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 .
DETAILED ACTION
Applicant’s election without traverse of Group I, claims 1, 5, 7, 8, and 10-22 in the reply filed on March 29, 2026 is acknowledged.
Applicant’s election without traverse of species: dexamethasone sodium phosphate (DSP) as the specific therapeutic agent, in the reply filed on March 29, 2026 is acknowledged.
Claims 2-4, 6, 9, and 27 were previously canceled.
Claims 1, 5, 7, 8, and 10-26 are pending.
Claims 16, 17, and 23-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions or species, there being no allowable generic or linking claim.
Claims 1, 5, 7, 8, 10-15, and 18-22 are pending and under consideration.
Priority
It is acknowledged that this application is a 371 application of International Patent Appl. No. PCT/US2022/018885, filed March 4, 2022, which claims the benefit of priority to U.S. Provisional Patent Appl. No. 63/157,113 filed March 5, 2021. The priority date has been established as March 5, 2021 for claims under consideration.
Information Disclosure Statement
The Information Disclosure Statements filed on 09/01/2023, 02/26/2026, and have been considered and entered by examiner.
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.
Claims 1, 5, 7, 8, 10-15, and 18-22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites the limitation "the active agent" in line 4. There is insufficient antecedent basis for this limitation in the claim.
The term “active agent” in claim 1 is a relative term which renders the claim indefinite. The term “active” is not defined by the claim. Paragraph [0050] of the specification indicates that “active agent” includes a therapeutic agent or an imaging agent. Given Broadest Reasonable Interpretation (BRI), the term encompasses all agent with activity in any function. The specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear what standards are applied to classify an agent as active or inactive.
Claim 1 recites the limitation "the eye" in line 8 and line 9. There is insufficient antecedent basis for this limitation in the claim.
Claims 5, 7, 8, 10-15, and 18-22 are rejected because these claims depend on claim 1.
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, 7, 8, 10-15, and 18-22 are rejected under 35 U.S.C. 103 as being unpatentable over Hong (Hong et al., US 2018/0193461, Publication Date: 07/12/2018) in view of Lopez-Cano (Lopez-Cano et al., Expert Opinion on Drug Delivery, 18:7, 819-847, Publication Date: 01/22/2021).
Hong teaches that intravitreal corticosteroid injection can be a treatment for various eye related disorders, including chronic macular edema, uveitis, branch retinal vein occlusion, or central retina vein occlusion ([0003], [0004]).
Hong teaches repetitive intravitreal injection is required to maintain the optimal and efficient corticosteroid concentration in the eye, and this is associated with complications ([0004]). There is a need for intravitreal steroid injection with reduced side effects
Hong teaches a pharmaceutical composition comprising a mixture of phospholipids, with or without cholesterol (lipid cake); and an ocular steroid ([0006]).
Hong teaches that the pharmaceutical composition can reduce the side effects of said ocular steroid ([0006].
Hong teaches that the ocular steroid is dexamethasone sodium phosphate (DSP) (the elected species) (Examples 2 and 3).
Hong teaches a specific lipid mixture of DOPC, DOPG and cholesterol in a molar ratio of 67.5:7.5:25 (see Example 1 and Table 1).
Hong teaches a pharmaceutical composition comprising a therapeutic agent: DSP, and a liposome comprising DOPC, DOPG and cholesterol (Example 2).
Hong teaches that liposomes were known to affect the vitreous clarity ([0069]). Consistent with this, in some cases the pharmaceutical compositions induce reduced vitreous clarity (vitreous haze) (Table 3).
Hong’s teachings are described above. However, Hong does not teach that the pharmaceutical composition comprising a biocompatible hydrogel comprising hyaluronic acid at a concentration ranging from about 0.01% (w/v) to about 0.75% (w/v), or reducing an ocular side effect comprising vitreous haze.
Lopez-Cano teaches that the development of ophthalmic formulations able to deliver hydrophilic and hydrophobic drugs to the inner structures of the eye and restore the preocular tear film has been a leading topic of discussion over the last few year. Liposomes represent a suitable strategy to achieve these objectives in ocular drug delivery (§ Abstract – Introduction).
Lopez-Cano teaches for treatment of posterior segment diseases, drugs administered by the topical route do not achieve the target site as easily due to the ocular barriers, so intravitreal and periocular administrations are preferred (page 819, col. 2, para. 1). As a drawback, these routes must be used repeatedly to maintain therapeutic drug levels, which entails numerous adverse effects ([age 819, col. 2, para. 1).
Lopez-Cano teaches that hyaluronic acid (HA) is biocompatible and biodegradable with low toxicity. HA is able to retain water forming a hydrogel with mucoadhesive properties. Liposomes loaded with doxorubicin and coated with HA showed a longer in vitro release. In addition, liposomes in HA solution reached cell nucleus the most compared to liposome in an aqueous solution and the free drug (the bridging paragraph of pages 835-836).
Lopez-Cano teaches that in vivo, a longer retention time and higher bioavailability were observed with the formulation comprising HA (the bridging paragraph of pages 835-836). Lopez-Cano teaches the HA concentration is 0.5% (w/v) (Table 2, on page 831).
Lopez-Cano teaches another study combining HA hydrogel and fluconazole-loaded liposomes. In vitro, HA hydrogel at 0.7% increases permeation of liposomes. The cumulative concentration of fluconazole in corneal tissues resulted much higher compared to conventional liposomes and drug suspension, being 1.86 and 2.6 folds higher respectively. In vivo, the liposome formulation with 0.7% HA and 0.9% fluconazole shows a more sustained permeation profile and a higher value of area under the curve compared to fluconazole suspension (the bridging paragraph of pages 835-836).
It would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to modify the pharmaceutical composition of Hong by adding HA hydrogel at a concentration about 0.5% or 0.7% (w/v) as taught by Lopez-Cano, because the Lopez-Cano teaches that HA hydrogel at those concentrations can increase retention time and bioavailability of liposome-drug significantly. Thus, one of ordinary skill in the art would have had a reasonable expectation that lower concentration of DSP-liposome in a formulation with HA hydrogel would be as effective as higher concentration of DSP-liposome in a formulation without HA hydrogel. Since DSP-liposome can result in ocular side effect such as vitreous haze, as taught by Hong, using lower concentration of DSP-liposome would reduce the side effect such as vitreous haze. In addition, because HA/DSP-liposome would release the liposome slower (longer retention) in the vitreous humor and thus cause less vitreous clouding or haze after administration. The motivation would have been to further reduce the side effect of the treatment and to reduce the cost of therapeutic materials.
In addition, regarding the range “about 0.01% (w/v) to 0.75% (w/v)” (claim 1) or “0.09% (w/v) to about 0.5% (w/v)” (claim 7), it is noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here 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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A). In this case, one ordinary skill in the art would have known to adjust concentration of HA based on the properties of lipids, properties of therapeutic agent and/or the administration route, through routine and conventional practice.
Regarding claims 8, 10, and 11, Hong teaches a specific lipid mixture of DOPC, DOPG and cholesterol (see Example 1 and Table 1).
Claim 12 is considered as a “product-by-process” claim. Thus, the claimed composition is evaluated based on its inherent structure, not the process limitations. In this case, the pharmaceutical composition essentially comprises a mixture of lipid nanoparticle and the biocompatible hydrogel of HA. Hong teaches that the lipid mixture forms liposome (a nanoparticle). Lopez-Cano teaches that hyaluronic acid (HA) is biocompatible and biodegradable with low toxicity. HA is able to retain water forming a hydrogel with mucoadhesive properties (the bridging paragraph of pages 835-836). Therefore, the combination of liposome of Hong and HA of Lopez-Cano would have the structure of instant claim 12.
Regarding claims 13, 14, 15, and 19, Hong teaches that the therapeutic agent is dexamethasone sodium phosphate (DSP) (the elected species) (Examples 2 and 3).
Regarding claims 19 and 20, Hong teaches 1.25 μmol, 2.5 μmol, and 5 μmol phospholipids in 50 μl of pharmaceutical composition ([0059]-[0064]), which represent 25 μmol, 50 μmol, and 100 μmol per ml of the pharmaceutical composition, respectively (or about 25 mM, 50 mM and 100 mM, respectively). It is also noted that optimum suitable ranges may be obtained by routine experimentation, absent a showing of criticality or unexpected results. “[W]here 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.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A).
Regarding claim 21, Hong teaches the pharmaceutical composition is administered through an intravitreal injection ([0065], Example 3) which is injected directly into the jelly-like vitreous humor.
Regarding claim 22, as set forth above, Hong and Lopez-Cano teach a pharmaceutical composition of HA/liposome-DSP comprising 50mM or 100mM of lipid mixture (DOPC, DOPG and cholesterol in a molar ratio of 67.5:7.5:25) and about 0.5% or 0.7% of HA hydrogel. Thus, the pharmaceutical composition taught by Hong and Lopez-Cano would have the viscosity as claimed, as evidenced by the Table 4 of the instant specification in which similar pharmaceutical compositions (e.g. H3) are tested.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Hong (Hong et al., US 2018/0193461, Publication Date: 07/12/2018) in view of Lopez-Cano (Lopez-Cano et al., Expert Opinion on Drug Delivery, 18:7, 819-847, Publication Date: 01/22/2021), as applied to claims 1, 7, 8, 10-15, and 18-22 above, and further in view of Keller (Keller et al., EP 0244178 A2, Publication Date: 11/04/1987).
Hong and Lopez-Cano teaches the pharmaceutical composition of claim 1, as set forth above. However, Hong and Lopez-Cano do not teach that the biocompatible hydrogel has a molecular weight of about 4kDa to about 8000kDa.
Keller teaches that HA is a naturally-occurring polymer of D-glucuronic acid and N-acetyl-D-glucosamine. HA is found in animal tissues including vitreous humor. The molecular weight of naturally occurring polymer ranges from about 50 kDa to about 8000 kDa. A preferred HA is an ultrapure polymer having a molecular weight less than 750,000 kDa which is dissolved in an isotonic aqueous solution substantially devoid of electrolytes (col. 3, para. 1). Keller teach using HA in combination with DSP for eye treatment (Example).
It would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to combine teachings of Hong, Lopez-Cano and Keller, and to make a HA/DSP-liposome composition as taught by Hong and Lopez-Cano, and to use a HA with a molecular weight about 750 kDa as taught by Keller. Given all the components are well known in the art, as evidenced by references, one of ordinary skill in the art would have had a reasonable expectation that HA of molecular weight of 750 kDa would be suitable for the pharmaceutical composition, because the HA is naturally occurring, has good solubility and has been tested in combination with DSP as taught by Keller. The motivation would have been to make a better therapeutic product with a well-tested agent.
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 conflicting claims 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) 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 www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
U.S. Patent No. 8,956,600
Claims 1, 5, 7, 8, 10-15, and 18-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-38 of U.S. Patent No. 8,956,600 B2 (hereinafter Pat. 600, corresponding application: 12/538,435) in view of Hong (Hong et al., US 2018/0193461, Publication Date: 07/12/2018), Lopez-Cano (Lopez-Cano et al., Expert Opinion on Drug Delivery, 18:7, 819-847, Publication Date: 01/22/2021) and Keller (Keller et al., EP 0244178 A2, Publication Date: 11/04/1987).
The claims of Pat. 600 teach a drug delivery system, comprising (a) a delivery vehicle suitable for vitreous humor drug delivery consists essentially of a phospholipid or a mixture of phospholipids selected from the group consisting of DOPC, POPC, SPC, EPC, PEG-DSPE and DOPG, and cholesterol, wherein cholesterol is present in an amount of 10-33 mole percent relative to the delivery vehicle; and (b) one or more therapeutic agents to the eye; wherein 50-90% of the therapeutic agent to the eye is in non-associated form, the weight ratio of the phospholipid and cholesterol in combination to the therapeutic agent to the eye is 5-80 to 1 and the life time of the therapeutic agent is extended in the vitreous humor (claim 19).
The claims of Pat. 600 teach the drug delivery system of claim 19, wherein the therapeutic agent to the eye is an anti-inflammation molecule (claim 25), wherein the anti-inflammation molecule is a corticosteroid (claim 26), wherein the corticosteroid can be dexamethasone (claim 38).
The claims of Pat. 600 teach the drug delivery system of claim 19, the therapeutic agent to the eye is an antagonist specific to VEGF, such as Avastin (claims 20-23).
The claims of Pat. 600 teach wherein the ratio of DOPC:DOPG:cholesterol is 56.25-72.5:7.5-18.75:20-25 by mole percent (claim 33).
Thus, the claims of Pat. 600 teach a pharmaceutical composition (drug delivery system) comprising a mixture of lipids (DOPC, DOPG and cholesterol) and a therapeutic agent (e.g. dexamethasone or Avastin same as bevacizumab). Thus, the subject matter of the claims of Pat. 600 overlap with the subject matter of the instant claims.
However, the claims of Pat. 600 do not teach the pharmaceutical composition comprising a biocompatible hydrogel as instantly claimed, or for reducing an ocular side effect comprising vitreous haze, or specific concentrations as instantly claimed.
As set forth above, Hong, Lopez-Cano and Keller teach the instant claims 1, 5, 7, 8, 10-15, and 18-22. In particular, Hong teaches the DSP-liposome comprising (DOPC, DOPG and cholesterol), method of using the DSP-liposome for eye treatment, and potent side effect such as vitreous haze caused by liposome. Lopez-Cano teach HA hydrogel can significantly increase retention time of drug-liposome in eyes and enhance the drug bioavailability in eyes. Keller teaches that HA of molecular weight of 750 kDa are suitable for drug delivery into eyes.
It would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to modify the pharmaceutical composition of Pat. 600 by adding HA hydrogel at a concentration about 0.5% or 0.7% (w/v) as taught by Lopez-Cano, because the Lopez-Cano teaches that HA hydrogel at those concentrations can increase retention time and bioavailability of liposome-drug significantly. Thus, one of ordinary skill in the art would have had a reasonable expectation that lower concentration of DSP-liposome in a formulation with HA hydrogel would be as effective as higher concentration of DSP-liposome in a formulation without HA hydrogel. Since DSP-liposome can result in ocular side effect such as vitreous haze, as taught by Hong, using lower concentration of DSP-liposome would reduce the side effect such as vitreous haze. In addition, because HA/DSP-liposome would release the liposome slower (longer retention) in the vitreous humor and thus cause less vitreous clouding or haze after administration. The motivation would have been to further reduce the side effect of the treatment and to reduce the cost of therapeutic materials.
Regarding molecular weight of HA, it would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to combine teachings of the claims of Pat. 600, Hong, Lopez-Cano and Keller, and to make a HA/DSP-liposome composition as taught by Hong and Lopez-Cano, and to use a HA with a molecular weight about 750 kDa as taught by Keller. Given all the components are well known in the art, as evidenced by references, one of ordinary skill in the art would have had a reasonable expectation that HA of molecular weight of 750 kDa would be suitable for the pharmaceutical composition, because the HA is naturally occurring, has good solubility and has been tested in combination with DSP as taught by Keller. The motivation would have been to make a better therapeutic product with a well-tested agent.
U.S. Patent No. 9,987,360
Claims 1, 5, 7, 8, 10-15, and 18-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 9,987,360 B2 (hereinafter Pat. 360, corresponding application: 14/572,062) in view of Hong (Hong et al., US 2018/0193461, Publication Date: 07/12/2018), Lopez-Cano (Lopez-Cano et al., Expert Opinion on Drug Delivery, 18:7, 819-847, Publication Date: 01/22/2021) and Keller (Keller et al., EP 0244178 A2, Publication Date: 11/04/1987).
The claims of Pat. 360 teach a drug delivery system, comprising (a) a delivery vehicle comprising cholesterol and a phospholipid or a phospholipid mixture, wherein the phospholipid mixture comprises a first phospholipid and a second phospholipid, wherein the first phospholipid is DOPC, POPC, SPC, or EPC and the second phospholipid is PEG-DSPE or DOPG, and wherein the cholesterol is present in, an amount of 5-40 mole percent relative to the delivery vehicle; and (b) one or more therapeutic agent for treating ophthalmic disease, wherein 50-90% of the therapeutic agent is in non-associated form and the weight ratio of the combination of the phospholipid or the phospholipid mixture and cholesterol to the therapeutic agent is 5-80 to 1 (claim 1).
The claims of Pat. 360 teach wherein the therapeutic agent for treating ophthalmic disease is an antagonist specific to VEGF, such as Avastin (same as bevacizumab) (claims 2-5);
The claims of Pat. 360 teach the drug delivery system of claim 1, wherein the therapeutic agent for treating ophthalmic disease is an anti-inflammation molecule (claim 7); wherein the anti-inflammation molecule is a corticosteroid (claim 8).
Thus, the claims of Pat. 360 teach a pharmaceutical composition (drug delivery system) comprising a mixture of lipids (DOPC, DOPG and cholesterol) and a therapeutic agent (e.g. corticosteroid or Avastin same as bevacizumab). Thus, the subject matter of the claims of Pat. 360 overlap with the subject matter of the instant claims.
However, the claims of Pat. 360 does not teach the pharmaceutical composition comprising a biocompatible hydrogel as instantly claimed, or for reducing an ocular side effect comprising vitreous haze, or specific concentrations as instantly claimed.
As set forth above, Hong, Lopez-Cano and Keller teach the instant claims 1, 5, 7, 8, 10-15, and 18-22. In particular, Hong teaches the DSP-liposome comprising (DOPC, DOPG and cholesterol), method of using the DSP-liposome for eye treatment, and potent side effect such as vitreous haze caused by liposome. Lopez-Cano teach HA hydrogel can significantly increase retention time of drug-liposome in eyes and enhance the drug bioavailability in eyes. Keller teaches that HA of molecular weight of 750 kDa are suitable for drug delivery into eyes.
It would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to modify the pharmaceutical composition of Pat. 360 by adding HA hydrogel at a concentration about 0.5% or 0.7% (w/v) as taught by Hong and Lopez-Cano, because the Lopez-Cano teaches that HA hydrogel at those concentrations can increase retention time and bioavailability of liposome-drug significantly. Thus, one of ordinary skill in the art would have had a reasonable expectation that lower concentration of DSP-liposome in a formulation with HA hydrogel would be as effective as higher concentration of DSP-liposome in a formulation without HA hydrogel. Since DSP-liposome can result in ocular side effect such as vitreous haze, as taught by Hong, using lower concentration of DSP-liposome would reduce the side effect such as vitreous haze. In addition, because HA/DSP-liposome would release the liposome slower (longer retention) in the vitreous humor and thus cause less vitreous clouding or haze after administration. The motivation would have been to further reduce the side effect of the treatment and to reduce the cost of therapeutic materials.
Regarding molecular weight of HA, it would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to combine teachings of the claims of Pat. 360, Hong, Lopez-Cano and Keller, and to make a HA/DSP-liposome composition as taught by Hong and Lopez-Cano, and to use a HA with a molecular weight about 750 kDa as taught by Keller. Given all the components are well known in the art, as evidenced by references, one of ordinary skill in the art would have had a reasonable expectation that HA of molecular weight of 750 kDa would be suitable for the pharmaceutical composition, because the HA is naturally occurring, has good solubility and has been tested in combination with DSP as taught by Keller. The motivation would have been to make a better therapeutic product with a well-tested agent.
U.S. Patent No. 10,660,960
Claims 1, 5, 7, 8, 10-15, and 18-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10,660,960 B2 (hereinafter Pat. 960, corresponding application: 15/888,776) in view of Hong (Hong et al., US 2018/0193461, Publication Date: 07/12/2018), Lopez-Cano (Lopez-Cano et al., Expert Opinion on Drug Delivery, 18:7, 819-847, Publication Date: 01/22/2021) and Keller (Keller et al., EP 0244178 A2, Publication Date: 11/04/1987).
The claims of Pat. 960 teach a method for delivering a therapeutic agent to an eye of a subject by intravitreal injection, which comprises: providing a composition comprising: (a) a delivery vehicle comprising a phospholipid or a mixture of phospholipids selected from DOPC, POPC, SPC, EPC, PEG-DSPE or DOPG, and cholesterol, wherein cholesterol is present in an amount of 5-40 mole percent relative to the delivery vehicle; and (b) one or more therapeutic agent, wherein 50-90% of the therapeutic agent is in non-associated form and the weight ratio of the phospholipid and cholesterol in combination to the therapeutic agent is 5-80 to 1 (claim 1). Although the claim is drawn a method, the claim disclose a pharmaceutical composition comprising a lipid mixture and a therapeutic agent.
The claims of Pat. 960 teach wherein the therapeutic agent is an antagonist specific to VEGF, such as Avastin (same as bevacizumab) (claims 2-5);
The claims of Pat. 960 teach the drug delivery system of claim 1, wherein the therapeutic agent is an anti-inflammation molecule (claim 7); wherein the anti-inflammation molecule is a corticosteroid (claim 8).
Thus, although the claims of Pat. 960 are drawn to a method, the claims of Pat. 960 teach a pharmaceutical composition comprising a mixture of lipids (DOPC, DOPG and cholesterol) and a therapeutic agent (e.g. corticosteroid or Avastin same as bevacizumab) for eye treatment. Thus, the subject matter of the claims of Pat. 960 overlap with the subject matter of the instant claims.
However, the claims of Pat. 960 do not teach the pharmaceutical composition comprising a biocompatible hydrogel as instantly claimed, or for reducing an ocular side effect comprising vitreous haze, or specific concentrations as instantly claimed.
As set forth above, Hong, Lopez-Cano and Keller teach the instant claims 1, 5, 7, 8, 10-15, and 18-22. In particular, Hong teaches the DSP-liposome comprising (DOPC, DOPG and cholesterol), method of using the DSP-liposome for eye treatment, and potent side effect such as vitreous haze caused by liposome. Lopez-Cano teach HA hydrogel can significantly increase retention time of drug-liposome in eyes and enhance the drug bioavailability in eyes. Keller teaches that HA of molecular weight of 750 kDa are suitable for drug delivery into eyes.
It would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to modify the pharmaceutical composition disclosed by the claims of Pat. 960 by adding HA hydrogel at a concentration about 0.5% or 0.7% (w/v) as taught Lopez-Cano, because the Lopez-Cano teaches that HA hydrogel at those concentrations can increase retention time and bioavailability of liposome-drug significantly. Thus, one of ordinary skill in the art would have had a reasonable expectation that lower concentration of DSP-liposome in a formulation with HA hydrogel would be as effective as higher concentration of DSP-liposome in a formulation without HA hydrogel. Since DSP-liposome can result in ocular side effect such as vitreous haze, as taught by Hong, using lower concentration of DSP-liposome would reduce the side effect such as vitreous haze. In addition, because HA/DSP-liposome would release the liposome slower (longer retention) in the vitreous humor and thus cause less vitreous clouding or haze after administration. The motivation would have been to further reduce the side effect of the treatment and to reduce the cost of therapeutic materials.
Regarding molecular weight of HA, it would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to combine teachings of the claims of Pat. 960, Hong, Lopez-Cano and Keller, and to make a HA/DSP-liposome composition as taught by Hong and Lopez-Cano, and to use a HA with a molecular weight about 750 kDa as taught by Keller. Given all the components are well known in the art, as evidenced by references, one of ordinary skill in the art would have had a reasonable expectation that HA of molecular weight of 750 kDa would be suitable for the pharmaceutical composition, because the HA is naturally occurring, has good solubility and has been tested in combination with DSP as taught by Keller. The motivation would have been to make a better therapeutic product with a well-tested agent.
U.S. Patent No. 10,058,616
Claims 1, 5, 7, 8, 10-15, and 18-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 10,058,616 B2 (hereinafter Pat. 616, corresponding application: 14/377,211) in view of Hong (Hong et al., US 2018/0193461, Publication Date: 07/12/2018), Lopez-Cano (Lopez-Cano et al., Expert Opinion on Drug Delivery, 18:7, 819-847, Publication Date: 01/22/2021) and Keller (Keller et al., EP 0244178 A2, Publication Date: 11/04/1987). It is noted that Hong and Pat. 616 correspond to the same application: 14/377,211).
The claims of Pat. 616 teach a pharmaceutical composition suitable for ocular delivery of a steroid comprising a combination of: (a) a lipid cake mixture comprising a phospholipid or mixture of phospholipids; and (b) a steroid solution comprising about 0.05 mg to about 0.7 mg of a water soluble ocular steroid selected from the group consisting of dexamethasone sodium phosphate, …, or a pharmaceutically acceptable salt thereof; wherein the total amount of phospholipids in said composition is about 0.1 μmol to less than about 2.5 μmol per 50 μl of pharmaceutical composition and wherein the side effect profile of said composition is reduced, relative to the side effect of said composition having at least about 5 μmol of phospholipids per 50 μl of pharmaceutical composition (claim 1), wherein the lipid cake mixture further comprises cholesterol (claim 2); wherein the ocular steroid is dexamethasone sodium phosphate (claim 3); wherein the lipid cake mixture comprises at least one of DOPC and DOPG (claim 9).
The claims of Pat. 616 teach A pharmaceutical composition for ocular delivery, comprising: (a) a lipid cake mixture comprising a phospholipid or mixture of phospholipids; and (b) a steroid solution comprising an effective amount about 0.6 mg to about 0.7 mg of dexamethasone sodium phosphate, …; wherein the total amount of phospholipids in said composition is about 0.1 μmol to less than about 2.5 μmol per 50 μl of pharmaceutical composition and wherein the side effect profile of said composition is reduced, relative to the side effect of said composition having at least about 5 μmol of phospholipids per 50 μl of pharmaceutical composition (claim 10); wherein the lipid cake mixture further comprises cholesterol (claim 11); wherein the lipid cake mixture comprises at least one of DOPC and DOPG (claim 16)..
Thus, the claims of Pat. 616 teach a pharmaceutical composition comprising a mixture of lipids (DOPC, DOPG and cholesterol) and a therapeutic agent (e.g. DSP) for eye treatment with reduced side effects. Thus, the subject matter of the claims of Pat. 616 overlap with the subject matter of the instant claims.
However, the claims of Pat. 616 do not teach the pharmaceutical composition comprising a biocompatible hydrogel as instantly claimed, or for reducing an ocular side effect comprising vitreous haze, or specific concentrations as instantly claimed.
As set forth above, Hong, Lopez-Cano and Keller teach the instant claims 1, 5, 7, 8, 10-15, and 18-22. In particular, Hong teaches the DSP-liposome comprising (DOPC, DOPG and cholesterol), method of using the DSP-liposome for eye treatment, and potent side effect such as vitreous haze caused by liposome. Lopez-Cano teach HA hydrogel can significantly increase retention time of drug-liposome in eyes and enhance the drug bioavailability in eyes. Keller teaches that HA of molecular weight of 750 kDa are suitable for drug delivery into eyes.
It would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to modify the pharmaceutical composition disclosed by the claims of Pat. 616 by adding HA hydrogel at a concentration about 0.5% or 0.7% (w/v) as taught by Lopez-Cano, because the Lopez-Cano teaches that HA hydrogel at those concentrations can increase retention time and bioavailability of liposome-drug significantly. Thus, one of ordinary skill in the art would have had a reasonable expectation that lower concentration of DSP-liposome in a formulation with HA hydrogel would be as effective as higher concentration of DSP-liposome in a formulation without HA hydrogel. Since DSP-liposome can result in ocular side effect such as vitreous haze, as taught by Hong, using lower concentration of DSP-liposome would reduce the side effect such as vitreous haze. In addition, because HA/DSP-liposome would release the liposome slower (longer retention) in the vitreous humor and thus cause less vitreous clouding or haze after administration. The motivation would have been to further reduce the side effect of the treatment and to reduce the cost of therapeutic materials.
Regarding molecular weight of HA, it would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to combine teachings of the claims of Pat. 616, Hong, Lopez-Cano and Keller, and to make a HA/DSP-liposome composition as taught by Hong and Lopez-Cano, and to use a HA with a molecular weight about 750 kDa as taught by Keller. Given all the components are well known in the art, as evidenced by references, one of ordinary skill in the art would have had a reasonable expectation that HA of molecular weight of 750 kDa would be suitable for the pharmaceutical composition, because the HA is naturally occurring, has good solubility and has been tested in combination with DSP as taught by Keller. The motivation would have been to make a better therapeutic product with a well-tested agent.
U.S. Patent No. 10,350,294
Claims 1, 5, 7, 8, 10-15, and 18-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 10,350,294 B2 (hereinafter Pat. 294, corresponding application: 15/913,466) in view of Hong (Hong et al., US 2018/0193461, Publication Date: 07/12/2018), Lopez-Cano (Lopez-Cano et al., Expert Opinion on Drug Delivery, 18:7, 819-847, Publication Date: 01/22/2021) and Keller (Keller et al., EP 0244178 A2, Publication Date: 11/04/1987). It is noted that Hong and Pat. 616 correspond to the same application: 14/377,211).
The claims of Pat. 294 teach a method of treating an ophthalmic disease and reducing the side effect of an ocular steroid, comprising administrating to a subject in need thereof an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprising: (a) a lipid cake mixture comprising a phospholipid or a mixture of phospholipids; and (b) a steroid solution comprising an effective amount of an ocular steroid, or a pharmaceutically acceptable salt thereof;
wherein the total amount of the phospholipids in the pharmaceutical composition ranges from about 0.1 μmol to about 2.5 μmol per 50 μl of the pharmaceutical composition, and wherein the ocular steroid side effect profile of the pharmaceutical composition is reduced, relative to the ocular steroid side effect of the pharmaceutical composition having at least about 5 μmol of phospholipids per 50 μl of the pharmaceutical composition (claim 1). Although the claim is drawn a method, the claim disclose a pharmaceutical composition comprising a lipid mixture and a therapeutic agent.
The claims of Pat. 294 teach wherein the pharmaceutical composition is administered by intravitreal injection (claim 8).
The claims of Pat. 294 teach wherein the lipid cake mixture further comprises cholesterol (claim 9)
Thus, although the claims of Pat. 294 are drawn to a method, the claims of Pat. 294 teach a pharmaceutical composition comprising a mixture of lipids and a therapeutic agent (ocular steroid) for eye treatment with reduced side effects. Thus, the subject matter of the claims of Pat. 294 overlap with the subject matter of the instant claims.
However, the claims of Pat. 294 do not teach the pharmaceutical composition comprising a biocompatible hydrogel as instantly claimed, or for reducing an ocular side effect comprising vitreous haze, or specific concentrations as instantly claimed.
As set forth above, Hong, Lopez-Cano and Keller teach the instant claims 1, 5, 7, 8, 10-15, and 18-22. In particular, Hong teaches the DSP-liposome comprising (DOPC, DOPG and cholesterol), method of using the DSP-liposome for eye treatment, and potent side effect such as vitreous haze caused by liposome. Lopez-Cano teach HA hydrogel can significantly increase retention time of drug-liposome in eyes and enhance the drug bioavailability in eyes. Keller teaches that HA of molecular weight of 750 kDa are suitable for drug delivery into eyes.
It would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to modify the pharmaceutical composition disclosed by the claims of Pat. 294 by adding HA hydrogel at a concentration about 0.5% or 0.7% (w/v) as taught Lopez-Cano, because the Lopez-Cano teaches that HA hydrogel at those concentrations can increase retention time and bioavailability of liposome-drug significantly. Thus, one of ordinary skill in the art would have had a reasonable expectation that lower concentration of DSP-liposome in a formulation with HA hydrogel would be as effective as higher concentration of DSP-liposome in a formulation without HA hydrogel. Since DSP-liposome can result in ocular side effect such as vitreous haze, as taught by Hong, using lower concentration of DSP-liposome would reduce the side effect such as vitreous haze. In addition, because HA/DSP-liposome would release the liposome slower (longer retention) in the vitreous humor and thus cause less vitreous clouding or haze after administration. The motivation would have been to further reduce the side effect of the treatment and to reduce the cost of therapeutic materials.
Regarding molecular weight of HA, it would have prima facie been obvious to one of ordinarily skilled in the art before the effective filing date of the claimed invention to combine teachings of the claims of Pat. 960, Hong, Lopez-Cano and Keller, and to make a HA/DSP-liposome composition as taught by Hong and Lopez-Cano, and to use a HA with a molecular weight about 750 kDa as taught by Keller. Given all the components are well known in the art, as evidenced by references, one of ordinary skill in the art would have had a reasonable expectation that HA of molecular weight of 750 kDa would be suitable for the pharmaceutical composition, because the HA is naturally occurring, has good solubility and has been tested in combination with DSP as taught by Keller. The motivation would have been to make a better therapeutic product with a well-tested agent.
Conclusion
No claims are allowed.
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/CHENG LU/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/ Supervisory Patent Examiner, Art Unit 1642
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