relative to the weight of the depot composition.” Emphasis added. As such, the presence of lipid is deemed to be an optional component of the compositions encompassed by independent claim 1 and dependent claims 2, 4-8, 10-12 and 18. In contrast, dependent claim 9 recites, in part, that “the ratio of the lipid to the pharmaceutically acceptable oil is between about 1:1 and about 1:99 by weight.” And as such, the presence of lipid is deemed to be a requisite component of the compositions encompassed by dependent claim 9.
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 12 is 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 12 recites the limitation "the VAMT2" in the first line of the claim. There is insufficient antecedent basis for this limitation in the claim. Examiner acknowledges that the recited limitation likely reflects a typographical error. And for that reason, in the interest of compact prosecution, the claim has been examined as if reciting "the VMAT2" (rather than "the VAMT2") in the first line of the claim. Appropriate correction and/or clarification is required.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
The instant application recites that “the term depot composition refers to a slow-release, or sustained release, or controlled release formulation of an active ingredient which releases the active ingredient over a long period of time to permit less frequent administration.” See instant application at Paragraph [0034].
The instant application recites that “the term of pharmaceutically acceptable oil is intended to includes any triglyceride oil, canola oil, castor oil, corn oil, cottonseed oil, grapeseed oil, olive oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, soybean oil, sunflower oil, “vegetable” oil, walnut oil, medium-chain triglyceride (MCT) oil, and the like.” See instant application at Paragraph [0058].
As discussed in the above Claim Interpretation section, the presence of lipid is deemed to be an optional component of the compositions encompassed by all claims (except for claim 9) that are currently under examination.
Claims 1, 5, 6, 7, 8 and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Li et al. (WO-2019094491-A1; published on 16 May 2019).
Regarding claims 1, 5, 6, 7 and 18, Li et al. disclose compositions comprising (a) a VMAT2 inhibitor or a pharmaceutically acceptable salt thereof, and (b) a pharmaceutically acceptable oil.
In particular, Li et al. disclose that “[t]he solubility of compounds of the present application in various oils were tested. The suspension of compounds in various pharmaceutical acceptable oils, including castor oil, sesame oil, cottonseed oil, peanut oil and soybean oil, were stirred at 37°C for 2-3 days.” Li et al. also disclose that “[a]s shown in Table 3, all compounds 1 -1 , 1 -2 and IV show fair to good solubility in pharmaceutical acceptable oils. The conjugation significantly increases the solubility in various oils. The higher oil solubility can be advantageously used to make long acting or sustained release formulation to deliver the active compounds.” See Paragraph [0082]. Li et al. disclose compound 1 -1 to be (2R,3R, 1 1 bR)-3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7, 1 1 b-hexahydro- 2H-pyrido[2, 1 -a]isoquinolin-2-yl palmitate]. See Paragraph [0068]. Li et al. disclose compound 1 -2 to be (2R.3R, 11 bR)-3-isobutyl-9,10-dimethoxy-1 ,3,4,6,7, 11 b-hexahydro- 2H-pyrido[2,1 a]isoquinolin-2-yl behenate. See Paragraph [0070]. Li et al. disclose compound IV to be (+)-(a)-DHTBZ. See Paragraph [0033].
Regarding claim 8, Li et al. disclose the maximum solubilities for nine disclosed depot compositions in Table 3 (found near Paragraph [0083]). Based on those disclosed maximum solubilities, each of the nine disclosed depot compositions disclosed in Table 3 comprise a VMAT2 inhibitor or the pharmaceutically acceptable salt thereof “in an amount less than about 70% by weight, relative to the weight of the depot composition.”
Regarding claim 18, Li et al. do not expressly disclose the viscosities of the depot compositions disclosed in Table 3. However, given that the components of the F-08 composition disclosed in the instant application are similar to the components of the depot compositions disclosed by Li et al. in Table 3, the examiner reasons that at least one, if not more, of the depot compositions disclosed by Li et al. in Table 3 have viscosities falling within the claimed ranges. As such, the examiner has provided a basis in fact and/or technical reasoning to reasonably support the determination that the allegedly inherent characteristic necessarily flows from the teachings of the applied prior art.
Once the examiner has presented evidence or reasoning to show inherency, the burden shifts to applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of the claimed product. See MPEP 2112.
Claim Rejections - 35 USC § 103
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 framework for the objective analysis for determining obviousness under 35 U.S.C. 103 is stated in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Obviousness is a question of law based on underlying factual inquiries. The factual inquiries enunciated by the Supreme Court in Graham are summarized as follows:
(A) Determining the scope and content of the prior art;
(B) Ascertaining the differences between the claimed invention and the prior art; and
(C) Resolving the level of ordinary skill in the pertinent art.
Objective evidence relevant to the issue of obviousness must be evaluated by Office personnel. Id. at 17-18, 148 USPQ at 467. The evidence may be included in the specification as filed, accompany the application on filing, or be provided in a timely manner at some other point during the prosecution. The weight to be given any objective evidence is determined on a case-by-case basis. The mere fact that an applicant has presented evidence does not mean that the evidence is dispositive of the issue of obviousness.
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. See MPEP 2143.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation (TSM) in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
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 instant application recites that “the term depot composition refers to a slow-release, or sustained release, or controlled release formulation of an active ingredient which releases the active ingredient over a long period of time to permit less frequent administration.” See instant application at Paragraph [0034].
The instant application recites that “the term of pharmaceutically acceptable oil is intended to includes any triglyceride oil, canola oil, castor oil, corn oil, cottonseed oil, grapeseed oil, olive oil, palm oil, peanut oil, rapeseed oil, safflower oil, sesame oil, soybean oil, sunflower oil, “vegetable” oil, walnut oil, medium-chain triglyceride (MCT) oil, and the like.” See instant application at Paragraph [0058].
As discussed in the above Claim Interpretation section, the presence of lipid is deemed to be an optional component of the compositions encompassed by all claims (except for claim 9) that are currently under examination.
Claims 1-2, 4-12 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Raval et al. (WO-2021081022-A1; published on 29 April 2021) in view of Bunnell et al. (US-6169084-B1; granted on 02 Jan 2001).
Raval et al. teach compositions comprising a vesicular monoamine transporter 2 (VMAT2) inhibitor, namely (+)-TBZ (also known as R,R-tetrabenazine) as an active ingredient for delivery as a depot. See Paragraphs [6], [8], [29], [31], [49], [50], [52], [65] and claim 14, for example. Moreover, Raval et al. teach that delivery of (+)-TBZ (also known as R,R-tetrabenazine) in a continuous or substantially continuous fashion offer many advantages over traditional oral delivery, such as avoiding first-pass metabolism, providing a pharmacokinetic profile with low peak to trough ratio, providing capacity for multiple-day therapy from a single application, avoiding food effects on absorption, and an easier patient compliance, etc. See Paragraph [5], for example. Raval et al. do not teach the particular depot components set forth in the claimed invention.
Bunnell et al. teach the particular depot components set forth in the claimed invention, but for delivering olanzapine as the lipophilic active ingredient, rather that (+)-TBZ, for delivery as a depot.
Relevant to claims 1-2, 4-12 and 18, Bunnell et al. teach depot compositions comprising (a) a lipophilic active ingredient, namely olanzapine, (b) a pharmaceutically acceptable oil; and (c) a lipid, wherein the lipid is a solid at a temperature between about 15 and about 30° C., and the lipid is present in an amount from 0% to about 50% by weight, relative to the weight of the depot composition.
Relevant to claim 5, Bunnell et al. teach sesame oil as a pharmaceutically acceptable oil. See Examples 34, 36, 40, 58, 59 and 60 at columns 20 and 21.
Relevant to claims 6 and 7, Bunnell et al. teach cholesterol as a lipid, wherein the lipid is a solid at a temperature between about 15 and about 30° C., and the lipid is present in an amount from 0% to about 50% by weight, relative to the weight of the depot composition. See Examples 126-129 and 131 at column 25.
Relevant to claim 8, Bunnell et al. teach that the concentration of active (in this case olanzapine) in vehicle the is restricted to 30mg/ml for each of Examples 34, 36, 40, 58, 59 and 60. See columns 20 and 21. As such, the concentration of active for each of Examples 34, 36, 40, 58, 59 and 60 is “in an amount less than about 70% by weight, relative to the weight of the depot composition.”
Relevant to claim 9, Bunnell et al. teach that, as a step toward creating olanzapine-cholesterol microparticle, 1.2 g of olanzapine and 8.8g of cholesterol was dissolved in 100 ml of methylene chloride. See Example 118 on column 24. While the final ratio of olanzapine to cholesterol was not disclosed, a ratio similar to the ratio between the starting mixture components would seem likely. Referring to Example 124, the concentration of active is reported to be 17.2%. Assuming that final ratio between olanzapine and cholesterol is similar to the ratio between the starting mixture components, the ratio of the lipid (cholesterol) to the pharmaceutically acceptable oil (ethyl oleate, in this example) must be between about 1:1 and about 1:99 by weight.
The examiner has provided a basis in fact and/or technical reasoning to reasonably support the determination that the allegedly inherent characteristic necessarily flows from the teachings of the applied prior art.
Once the examiner has presented evidence or reasoning to show inherency, the burden shifts to applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of the claimed product. See MPEP 2112.
In any event, while Bunnell et al. doesn’t expressly recite the ratio of the lipid to the pharmaceutically acceptable oil for the disclosed examples, Bunnell et al. indicates that each of these components and ratios imparts to the compositions containing them certain desirable properties or characteristics; therapeutic activity, modification of release rate, or ability to be injected via syringe; On this basis, a person of ordinary skill in the art would reasonably conclude that the amounts of each are result-effective variables that achieve the results each of the components referred to provide. As such, it would have been routine to optimize the amounts/ratios of these components within the total composition suggested by Bunnell et al. to obtain the concentrations recited by claim 9. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (indicating that where 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.).
Relevant to claims 10 and 11, Bunnell et al. teach various particle sizes and methods for creating various particle sizes. For example, Column 16, line 55 disclose olanzapine milled fine (O-F) having a particle size less than 5 μm and olanzapine milled coarse (O-C) having a particle size from 20-60 μm. While Bunnell et al. don’t disclose particle sizes using the D(50) standard, the disclosed particle sizes would seem to fall within the claimed ranges.
The examiner has provided a basis in fact and/or technical reasoning to reasonably support the determination that the allegedly inherent characteristic necessarily flows from the teachings of the applied prior art.
Once the examiner has presented evidence or reasoning to show inherency, the burden shifts to applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of the claimed product. See MPEP 2112.
In any event, while Bunnell et al. doesn’t expressly recite the D(50) for particle size distributions, Bunnell et al. indicates that particle size imparts to the compositions containing them certain desirable properties or characteristics; therapeutic activity, modification of release rate, or ability to be injected via syringe; On this basis, a person of ordinary skill in the art would reasonably conclude that the particle sizes are result-effective variables that achieve the results each of the components referred to provide. As such, it would have been routine to optimize the particle sizes within the total composition suggested by Bunnell et al. to obtain the sizes recited by claims 10 and 11. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (indicating that where 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.).
Relevant to claims 12, Bunnell et al. disclose that “[t]hree rabbits of the same sex were used for each formulation with selection based on availability. The rabbits were at least 5 months old and weigh between 2.5 to 5 kg. Rabbits were given a single injection with a 20- or 21-gauge needle into the biceps femoris. The dose volume varied with the concentration of the formulation but did not exceed 2 mL per injection. The rabbits were given 10 mg of olanzapine/kg body weight.” See Column 29, lines 42-53. Moreover, Bunnell et al. disclose that suitable packaging materials include “polypropylene syringes.” See Column 11, lines 65-66.
Relevant claim 18, Bunnell et al. do not expressly disclose the viscosities of the disclosed depot compositions. However, given that the components of the F-08 composition disclosed in the instant application are similar to the components of the depot compositions disclosed by Bunnell et al., the examiner reasons that at least one, if not more, of the depot compositions disclosed by Bunnell et al. have viscosities falling within the claimed ranges. As such, the examiner has provided a basis in fact and/or technical reasoning to reasonably support the determination that the allegedly inherent characteristic necessarily flows from the teachings of the applied prior art.
Once the examiner has presented evidence or reasoning to show inherency, the burden shifts to applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of the claimed product. See MPEP 2112.
In any event, while Bunnell et al. doesn’t expressly recite the viscosities of the disclosed depot compositions, Bunnell et al. indicates that viscosity imparts to the compositions containing them certain desirable properties or characteristics; therapeutic activity, modification of release rate, or ability to be injected via syringe; On this basis, a person of ordinary skill in the art would reasonably conclude that the viscosities are result-effective variables that achieve the results each of the components referred to provide. As such, it would have been routine to optimize the viscosities within the total composition suggested by Bunnell et al. to obtain the viscosities recited by claim 18. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (indicating that where 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.).
It would have been prima facie obvious to combine prior art elements according to known methods to yield predictable results.
As discussed above, Raval et al. provide motivation for preparing the claimed depot formulations. In particular, Raval et al. teach that delivery of (+)-TBZ (also known as R,R-tetrabenazine) in a continuous or substantially continuous fashion offer many advantages over traditional oral delivery, such as avoiding first-pass metabolism, providing a pharmacokinetic profile with low peak to trough ratio, providing capacity for multiple-day therapy from a single application, avoiding food effects on absorption, and an easier patient compliance, etc. See Paragraph [5], for example.
Moreover, depot compositions teach by Bunnell et al. are well know the art, and as such, one of ordinary skill would have had a reasonable expectation that the lipophilic olanzapine taught by Bunnell et al. could be substituted with the (+)-TBZ (also known as R,R-tetrabenazine) taught by Raval et al.
Given that depot formulations comprising (+)-TBZ (also known as R,R-tetrabenazine) show many potential advantages over traditional oral delivery, one of ordinary skill in the art would have been motivated to develop such depot formulations. Therefore, 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.
Conclusion
Claims 1-2, 4-12 and 18 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRADLEY S MAYHEW whose telephone number is 571-272-8428. The examiner can normally be reached Mon-Fri, 11:00 AM-7:00 PM.
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/BSM/Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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