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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 28 October 2025 has been entered.
Status of the Claims
Claims 1, 4-7, and 9-19 are pending.
Claims 14-18 are withdrawn as being directed to non-elected inventions.
Claims 1, 4-7, 9-13, and 19 are presented for examination and rejected as set forth in greater detail below.
Specification
The disclosure is objected to because of the following informalities: Review of the specification as originally filed during the Examiner’s consideration of the incomplete data provided by the Li declaration led the Examiner to discover a number of instances where the description does not appear to accurately correlate to data presented in drawings.
Applicants attention is specifically directed to paragraphs [00115-0011] on pages 44-46 of the specification as originally filed describing “Figure 5.” Applicants indicate that, in Figure 5A, data presented demonstrates that drug release is not correlated with particle size. However, Figure 5A only reflects data concerning a single particle size (small), but of various PLGA/NMP ratios. In addition, the X axis lacks a designation of what each of the vertical bars above each of the polymer designations corresponds to. In a similar manner, Figure 5B only reflects data measuring release of DHTBA from “large” particles, again of varying polymer/NMP ratios. Figure 5C referred to in paragraph [00118] does not exist. (Figures 5A and 5B reproduced below).
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In a similar manner, paragraphs [00104-00105] on pages 49-50 of the specification as originally filed describe the data presented as Figure 8. Figure 8 is described as a double axes chart containing solid and dashed axes. However, Figure 8 of the drawings is broken into three distinct charts, figures 8A, 8B, and 8C, none of which contain a solid or dashed axis. (Figures 8A, 8B, and 8C reproduced below).
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Appropriate correction is required.
Applicants are additionally advised to review the remainder of the disclosure to ensure that the description provided in the specification corresponds accurately to the various drawings provided.
Claim Interpretation
The instant claims encompass injectable compositions combining a VMAT2 inhibitor selected from either (+)-TBZ or (+)-(a)-DHTBZ with a biodegradable polymer selected from a Markush-type listing of alternative carboxylic acid terminated polymers, and an organic solvent selected from a Markush-type listing of alternatives. Claim 4 specifying the organic solvent to be N-methyl-2-pyrrolidone. Claims 5, 6, and 10 specify the concentration of inhibitor, or polymer, or solvent, respectively, to be included in the composition, with Claim 7 specifying particular limitations on the identity of the polymer to be used, Claim 9 specifying that the weight of the polymer falls within the range of about 5-22.275 kilodaltons. Claim 11 requires the inclusion of additional excipients, with Claim 12 specifying a particular particle size of the VMAT2 inhibitor present in the composition. Claim 13 homogeneously disperses the VMAT2 inhibitor in the composition and places the composition within a syringe for injection. Claim 19 indicates that the composition is to release the MVAT2 inhibitor over a period of at least four weeks.
Response to Amendment
The Declaration of Inventor Yuhua Li under 37 CFR 1.132 filed 28 October 2025 is insufficient to overcome the rejection of claims 1, 4-7, 9-13, and 19 based upon the combined teachings of O’Brien, Johannes, Altmann, and Gutierro Aduriz as set forth in the last Office action because the inventor declarant fails to provides evidence to establish anything unexpected that is achieved by the invention claimed, the inventor/declarant asserts facts that are not in evidence, and finally offers their opinion as to the ultimate question of patentability which is per se incapable of persuasion.
Inventor/Declarant Li first asserts that the compositions as claimed give rise to an unexpected stability of the active agents, which are asserted to be labile under acidic conditions which the inventor declarant asserts are established when acid-terminated PLGA polymers degrade over time. The examiner notes that applicants via the inventor declarant assert that degradation of the VMAT2 inhibitors of the present claims is brough about by the exposure of the TBZ or DHTBZ to acid generated by the degradation of the acid-capped, rather than ester-capped, PLGA polymers into which the actives are formulated. No evidence of record supports this assertion. The evidence provided concerning the stability, or lack thereof, of TBZ and DHTBZ combine the actives with lactic acid, rather than each of the ester or acid capped PLGA polymers applicants argue give rise to the asserted increase in stability that remains absent from the record. Applicant’s data combining the actives with NMP and lactic acid represent a speculative point of comparison, rather than the required comparison to the closest prior art, which is the combination of TBA with each of NMP and PLGA suggested by O’Brien. Evidence of unexpected results must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). In addition, the evidence relied upon should establish “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance.” Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). Here, none of the data presented by the inventor declarant provides any indication that whatever differences demonstrated are in fact statistically or practically significant, and as a result, this evidence is insufficient to overcome the Prima facie case of obviousness.
Inventor/Declarant Li’s second argument asserts that the data of record establishes a deviation from the particle size effect rule, whereby particles having a greater volume/surface area ratio, such as is provided by smaller particles, release drug at a greater rate. Applicants assert, and provide graphs which the inventor/declarant asserts demonstrates no relation between particle size and drug release rates. The Examiner notes the images inventor/declarant Li attempts to rely on in the declaration of 28 October 2025are impossible to read, but appear to be low-fidelity reproductions of 8A, 8B, and 8C as originally presented in the disclosure as originally filed, augmented to include bars indicating degrees of statistical significance. Figures 8A, 8B, and 8C are reproduced below.
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Per applicants’ specification, a particle size designation of “(S)” has a D50 of 10-35 microns, “(M)” of 50-80 microns, and “(L) 100-130 microns. (Specification paragraph 92). As these data show, applicants microparticles, contrary to applicants’ assertions, indeed subscribe to the expectation that smaller particles, those having a greater volume to surface area ratio, release drug at a greater rate than larger particles having a smaller volume to weight ratio. This is precisely what a skilled artisan would expect from such an arrangement. See, e.g., Weiluan Chen, et al, Effect of Particle Size on Drug Loading and Release Kinetics of Gefitinib-Loaded PLGA Microspheres, 14 Mol. Pharmaceutics 459 (2017). “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.” In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967), see also In re Skoner, 517 F.2d 947, 950 (CCPA 1975).
Finally, Inventor Declarant Li offers their opinion as to the ultimate legal question of patentability vis-à-vis a review of the state of the art concerning the various parameters which factor into controlling the rate of release of drugs from microparticles such as those of the instant claims. While an opinion as to a legal conclusion is not entitled to any weight, the underlying basis for the opinion may be persuasive. In re Chilowsky, 306 F.2d 908, 134 USPQ 515 (CCPA 1962). In assessing the probative value of an expert opinion, the examiner must consider the nature of the matter sought to be established, the strength of any opposing evidence, the interest of the expert in the outcome of the case, and the presence or absence of factual support for the expert’s opinion. Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281, 227 USPQ 657 (Fed. Cir. 1985), cert. denied, 475 U.S. 1017 (1986). Here, the nature of the matter to be established is the unpredictability of drug depot formulation in terms of establishing drug release rates giving rise to therapeutically desirable outcomes. Contrary to the assertions of the inventor/declarant, the evidence relied on tends to support the Examiner’s position that the factors controlling rates of drug release are in fact rather well-known and well within the skill set of the ordinary artisan. "[A] prior art publication cited by an Examiner is presumptively enabling barring any showing to the contrary by a patent applicant." In re Antor Media Corp., 689 F.3d 1282, 1288 (Fed. Cir. 2012). Applicants have failed to provide sufficient evidence tending to establish the unpredictability of the art of record, because affidavits or declarations attacking the operability of a patent cited as a reference must rebut the presumption of operability by a preponderance of the evidence. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). Finally, as a named inventor of the present application the Declarant’s interest in the outcome of the case is straightforward.
For all of these reasons, the Declaration of inventor Li is unpersuasive.
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, 4-7, 9-13, and 19 stand rejected under 35 U.S.C. 103 as being unpatentable over O’Brien (U.S. PGPub. 2020/0268744), in view of Johannes (Manuel Johannes & Karl-Heinz Altmann, A Ring-Closing Metathesis-Based Approach to the Synthesis of (+)-Tetrabenazine, 14 Org. Lett. 3752 (2012)), and Gutierro Aduriz (U.S.PGPub. 2019/0151230).
O’Brien describes compositions containing VMAT2 inhibitors. (Abs.). The (+)-(α)-DHTBZ of Claim 3 is recited as just one specific, yet non-exclusive, VMAT2 inhibitor for use in such compositions. [0020]. O’Brien indicates that these VMAT2 inhibitors may be formulated as, among others, microspheres delivered by parenteral administration via injection, [0169], including implanted depot formulations, [0176], such as by containing the composition within a syringe recited by Claim 13. [0173]. O’Brien indicates that suitable carriers for injection include the N-methyl-2-pyrrolidone of Claims 1 and 4, and that additional excipients known to be useful in such compositions include the buffering agents, antioxidants, stabilizers, solubility enhancers recited by Claim 11. [0170-71]. O’Brien indicates that the compositions may be provided as modified release dosage forms, including multiparticulate dosage forms made from, among others, degradable lactic acid/glycolic acid copolymers. [0194-98]. O’Brien indicates that the multiparticulate controlled-release dosage forms have pellet sizes falling within the range of about 100pm-1mm in diameter. [0214]. While O’Brien does not specify any particular concentrations of VMAT2 inhibitor, polymer, or solvent to be present in the injectable dosage forms recited, O’Brien does indicate that each of these components 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 of these components within the total composition suggested by O’Brien to obtain the concentrations recited by Claims 5, 6, and 10. 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.).
The specific combination of VMAT2 inhibitor, polymer, and solvent claimed is disclosed within the broad generic ranges taught by the reference but such “picking and choosing” within several variables does not necessarily give rise to anticipation. Corning Glass Works v. Sumitomo Elec., 868 F.2d 1251, 1262 (Fed. Circ. 1989). Where, as here, the reference does not provide any motivation to select this specific combination of (+)-(α)-DHTBZ with N-methyl-2-pyrrolidone and a PLGA copolymer in a syringe with suitable excipients as an injectable depot formulation containing drug microparticles per the instant claims, anticipation cannot be found.
That being said, however, it must be remembered that “[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)). “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious,” the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR at 1741. The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.” Id. at 1742.
Consistent with this reasoning, it would have been prima facie obvious to have selected various combinations of (+)-(α)-DHTBZ with N-methyl-2-pyrrolidone and a PLGA copolymer in a syringe with suitable excipients as an injectable depot formulation containing drug microparticles per the instant claims from within a prior art disclosure, to arrive at compositions “yielding no more than one would expect from such an arrangement.”
That having been said, O’Brien does not disclose the use of the elected (+)-TBZ as the particular VMAT2 inhibitor, nor is the use of a PLGA complying with the requirements of Claims 1, 7, 9, and 12 recited.
Johannes, however, indicates that (+)-TBZ demonstrates increased inhibitory properties when compared to its racemate, providing the skilled artisan motivation to use this enantiomer as a pharmaceutical active agent where inhibition of VMAT2 is desired. (Pg.3752-53).
Gutierro Aduriz describes injectable depot formulations combining biodegradable PLGA copolymers with polar solvents and psychoactive medications for providing sustained release of the drugs so contained. (Abs.). Gutierro Aduriz indicates that these formulations are particularly suited for use in delivering agents being treated for diseases such as schizophrenia, but may include antipsychotics and more broadly any agents capable of producing a biological effect locally or systemically. [0003; 0110]. These drugs are described as representing between 4-40% by weight of the composition. [0112]. Gutierro Aduriz indicates that these formulations advantageously include DMSO or N-methylpyrrolidone of Claims 1 and 4 as the solvent, and provide for the sustained release of the drugs so formulated for periods of at least 14 days post implantation, a range overlapping and therefore rendering obvious that of newly added Claim 19. [0019-20], see In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (“A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.”). Gutierro Aduriz goes farther, indicating that dosing periods can exceed periods of 28 days, addressing the limitations of newly added Claim 19, and can be adjusted or controlled by modifying any of a number of different variables. [0027-31; 0111-16; 0139]. Gutierro Aduriz indicates that the polymer may be present in concentrations of about 20-25% of the composition, and is selected from a group containing the claimed PLGA having a ratio of lactic to glycolic acid falling within the range of about 48:52 to 100:0, ranges both sufficiently close to as well as overlapping that of Claims 1, 6 and 7. [0041], see Peterson, supra, see also Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (indicating 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). Both acid-and ester-endcapped polymers are described by Gutierro Aduriz as suitable for use in these compositions. [0106]. Gutierro Aduriz indicates that the polymer should have a molecular weight falling within the range of about 10-43KDa, a range overlapping and therefore rendering obvious that of amended Claim 9. [0136], see Peterson, supra. Gutierro Aduriz indicates that the drug to be contained within the composition should be present as particles having a d(50) of 40-200 microns, a range overlapping and therefore rendering obvious that of the present claims. [0042], see Peterson, supra. Gutierro Aduriz indicates the solvent is to be present in these compositions in a ratio relevant to the polymer of between about 4:1-1:1, ratios overlapping and therefore rendering obvious the 10-90%by weight of solvent relative to the combined amount of solvent and polymer recited by Claim 10. [0041], see Peterson, supra.
It would have been prima facie obvious to have provided the VMAT2 inhibitors (+)-(α)-DHTBZ or (+)-TBA as particles having a D50 of between 60-130 microns and used a carboxylic acid endcapped 50:50 PLGA copolymer of molecular weight between 30-36KDa as the drug particle size and polymer of the injectable sustained-release depot of O’Brien. One having ordinary skill in the art would have been motivated to do so owing to the fact that O’Brien specifies the use of PLGA copolymers as the release-modifying means of their disclosure, similar to the manner in which Gutierro Aduriz employs the carboxylic acid endcapped 50:50 PLGA copolymer having a molecular weight of 30-36KDa as the means for controlling the release of CNS agents from injectable depots. This selection of polymer and drug particle size likewise appears little more than the use of old elements with each performing the same function it had been known to perform and yielding no more than one would expect from such an arrangement, and obvious thereby. KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)) (indicating that “when the question is whether a patent claiming the combination of elements of prior art is obvious,” the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.”).
Response to Arguments
Applicant's arguments filed 28 October 2025 have been fully considered but they are not persuasive.
Applicants repeated arguments concerning the art “teaching away from” combining TBZ with acidic terminated PLGA polymers is no more persuasive upon its repetition. PLGA copolymers are specifically enumerated as particular polymers DHTBZ may be combined with to formulate a drug delivery system (O’Brien [0198]), and Gutierro Aduriz establishes that, absent a specific teaching concerning the nature of an endcap provided in PLGA copolymers, PLGA possess a carboxylate terminal group. [0106; 0274; 0299]. Applicants assertion that Gutierro Aduriz teaches away from the use of acid-terminated PLGA polymers misrepresents what Gutierro Aduriz actually teaches, as nothing of Gutierro Aduriz criticizes, discredits, or otherwise discourages the use of acid-terminated PLGA copolymers. In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). Gutierro Aduriz merely indicates that ester capped PLGA copolymers are preferred in certain embodiments of the invention described. Applicants are reminded that art is art, not only for what it expressly teaches, but also for what it would reasonably suggest to the skilled artisan, including alternative or non-preferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). Furthermore, a known or obvious invention does not become patentable simply because it has been described as somewhat inferior to some alternative for the same use. In re Gurley, 27 F.3d 551, 554 (Fed. Cir. 1994).
Applicants assert that the single sentence mentioning that “polymers that are end-capped with esters (as opposed to free carboxylic acid) demonstrate longer degradation half-lives” amounts to the criticism required to teach away from the use of an acid capped PLGA copolymer in the formulations of the Gutierro Aduriz disclosure. This is unpersuasive as Gutierro Aduriz establishes that a number of factors contribute to the control of release from polymeric drug delivery agents, including but not limited to the viscosity of the polymer solution, the inherent or intrinsic viscosity of the polymer in solution and the water solubility of the active ingredient. [0027-31]. Moreover, Gutierro Aduriz establishes that degradation rates of PLGA copolymers may be adjusted by controlling the ratio of glycolide to lactide units. [0106]. As such, multiple factors aside from the nature of the terminus of the copolymer are acknowledged by the art as contributing to the degradation and release of agent from drug delivery depots containing them, and nothing of the function of the disclosure of Gutierro Aduriz can be said to be frustrated by the employ of an acid-terminated PLGA copolymer taught as an alternative to the ester-capped PLGA copolymers in the Gutierro Aduriz disclosure.
Applicants again assert that carboxylic acid terminated PLGA copolymers are not taught by the art of record. This position should fail at the outset as this position is in direct contrast to the arguments presented by applicants in multiple pages of argument already of record. Applicants, relying solely on the disclosure of Gutierro Aduriz, suggest that ester endcapped PLGA copolymers offer particular benefits over the alternative carboxylic acid terminated PLGA copolymers that represent the only alternative to ester-capped PLGA polymers of record.
Applicants arguments concerning the probative value of the declaration of inventor Li have been addressed above in the section of the present Office Action discussing the unpersuasive nature of the Li Declaration and will not be reproduced here.
Applicants assert that the Johannes reference fails to cure the deficiencies of the combination of O’Brien and Gutierro Aduriz; as set forth above, this is unpersuasive owing to the lack of deficiency in the combination of O’Brien and Gutierro Aduriz.
For at least these reasons, applicants arguments are unpersuasive.
Conclusion
No Claims are allowable.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN M BASQUILL whose telephone number is (571)270-5862. The examiner can normally be reached Monday through Thursday, 5:30 AM to 4 PM.
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/SEAN M BASQUILL/Primary Examiner, Art Unit 1614