DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . 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.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 10/19/2022 has been considered by the examiner.
Status of the Claims
The response filed 12/03/2025 is acknowledged.
Claims 9-10, 12-14, 17-19, 23-27, and 37-39 are pending.
Claims 37-39 are new.
Claims 19 and 23-27 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/23/2025.
Claims 9-10, 12-14, 17-18, and 37-39 are treated on the merits in this action.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. Rejections not reiterated herein have been withdrawn.
Withdrawn
Duplicate Claim Warning
The duplicate claim warning has been withdrawn because of Applicant’s amendment.
Response to Arguments
Applicant's arguments filed 12/03/2025 have been fully considered but they are not persuasive.
Applicant has argued Kassick/Majeti do not teach an oral formulation. Applicant argues Kassick teaches naloxone-containing compositions. However, Applicant argues that for in vivo treatment of mice with the naloxone-containing compositions, Kassick only teaches administration of parenteral injections to the mice such as intraperitoneal (IP) injections (see page 3421, second column, second paragraph). Applicant argues the 'suspensions' taught by Kassick are simply used in the preparation of the nanoparticles and are not indicative of an oral formulation.
Applicant argues that although Majeti mentions peroral administration of nanoparticles, none of the embodiments in Majeti include the active ingredient naloxone. Applicant argues that oral formulations of naloxone are not currently available due to the oral bioavailability of naloxone being very low (e.g., estimated to be 0.9-2%). See, e.g., page 1, lines 16-17 of the specification as filed for the captioned application. Applicant argues a person of ordinary skill in the art would not be motivated to modify the teachings of Kassick with the teachings of Majeti and arrive at the claimed pharmaceutical composition comprising naloxone as an oral formulation. In other words, there would be no reasonable expectation of success at arriving at the amended claims based on the combined teachings of Kassick/Majeti.
These arguments are unpersuasive.
The claimed invention is directed to a product rather than a method of use. The cited prior art does not need to teach a step of orally administering the composition to meet the claimed limitations. The claimed invention does include the limitation of an oral formulation. However, as evident from claims 12-14, a suspension or reconstitutable suspension is an oral formulation. The prior art teaches the nanoparticle composition in the form of a suspension (Kassick, e.g., pg. 3420, Naloxone Release Rate Determination) or a lyophilized powder (aka reconsitutable suspension since the solid is redispersible in water, see Kassick, e.g., pg. 3420, c2: Preparation of Covalently Linked Naloxone−PLA Nanoparticles, and pg. 3425, c1: Nanoparticle Preparation and Characterization). Here, the prior art teaches specific forms which Applicant considers to be oral formulations as evident from the dependent claims.
The term “oral formulation” is not afforded any special definition in the specification. There does not appear to be any claimed structural distinction between a lyophilized solid, or suspension oral formulation as claimed and a lyophilized solid, powder or suspension formulation as taught by the prior art. Kassick need not call the suspension, lyophilized solid, or powder an “oral formulation” to meet the claim limitations. Identical language between the prior art and claims is not required to sustain a prior-art rejection. In re Skoner, 517 F.2d 947, 950 (CCPA 1975) ("Any other result would permit the allowance of claims drawn to unpatentable subject matter merely through the employment of descriptive language not chosen by the prior art").
The composition is able to be used orally (Majeti, e.g., 0002 and 0004 and 0029). Thus, compositions comprising PLA nanoparticles with a conjugated ligand and drug would be considered an oral formulation according to Majeti.
Majeti suggests modifying PLA nanoparticles with a conjugated ligand to improve gastrointestinal and/or blood brain barrier absorption of the particle irrespective of the nature of the drug (Majeti, e.g., 0002-0003). On this basis the skilled artisan would have had a reasonable expectation of successfully modifying Kassick’s nanoparticles with a ligand as suggested by Majeti.
Majeti also shows there was a desire in the art to formulate PLA nanoparticle drug carriers for oral delivery because it avoids the need for invasive routes of administration (Majeti, e.g., 0002-0003). Even if, arguendo, e.g., oral suspensions were distinct from injectable suspensions, there was motivation from Majeti to formulate PLA nanoparticle drug carriers as an oral formulation to simplify administration. Thus, the prior art teaches an oral formulation as claimed.
Applicant argues the combined teachings of Averick/Majeti do not teach an oral formulation. Averick teaches naloxone-containing compositions. Applicant argues Averick teaches that "dosage form[s] may be for intramuscular injection, nasal inhalation, subcutaneous injection, or adipose tissue injection." See [0046]. Applicant argues the rehydrated dry powders suggested by Averick seem to pertain to a powder that is rehydrated for injection of the described dosage forms (e.g., intramuscular injection, subcutaneous injection, or adipose tissue injection) and are not indicative of an oral formulation. Applicant argues Majeti mentions peroral administration of nanoparticles, none of the embodiments in Majeti include the active ingredient naloxone. Applicant argues that it is well known that oral formulations of naloxone are not currently available due to the oral bioavailability of naloxone being very low (e.g., estimated to be 0.9-2%). See, e.g., page 1, lines 16-17 of the specification as filed for the captioned application. Thus, Applicant argues a person of ordinary skill in the art would not be motivated to modify the teachings of Averick with the teachings of Majeti and arrive at the claimed pharmaceutical composition comprising naloxone as an oral formulation. In other words, there would be no reasonable expectation of success at arriving at the amended claims based on the combined teachings of Averick/Majeti. Applicant further argues Averick does not cure the deficiencies in the double patenting rejection.
These arguments are unpersuasive.
The claimed invention is directed to a product rather than a method of use. The cited prior art does not need to teach a step of orally administering the composition to meet the claimed limitations. The claimed invention does include the limitation of an oral formulation. However, as evident from claims 12-14, a suspension or reconstitutable suspension is an oral formulation. The prior art teaches the nanoparticle composition in the form of a suspension: rehydrated powder is a suspension (Averick, e.g., 0047). Averick also teaches an emulsion (Averick, e.g., 0048). Reconstitutable suspension reads on a rehydratable powder (Averick e.g., 0047). The prior art teaches a lyophilized powder (also a reconsitutable suspension since the solid is redispersible in water, see Averick, e.g., 0034). Here, the prior art teaches specific forms which Applicant considers to be oral formulations as evident from the dependent claims.
The term “oral formulation” is not afforded any special definition in the specification. There does not appear to be any claimed structural distinction between a lyophilized solid, or suspension oral formulation as claimed and a lyophilized solid, powder or suspension formulation as taught by the prior art. Averick need not call the suspension, lyophilized solid, or powder an “oral formulation” to meet the claim limitations. Identical language between the prior art and claims is not required to sustain a prior-art rejection. In re Skoner, 517 F.2d 947, 950 (CCPA 1975) ("Any other result would permit the allowance of claims drawn to unpatentable subject matter merely through the employment of descriptive language not chosen by the prior art").
Averick teaches compositions comprising naloxone/PLA nanoparticles (Averick, e.g., example 4, 0062).
The composition is able to be used orally (Majeti, e.g., 0002 and 0004 and 0029). Thus, compositions comprising PLA nanoparticles with a conjugated ligand and drug would be considered an oral formulation according to Majeti.
Majeti suggests modifying PLA nanoparticles with a conjugated ligand to improve gastrointestinal and/or blood brain barrier absorption of the particle irrespective of the nature of the drug (Majeti, e.g., 0002-0003). On this basis the skilled artisan would have had a reasonable expectation of successfully modifying Averick’s nanoparticles with a ligand as suggested by Majeti.
Majeti also shows there was a desire in the art to formulate PLA nanoparticle drug carriers for oral delivery because it avoids the need for invasive routes of administration (Majeti, e.g., 0002-0003). Even if, arguendo, oral suspensions were distinct from injectable suspensions, there was motivation from Majeti to formulate PLA nanoparticle drug carriers as an oral formulation to simplify administration. Thus, the prior art teaches an oral formulation as claimed.
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 of this title, 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.
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 9-10, 12-14, 17-18, and 37-39 are rejected under 35 U.S.C. 103 as being unpatentable over Kassick, Applied Bio Materials, 2, 2019 and Majeti, US 20180214386 A1.
Kassick teaches a nanoparticle composition comprising naloxone and a polymeric nanoparticle (Kassick, entire document, e.g., Abstract, and pp. 3420 and 3426: Conclusion).
Kassick does not expressly teach one or more ligands conjugated to the polymeric nanoparticle.
However, Majeti teaches conjugating ligands to polymeric nanoparticles for drug delivery (Majeti, e.g., Abstract, examples, claims), wherein the ligand is, e.g., gambogic acid, and wherein the ligand promotes penetration across biological barriers, e.g., intestine and blood brain barrier (Majeti, e.g., 0031, claim 7, 0002, 0003, 0004, 0012, 0018) thereby facilitating absorption of the desired bioactive agent (Majeti, e.g., claim 5). The composition is able to be used orally (Majeti, e.g., 0002 and 0004 and 0029).
Applicable to claim 10:
It would have been obvious before the effective filing date of the presently claimed invention to modify nanoparticles as understood from Kassick by conjugating ligands to the nanoparticles using techniques known from Majeti to improve the nanoparticles in the same way with a reasonable expectation of success. The skilled artisan would have been motivated to make this modification to improve the transit of the nanoparticles across biological barriers in the intestine and blood brain barrier. The skilled artisan would have had a reasonable expectation of success because Majeti teaches the technique is effective to modify nanoparticles composed of the same polymers employed in Kassick’s nanoparticles.
Applicable to claim 17: Kassick teaches polylactide (Kassick, e.g., pg. 3422). Majeti teaches the claimed polymers in claim 4.
Applicable to claims 37-39: Majeti teaches a ratio of drug to polymer of about 1:5, e.g., 0.0242 mmol paclitaxel and 0.0048 mmol plga (Majeti, e.g., 0045). Kassick teaches the ratio is a result effective parameter the skilled artisan would have optimized to achieve a desired naloxone loading in the polymer matrix, e.g., wherein the ratio is 10:1 monomer to naloxone initiator (Kassick, e.g., pg. 3423, c2). It would have been obvious before the effective filing date of the presently claimed invention to optimize the ratio between naloxone and polymer to arrive at nanoparticles having a naloxone to polymer ratio ranging from about 1:5 to about 1:10 with a reasonable expectation of success. The skilled artisan would have been motivated to optimize this ratio based on the express teaching in Majeti with a reasonable expectation of success. See MPEP 2144.05 II.
Applicable to claim 18: Majeti teaches gambogic acid (Majeti, e.g., 0031-0032 plga-ga).
Applicable to claim 9: Kassick teaches wherein the nanoparticle composition is lyophilized to facilitate isolating the nanoparticle composition (Kassick, e.g., pg. 3420, c2: Preparation of Covalently Linked Naloxone−PLA Nanoparticles, and pg. 3425, c1: Nanoparticle Preparation and Characterization).
Applicable to claims 12-13: Kassick teaches a suspension (Kassick, e.g., pg. 3420, Naloxone Release Rate Determination).
Applicable to claim 14: Kassick teaches a fluffy solid isolated from lyophilization which is a reconstitutable suspension since the solid is redispersible in water.
Accordingly, the subject matter of claims 9-10, 12-14, 17-18, and 37-39 would have been prima facie obvious before the effective filing date of the presently claimed invention, absent evidence to the contrary.
Claims 9-10, 12-14, 17-18, and 37-39 are rejected under 35 U.S.C. 103 as being unpatentable over Averick, US 20220152017 and Majeti, US 20180214386 A1.
Averick teaches naloxone polymer nanoparticles (Averick, e.g., Fig. 1, examples 1-4, and claims 1-3 and 16-17).
Averick does not expressly teach one or more ligands conjugated to the polymeric nanoparticle.
However, Majeti teaches conjugating ligands to polymeric nanoparticles for drug delivery (Majeti, e.g., Abstract, examples, claims), wherein the ligand is, e.g., gambogic acid, and wherein the ligand promotes penetration across biological barriers, e.g., intestine and blood brain barrier (Majeti, e.g., 0031, claim 7, 0002, 0003, 0004, 0012, 0018) thereby facilitating absorption of the desired bioactive agent (Majeti, e.g., claim 5).
Applicable to claim 10:
It would have been obvious before the effective filing date of the presently claimed invention to modify nanoparticles as understood from Averick by conjugating ligands to the nanoparticles using techniques known from Majeti to improve the nanoparticles in the same way with a reasonable expectation of success. The skilled artisan would have been motivated to make this modification to improve the transit of the nanoparticles across biological barriers in the intestine and blood brain barrier. The skilled artisan would have had a reasonable expectation of success because Majeti teaches the technique is effective to modify nanoparticles composed of the same polymers employed in Averick’s nanoparticles.
The composition is able to be used orally (Majeti, e.g., 0002 and 0004 and 0029). Averick teaches the nanoparticles in forms suitable for administration (Averick, e.g., 0046-0047), e.g., powder or rehydrated powder. The forms in Averick are capable of being orally administered.
Applicable to claim 17: recited polymers are named in Majeti (claim 4) and Averick, e.g., claim 5.
Applicable to claims 37-39: Averick teaches a naloxone to polymer ratio of 1:10 (Averick, e.g., 0060, table 1). Averick teaches the ratio of naloxone to monomer is a result effective parameter the skilled artisan would optimize for desired drug loading (Averick, e.g., 0030). Majeti teaches a ratio of drug to polymer of about 1:5, e.g., 0.0242 mmol paclitaxel and 0.0048 mmol plga (Majeti, e.g., 0045). It would have been obvious before the effective filing date of the presently claimed invention to optimize the ratio between naloxone and polymer to arrive at nanoparticles having a naloxone to polymer ratio ranging from about 1:5 to about 1:10 with a reasonable expectation of success. The skilled artisan would have been motivated to optimize this ratio based on the express teaching in Averick with a reasonable expectation of success. See MPEP 2144.05 II.
Applicable to claim 18: Majeti teaches gambogic acid (Majeti, e.g., 0031-0032 plga-ga).
Applicable to claim 9: Averick teaches wherein the nanoparticle composition is lyophilized to facilitate isolating the nanoparticle composition (Averick, e.g., 0034).
Applicable to claims 12-14: rehydrated powder is a suspension (Averick, e.g., 0047). Averick also teaches an emulsion (Averick, e.g., 0048). Reconstitutable suspension reads on a rehydratable powder (Averick e.g., 0047).
Accordingly, the subject matter of claims 9-10, 12-14, 17-18, and 37-39 would have been prima facie obvious before the effective filing date of the presently claimed invention, absent evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claim(s) 9-10, 12-14, 17-18, and 37-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim(s) 1-13 of US 10786465 in view of Averick, US 20220152017.
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The reference claims are directed to a composition comprising a nanoparticle, wherein the nanoparticle comprises a polymer/copolymer conjugated to gambogic acid.
2. The composition of claim 1, wherein a concentration of the polymer/copolymer may be adjusted to suit a specific target.
3. The composition of claim 1, wherein the composition possesses target specificity.
4. The composition of claim 1, wherein the polymer/copolymer are polylactide, poly(lactide-co-glycolide) or polycaprolactone.
5. The composition of claim 1, wherein the composition facilitates absorption of a desired bioactive.
6. The composition of claim 1, wherein surface expression of the nanoparticle makes the polymer/copolymer conjugated to gambogic acid accessible to respective receptors on a target site.
7. The composition of claim 1, wherein the composition expresses covalently bound ligands to interact non-competitively with receptors on cell membranes for receptor-mediated uptake.
8. The composition of claim 1, wherein the composition comprises a ligand with amine, carboxyl or hydroxyl functionality.
9. The composition of claim 1, wherein the conjugated polymer/copolymer can form stable nanoparticles via emulsion-diffusion techniques.
10. The composition of claim 1, wherein the gambogic acid is linked to carboxyl end groups of the polymer/copolymer via a linker.
11. The composition of claim 10, wherein the linker is an ethylenediamine linker.
12. The composition of claim 1, wherein the composition includes more than one ligand to tailor a distribution profile of the composition in a subject based on needs of a disease and/or drugs encapsulated.
13. A method of producing the composition of claim 1, the method comprising:
synthesizing a copolymer conjugated with gambogic acid; and
preparing the nanoparticles by utilizing an emulsion-diffusion-evaporation method to entrap a desired bioactive within the nanoparticles.
The reference claims teach the nanoparticles comprising an active agent but do not expressly teach naloxone.
Averick teaches naloxone may be formulated as nanoparticles to improve the steady, effective dose of naloxone for improved opioid overdose reversal over a sustained period while avoiding the effects of opioid withdrawal (Averick, e.g., 0018). Formulating naloxone as nanoparticles in the same polymers used by the nanoparticles of the reference claims enables longer lasting opioid agonist effects effective to rescue from opioid overdose with fewer administrations (Averick, e.g., 0006). The teachings of Averick enumerated above are reiterated here.
It would have been obvious before the effective filing date of the presently claimed invention to modify nanoparticles functionalized with gambogic acid claimed by the reference patent with naloxone with a reasonable expectation of success. Since the reference claims nanoparticles for active agents, the skilled artisan would have found it obvious to use the ligand functionalized nanoparticles of the reference claims to formulate naloxone with a reasonable expectation of success. The skilled artisan would have been motivated to make this modification to render the nanoparticles of the reference claims useful for improved opioid rescue in the same way suggested by Averick while taking advantage of the improved absorption offered by gambogic acid functionalization. The skilled artisan would have had a reasonable expectation of success because both references teach nanoparticle formulations for active agents.
The additional teachings of Averick enumerated above as they relate to the dependent claims are reiterated here.
Accordingly, the subject matter of claims 9-10, 12-14, 17-18, and 37-39 would have been prima facie obvious before the effective filing date of the presently claimed invention, absent evidence to the contrary.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 WILLIAM A CRAIGO whose telephone number is (571)270-1347. The examiner can normally be reached on Monday - Friday, 9am - 6pm, PDT.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A WAX can be reached on 571-272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM CRAIGO/Examiner, Art Unit 1615
/SUSAN T TRAN/Primary Examiner, Art Unit 1615
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