DETAILED ACTION
Claims 46-47, 49-50, 52, 68-74, 79-80 are currently pending. Claims 46-47, 49-50, 68-69, 72-73 are currently under examination.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 08/15/2025 has been entered.
Withdrawn Rejections
The prior rejection of claims 46-47, 68, 72-73 and 75-77 under 112 (b) is withdrawn as a result of Applicant amending claims 46 to clearly refer to lurasidone particles and canceling claim 75-76.
The prior rejection claims 75-76 under 112(d) is withdrawn as a result of Applicant canceling claims 75-76.
Examiner’s Note
Applicant's amendments and arguments filed 08/15/2025 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. In the Applicant’s response, filed 08/15/2025, it is noted that claims 46 and 49 have been amended and no new matter or claims have been added.
Modified Rejections:
The following rejections are modified based on Applicant’s claim amendments.
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 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.
Claim(s) 46-47, 49-50, 68-69 and 72-73 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 2006/0154918 (Applicant provided) in view of US 2002/0160967 (Applicant provided), US 2008/0247957 (Applicant provided) and US 2009/0286805 (Applicant provided).
Regarding claims 46 and 49, the limitation of a processing for preparing a long acting injectable formulation comprising mixing about 0.1% to about 10% by weight of an amphiphilic agent selected from a group including benzyl alcohol with about 80% to about 95% by weight of a non-aqueous liquid vehicle comprising a hydrophobic lipid comprising a glyceryl ester of a c6-c24 fatty acid, dispersing about 5% to about 20% by weight of a poorly water-soluble active pharmaceutical ingredient in the mixture of (i) and mixing to form a dispersion and milling the dispersion is met the ‘918 publication teaching injectable formulation of nanoparticulate olanzapine that produce a prolonged duration of action upon administration (abstract) wherein olanzapine is taught to be practically insoluble in water [0009]. The olanzapine is taught at 5 to 50% [0058]. Excipients are taught to include benzyl alcohol as a preservative at up to 2% ([0092], elected amphiphilic agent). The liquid medium is taught to be from 5 to 60 wt% [0113] wherein the liquid medium is taught to be selected from vegetable oils ([0132], non-aqueous liquid vehicle). Release is taught to be over about one week or greater [0020].
The limitation of wherein the active pharmaceutical ingredient is dispersed as discrete particles having a D90 particle size of about 0.5 um to about 25 um in the formulation is met by the ‘918 publication teaching the nanoparticulate is taught to have D90 and D99 of less than about 5 microns [0095].
The ‘918 publication teaches methods of making the formulation (abstract). Nonaqueous examples of media include safflower oil in which olanzapine is poorly soluble and dispersible can be used as the dispersion medial [0109]. Effective method of milling includes ball milling and media milling using milling media, drug, stabilizer and liquid placed in a milling vessel reduce the particle size [0110]. Media milling is a high energy milling process. Drug, stabilizer, and liquid are placed in a reservoir and recirculated in chamber containing medial and a rotating impeller which agitates the medial thereby reducing the drug particle size [0111]. The premix is taught to containing liquid medial in which olanzapine is essentially insoluble, surface stabilizer, which can be present in the premix or added to the dispersion following particle size reduction [0113]. The premix can be used directly by subjecting to mechanical means [0114]. The ‘918 publication teaches mixing the amphiphilic agent (surface stabilizer) and the non-aqueous vehicle and dispersing the poorly water-soluble active agent, however does not specifically recite mixing step before the dispersing step. Selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. MPEP 2144.049 IV (C).
Regarding claims 47 and 50, the limitation of wherein the process further comprises adding additional excipients to form a final dosage form is met by the ‘918 publication teaching additional adjuvants such as preserving, wetting and emulsifying agents and agents to prevent growth of microorganisms being added [0133]. Selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. MPEP 2144.049 IV (C).
Regarding claims 72-73, the limitation of wherein the milling is wet milling process comprising ball/media, high shear or high-pressure homogenizer milling is met by the ‘918 publication teaching ball milling [0110].
The ‘918 publication does not specifically recite wherein the hydrophobic lipid comprising a glyceryl ester of a c6-c24 fatty acid the non-aqueous liquid vehicle (claims 46, 47, 68-69).
The ‘918 publication does not specifically teach the poorly water soluble active pharmaceutical ingredient is lurasidone as a free base or salt (claim 46).
The ‘967 publication teaches injection formulations based on sesame oil, medium chain triglycerides and a further solvent including aromatic alcohols (abstract). The injection formulation includes active compound from 0.2 to 5%, sesame oil from 60 to 90% and 1 to 20% benzyl alcohol ([0008]-[0012]). Viscosity can be adjusted to a desired low value by addition of medium chain triglycerides. Additionally, the solubility of the active compound can be improved, the viscosity further reduced and the bioavailability of the active compound can be improved by addition of small amounts of benzyl alcohol [0015]. The instant specification evidences sesame oil is a C6-C24 fatty acid [00103].
The ‘957 teaches injectable formulations (abstract). Liquid suspensions are prepared using conventional methods wherein vegetable oils such as olive and sesame oils [0016].
The ‘805 publication teaches a solution type preparation of lurasidone as an active ingredient containing at least benzyl alcohol (abstract). The preparation is a parenteral preparation [0008], wherein the injection is intramuscular [0009]. The solution contains 5-25% lurasidone [0014] and 2-15% benzyl alcohol [0015]. The preparation may be an oily preparation including sesame oil [0020]. Lurasidone is taught as hardly soluble [0003] and in free form or pharmaceutically acceptable acid addition salt thereof (abstract, [0007]), thus salt form.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute a vegetable oil, olive oil, as taught by the ‘918 publication with a second vegetable oil, sesame oil, as taught by the ‘967 publication with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06.
One of ordinary skill in the art before the effective filing date of the claimed invention would have a reasonable expectation of success in using the sesame oil in the composition taught by the ‘918 publication as the ‘918 publication teaches vegetable oils, such as olive oil, to be used in injectable formulations and the ‘967 publication teaches sesame oil can be used in injectable formulations. One of ordinary skill in the art at the time the invention was made would have a reasonable expectation of success in using sesame oil in the formulation taught by the ‘918 publication because the ‘957 publication teaches sesame oil and olive oil are both vegetable oils and the ‘918 publication teaches the use of vegetable oils in the injectable formulation. One of ordinary skill in the art before the filing date of the claimed invention would have a reasonable expectation of success as the ‘918 publication and the ‘967 publication teaches olive oil and sesame oil are both known to be used in injectable formulations.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use lurasidone as taught by the ‘805 publication in place of olanzapine as taught by the ‘918 publication (abstract) because lurasidone and olanzapine are both taught to be formulated as injectable compositions used in vegetable oil (‘805: abstract, [0020]; ‘918: abstract; [0132]). One of ordinary skill in the art before the effective filing date of the claimed invention would have a reasonable expectation of success in substituting lurasidone for olanzapine in the injectable formulation as lurasidone and olanzapine are both low water-soluble compounds to be in oil injectable solutions (‘805: abstract; [0031], [0003]; ‘918: abstract, [009], [0132]). It would have been obvious to one of ordinary skill in the art to substitute a first medicinal agent as taught by the ‘918 publication with a second medicinal agent, lurasidone, as taught by the ‘805 publication with a reasonable expectation of success because the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06.
The combination of references teaches the structure of the claims, including the poorly water-soluble active ingredient, the elected non-aqueous liquid vehicle and elected amphiphilic agent and particle sizes of the active ingredient in the claimed concentration and thus would necessarily have the functional features of the claim, including the formulation being thixotropic at the claimed shear rate and release. The ‘957 publication teaches the specifically claimed non-aqueous liquid vehicle, sesame oil, and additionally teaches it is known to optimize the viscosity using additives such as medium chain triglycerides. The U.S. Patent Office is not equipped with analytical instruments to test prior art compositions for the infinite number of ways that a subsequent Applicant may present previously unmeasured characteristics. When as here, the prior art appears to contain the exact same ingredients and Applicant’s own disclose supports the suitability of the prior composition as the inventive composition component, the burden is property shifted to Applicant to show otherwise.
37 CFR 1.132 Declaration
The examiner acknowledges receipt of the Declaration under 37 CFR 1.132 by Dr. Salah U. Ahmed filed on 04/30/2021.
The Declaration under 37 CFR 1.132 filed 08/15/2025 is insufficient to overcome the rejection of 46-47, 49-50, 68-69 and 72-73 under 35 U.S.C. 103 as being unpatentable over US 2006/0154918 in view of US 2002/0160967, US 2008/0247957 and US 2009/0286805 as set forth in the last Office action because:
Declaration A:
Applicant presents data where poorly water soluble active pharmaceutical ingredients demonstrate formation of particle agglomeration or crystal growth. The tested active agents were lurasidone, cariprazine and brexpiprazole which were present at 300 mg, polysorbate 80 at 30 mg and water at 3 ml. The non-aqueous formulations contain lurasidone, cariprazine or brexpiprazole which were present at 300 mg, benzyl alcohol at 30 mg and sesame oil. The formulations were ground into a wet mass wherein agglomerated particles and crystals were not formed. Thus the non-aqueous formulation unexpectedly provided stable injectable formulation that did not form agglomerated particles when stored. Additionally the claimed thixotropic properties were found.
In response, Applicant’s presented data is not commensurate in scope with the instant claims. The instant claims are broadly directed to lurasidone at 5-20 wt%, a non-aqueous vehicle selected from a hydrophilic lipid and a hydrophilic organic compound selected from PEG, propylene glycol, glycerin and dimethylsulfoxide and an amphiphilic agent, wherein the active agent particles have a specific size range. The supplied examples are to a single concentration range of 3 specific drugs, benzyl alcohol and sesame oil, wherein the claims are broadly directed to lurasidone at a broad concentration range, the non-aqueous vehicle which is broadly claimed in both components and concentration range and amphiphilic agent with a broad concentration range. Thus the examples containing 3 tested active agents, a single vehicle and a single amphiphilic agent, wherein the active agent particle size is not even disclosed is not commensurate in scope with the instant claims. Additionally, the agents are changed from polysorbate 80 in the water example to benzyl alcohol in the sesame oil example, thus making the comparison as to the aggregation cause not comparable due to changing multiple variables in the test examples. Additionally the reduced particle size demonstrated in sesame seed oil containing examples appears to demonstrate better solubility of the active agent, which would be expected as the active agents are poorly-soluble in water and placed in an oil. The showing of unexpected results must be commensurate in scope with the invention as claimed MPEP 716.02(d).
Further the ‘918 publication teaches the use of vegetable oils (such as olive oil) as the injectable fluid. Applicant is required to compare to the closest subject matter that exists in the prior art. MPEP 716.02(e).
Declaration B:
Declarant states that the claimed specific combination of elements at the indicated concentrations provides a formulation that is stable, i.e. without particle agglomeration, has a specific viscosity suitable for administration, is thixotropic and provides for an in vivo release of the active pharmaceutical ingredient over a period of greater than about 1 week.
In response, as stated by Applicant the specific concentration and elements result in the presented superior results. The instant claims are directed to a broad concentration of lurasidone and amphiphilic agent, wherein the element of amphiphilic agent is also broad.
Applicant presents data wherein lurasidone is at 30 wt% it is too viscous to be injected. Applicant presented data wherein no amphiphilic agent is used results in failed visual inspection as the product showed significant change in color from off white to dark brown. Applicant presents data containing 20% benzyl alcohol which resulted in phase separation.
In response, Applicant has presented data demonstrating 30 wt% lurasidone is too viscous, no benzyl alcohol results in color change to 20% benzyl alcohol results in phase separation. The data presented is not commensurate in scope with the instant claim. The instant claims are more broadly directed to the composition including an amphiphilic agent at 0.1 to 10 wt%. The presented examples are directed to benzyl alcohol as the only amphiphilic agent tested and thus are not commensurate in scope. Additionally the results tested include no benzyl alcohol and 20% benzyl alcohol result in a problem with the formulation. Applicant has not tested the outer limits of the claimed range for the amphiphilic agent to demonstrate color change or phase separation are not resulted through the upper and lower limits of the claimed range, and thus the data presented is not commensurate in scope. Additionally Applicant has tested lurasidone at 30 wt% to demonstrate too high of a viscosity, however Applicant has not tested the upper limit of the claimed range, 20 wt%. Thus the presented data is not commensurate in scope. It is further noted that the data presented does not include the particle size of the dispersed lurasidone particle, and thus a proper comparison to the claims cannot be made.
In addition to the facts provided above, the examiner notes that the Affiant is the same as the Inventor of the instant application. Therefore, the Affiant has an interest in the outcome of the instant application.
In assessing the weight to be given expert testimony, the examiner may properly consider, among other things, the nature of the fact 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. See Ex parte Simpson, 61 USPQ2d 1009 (BPAI 2001), Cf. Redac Int’l. Ltd. v. Lotus Development Corp., 81 F.3d 1576, 38 USPQ2d 1665 (Fed. Cir. 1996), Paragon Podiatry Lab., Inc. v. KLM Lab., Inc., 948 F.2d 1182, 25 USPQ2d 1561, (Fed. Cir. 1993).
Affidavits or declarations are provided as evidence and must set forth facts, not merely conclusions. In re Pike and Morris, 84 USPQ 235 (CCPA 1949).
Upon consideration of the facts taught by the prior art and the information submitted by the Affiant, the balance of evidence indicates that the prior art teaches the instantly claimed inventions.
Response to Arguments:
Applicant’s arguments have been fully considered and are not deemed to be persuasive.
Applicant argues the cited combination of references failed to teach or suggest a preparation of the claimed combination of elements to achieve a long acting injectable formulation of lurasidone that is thixotropic, has a particular viscosity and provides for an in vivo release of the active pharmaceutical ingredient over a period of greater than 1 week. The cited combination of references do not teach or suggest the claimed process for producing a long acting injectable formulation of lurasidone with the viscosity and release recited in the claims.
In response, the ‘918 publication teaches olanzapine, at least one surface stabilizer and at least one acceptable carrier [0022] wherein the composition is taught to be injectable [0020]. The injection formation is taught to include aqueous and non-aqueous carriers wherein vehicles include water, polyols, suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters [0132]. The ‘967 publication teaches formation which includes an active agent, sesame oil and benzyl alcohol in the claimed amounts wherein the viscosity is taught to be adjustable by addition of medium chain triglycerides and benzyl alcohol (abstract, [0008]-[0012], [0015]). Thus providing a motivation to use the specific combination of sesame oil, benzyl alcohol with an active agent in an injectable formation and a method of obtained the desired viscosity of such formation. The combination of references teaches the structure of the claims, including the poorly water-soluble active ingredient, the elected non-aqueous liquid vehicle and elected amphiphilic agent and particle sizes of the active ingredient in the claimed concentration and thus would necessarily have the functional features of the claim, including the formulation being thixotropic at the claimed shear rate and release rate. The ‘957 publication teaches the specifically claimed non-aqueous liquid vehicle, sesame oil, and additionally teaches it is known to optimize the viscosity using additives such as medium chain triglycerides. The U.S. Patent Office is not equipped with analytical instruments to test prior art compositions for the infinite number of ways that a subsequent Applicant may present previously unmeasured characteristics. When as here, the prior art appears to contain the exact same ingredients and Applicant’s own disclose supports the suitability of the prior composition as the inventive composition component, the burden is property shifted to Applicant to show otherwise.
Applicant argues the ‘918 publication mentions safflower oil and olive oil as examples of non-aqueous dispersion media but the working examples teach aqueous suspensions. The teachings of the ‘918 publication re not practical for formulating non aqueous suspensions and provide no guidance to the skilled artisan.
In response, “Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).” (see MPEP 2123). Further, “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).” (see MPEP 2141.02). The ‘918 publication teaches olanzapine, at least one surface stabilizer and at least one acceptable carrier [0022] wherein the composition is taught to be injectable [0020]. The injection formation is taught to include aqueous and non-aqueous carriers wherein vehicles include water, polyols, suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters [0132]. The vehicle may be present at 94.4% w/w or less [0058]. The ‘967 publication teaches formation which includes an active agent, sesame oil and benzyl alcohol in the claimed amounts wherein the viscosity is taught to be adjustable by addition of medium chain triglycerides and benzyl alcohol (abstract, [0008]-[0012], [0015]). Thus providing a motivation to use the specific combination of sesame oil, benzyl alcohol with an active agent in an injectable formation and a method of obtained the desired viscosity of such formation. The ‘957 publication teaches the interchangeability of oil and sesame oil in injectable formulations (abstract, [0016]), thus one of ordinary skill in the art would have reasonable expectation of success in using sesame oil in place of the olive oil taught by the ‘918 publication.
Applicant argues the ‘967 publication is a solution not a suspension and is significantly different. Challenges associated with making a suspension include stabilizing the suspension, avoiding particle growth or caking and producing an injectable suspension capable of delivery a suspension product via narrow injection needle without jamming. Applicant points to a solution vs suspension study demonstrating extended drug release over a period of one week was not found for the solution.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The ‘918 publication is directed injectable formulation of nanoparticulate drug that produce a prolonged duration of action upon administration (abstract) wherein oil media is taught ([0132]).
Applicant argues the process of preparing the long acting injectable formulation produces a formation with unexpected results. Applicant points to the first and second declaration.
In response, the Declarations are addressed above in the declaration section.
Conclusion
No claims are allowed.
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/LYNDSEY M BECKHARDT/Examiner, Art Unit 1613
/ANDREW S ROSENTHAL/Primary Examiner, Art Unit 1613