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 .
Claim Status
Claims 1-20 are pending.
Claims 1-20 have are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 14-Jan-2025, 06-Aug-2025, and 23-Dec-2025 have been considered by the examiner.
Specification
The disclosure is objected to because of the following informalities:
Page 4, line 19 “ELVITEGRAVIR®” is the international nonproprietary name, ® is not required.
Page 18, line 7-8 and Page 25, line 19-20 “…drug loading is about 20, 21, 23, 24, 25, 26, 27, 28, 20, or 30%” 20% should be 29%.
Page 24, lines 13 and 14 “nanoparticless” should be nanoparticles.
Page 34, line 13 “approximately98 nm” is missing space.
Appropriate correction is required.
The use of the term “SILASTIC” on page 2, line 27, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The use of the term “Amicon”, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The use of the term “Sigma Aldrich”, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The use of the term “Omnipaque 300”, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 9 and 18 are objected to because of the following informalities:
Claim 9 is missing a period at the end of the claim.
Claim 18 is missing a period at the end of the claim.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 15 recites the broad recitation “surface hydroxyl groups”, and the claim also recites “the nanoparticles comprise a hydrophobic polymeric core conjugated via a hydrolyzable linker to a branched, star or dendrimeric polyoxyethylene polymer or hyperbranched polyglycerol polymer” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 16 recites the broad recitation “the hydrophobic polymer is selected from the group consisting of polyhydroxy esters, polyanhydrides, polyorthoesters, and polyhydroxyalkanoates”, and the claim also recites “hydroxyl groups on the surface of the branched, star or dendrimeric polyoxyethylene polymer or hyperbranched polyglycerol polymer are released from the polymer in the presence of low pH less than 5” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 17 recites the broad recitation “the nanoparticles are formed of hydrophobic polymer comprising functional adhesive groups”, and the claim also recites “the groups are aldehydes or amines” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 3 and 4 recites the limitation "the nanoparticles”. There is insufficient antecedent basis for this limitation in the claim.
Claim 6 recites the limitation "the surface”. There is insufficient antecedent basis for this limitation in the claim.
Claim 9 recites the limitation "agent”. There is insufficient antecedent basis for this limitation in the claim. Claim 1, that claim 9 depends on, recites diagnostic agent.
Claim 12 recites the limitation "agent”. There is insufficient antecedent basis for this limitation in the claim. Claim 1, that claim 12 depends on, recites diagnostic agent.
Claim Rejections - 35 USC § 102
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.
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 the appropriate paragraphs of pre-AIA 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) the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for a patent.
(e) the invention was described in (1) an application for patent, published under section 122(b), by another filed in the United States before the invention by the applicant for patent or (2) a patent granted on an application for patent by another filed in the United States before the invention by the applicant for patent, except that an international application filed under the treaty defined in section 351(a) shall have the effects for purposes of this subsection of an application filed in the United States only if the international application designated the United States and was published under Article 21(2) of such treaty in the English language.
Claim(s) 1, 9-10, and 12-13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Groenewegen et al. (WO2004103336, Published: 02-Dec-2004).
Regarding Claim 1, Groenewegen teaches a three-layer vaginal ring which comprises of two pharmaceutically active compounds that can be release independently of one another (Page 3, line 26-28).
Regarding Claim 9, Groenewegen teaches an intravaginal insert composition on Table 1 with ethinyl estradiol in the core and intermediate layer (Page 15, Table 1).
Regarding Claim 10, Groenewegen teaches an intravaginal insert composition on Table 1 with ethinyl estradiol in the core and intermediate layer (Page 15, Table 1).
Regarding Claim 12, Groenewegen teaches an intravaginal insert method of use via positioning the drug delivery system within the female vaginal tract (Page 12, line 23-26).
Regarding Claim 13, Groenewegen teaches in Example 1 that Evatane 28-25 or EVA copolymer (Page 15, Table 1), which is nondegradable, is used in making the intravaginal insert. Furthermore, the blend extrusion process forms a three layer ring design in which the core and intermediate later compartments are inherently closed and bound on all sides by the surrounding EVA polymeric matrix, forming layers varying from 50 to 300 µm (Page 18, line 15-16) and the fiber ends are welded/glued to form the ring (Page 18, line 9-13).
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claim(s) 1-8, 11, and 14-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Groenewegen, and further in view of Deng et al. (The effect of hyperbranched polyglycerol coatings on drug delivery using degradable polymer nanoparticles, 2014) and Mohideen et al. (Degradable bioadhesive nanoparticles for prolonged intravaginal delivery and retention of elvitegravir, 2017).
Groenewegen teaches the intravaginal insert comprising of two or more compartments releasing therapeutic, prophylactic, or diagnostic agent at two different times or rates as applied to claim 1 discussed above.
In regards to Claims 2-3, Groenewegen teaches an intravaginal ring with compartments comprising of the core and intermediate later are loaded with active compounds such as etonogestrel and ethyinl estradiol that is dissolved into a thermoplastic EVA polymer matrix (Page 15, Table 1). The active pharmaceutical ingredients then diffuse from the polymer matrix through the EVA skin layer and then released into the vagina at distinct and independently controlled rates (Page 17, Table 3).
In regards to Claims 4-5, Groenewegen teaches a multi compartment intravaginal ring comprising EVA polymer matrix as the drug carrying material in both the core and intermediate compartments (Page 3, line 26-28 and Page 15, Table 1).
In regards to Claims 6-8, Groenewegen teaches a vaginal ring designed for use in the nominally acidic conditions of the intravaginal environment, with drug released over 2 days to 21 days (Page 18).
In regards to Claim 11, Groenewegen teaches a multicompartment intravaginal ring in which the core and intermediate layers are formed by a continuous three layer coextrusion and are bound on all surfaces by the EVA polymer matrix, forming a continuous extrusion ring device (Page 15, line 24-27 to Page 16, line 1-18), with the ring enclosing all compartments.
In regards to Claims 14-20, Groenewegen teaches the complete method of making the intravaginal insert in Example I (Page 15, Example 1) by forming an EVA polymeric ring through co-extrusion to create the core and intermediate layer compartments , assembling the material into a ring shaped device by welding and gluing, and concluding that the intravaginal delivery device is retained vaginally for 21 days (Page 12). Groenewegen further teaches that the ring can contain agents including hormones, anti-microbials, anti-fungals, anti-virals, and anti-protozoals (Page 11).
However, Groenewegen does not teach that the compartments contain nanoparticles having a diameter of 40 nm to 500 nm comprising the therapeutic agent nor does it teach that the nanoparticles comprise surface hydroxyl groups effective to promote mucosal penetration of claims 2-3. Groenewegen does not teach that the hydrophobic polymeric core is conjugated to with a hydrolysable liner to a branched, star, or dendrimeric polyoxyethylene polymer or hyperbranched polyglycerol polymer, or that the hydrophobic polymer is selected from a group consisting polyhydroxy esters, polyanhydrides, polyorthoesters, and polyhydroxyalkanoates of claims 4-5. Groenewegen does not teach that the hydroxyl groups on the surface of the branched, star or dendrimeric polyoxyethylene polymer, or hyperbranched polyglycerol polymer are released in the presence of low pH of less than 5, nanoparticles formed of hydrophobic polymer comprising functional adhesive groups are exposed when the surface hydroxyl groups are removed, or that the functional adhesive groups are aldehydes or amines of claims 6-8. Groenewegen does not teach an intravaginal insert comprising compartments sealed at one end with a non-degradable polymer and the other end with a biodegradable polymer of claim 11. Groenewegen does not teach placing 40 nm to 500 nm nanoparticles into the compartments, nanoparticles with surface hydroxyl groups, PLA-HPG with hydrolysable linker, nanoparticles formed of hydrophobic polymer, nanoparticles with bioadhesive groups exposed at low pH, nanoparticles comprising agents consisting of proteins and peptides, nucleic acids, sugars and polysaccharides, small molecules (typically under 1500 Daltons), lipids and lipoproteins, nanoparticles with therapeutic agents selected from hormones, antifungal, antibiotic, and antiviral agents, or sealing open ends of compartments with degradable polymer selection for different degradation kinetic of claims 14-20. For this reason, Deng and Mohideen are added.
Deng teaches a polylactic acid-hyperbranched polyglycerol nanoparticle of 100 nm in diameter as measured by DLS (Page 6597), and the hyperbranched polyglycerol is a hydrophilic polymer with a high density of hydroxyl groups on its surface (Page 6599), noting that HPG is demonstrated to have better compatibility and non-specific resistance to biomolecules than PEG in certain applications (Page 6600). Deng teaches a one-step reaction using PLA and HPG dissolved in DMF with diisopropylcarboimide (DIC) and 4-(N,N-dimethylamino) pyridine (DMAP) to yield a PLA-HPG polymer (Page 6596) that was then dissolved in a solvent mixture and probe sonicated. The resultant emulsion was diluted with water and filtered, yield the nanoparticles (Page 6596). The ester bond linking PLA to HPG is a linker, HPG is a hyperbranched polyglycerol polymer, and PLA is a polyhydroxy ester. Deng teaches the complete method for nanoprecipitation via emulsion and NaIO4 oxidation for bioadhesive properties, the PLA core and the HPG with hydroxyl groups that promote mucosal penetration.
Mohideen teaches that the same PLA-HPG nanoparticles with a diameter of 102 ± 4 nm (Page 148, Fig 2a) and that the PLA-HPG nanoparticles are mucus-penetrating (Page 152). Mohideen teaches a PLA-HPG nanoparticles that are made bioadhesive via oxidation to sodium periodate that converts the vicinal diols on HPF to aldehydes, which can form stable Schiff base interactions with amines such as the N-terminal or lysine side chains of proteins (Page 145) that in vitro test in simulated vaginal fluid at pH 4.2 (Page 146) resulted in ~40% retention versus ~10% retention of non-bioadhesive nanoparticles (Page 150, Fig 4B). Mohideen teaches that the PLA-HPG materials are fully biocompatible via the in vitro cytotoxicity testing on vaginal and cervical epithelial cell (Page 148, Fig 2E).
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 incorporate the PLA-HPG nanoparticles taught by Deng and Mohideen into the multi-compartment intravaginal ring of Groenewegen in the place of the dissolved drug within the EVA matrix in order to provide controlled release of drug agents, enhanced mucosal penetration, and improved retention of the therapeutic eluting nanoparticles. Both Mohideen and Deng are directed to effective intravaginal drug delivery and teach that the polymeric PLA-HPG nanoparticles are suitable for improving mucosal transport and retention. It would have been obvious to prepare the nanoparticles according to the methods of Deng and Mohideen and incorporate them in the compartments of Groenewegen intravaginal ring as these modifications represent applying known nanoparticle formulations and surface chemistry to a known intravaginal delivery system to achieve expected with a reasonable expectation of success.
Further, it would have been prima facie obvious to modify the compartment design of the Groenewegen ring by sealing the individual compartments with biodegradable polymer caps having selected degradation rates to achieve staggered release profiles of therapeutic agents. Controlled release systems employing biodegradable and rate limited closures are known in the art, with Groenewegen disclosing the objective of delivering agents at different times or different rates. These modifications represents combining known elements according to their established functions to yield predictable results including controlled agent release, mucosal penetration, nanoparticle retention, and sequence of therapeutic agent delivery. For the forgoing reasons, Claims 1-8, 11, and 14-20 are rendered obvious by the teachings of the prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WENHAN LI whose telephone number is (571)272-9143. The examiner can normally be reached Monday-Friday 7:30 am-5 pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at (571)272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/W.L./Examiner, Art Unit 1614
/ALI SOROUSH/Supervisory Patent Examiner, Art Unit 1614
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