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 . 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.
Priority
The instant application is a 371 of PCT/SG2022/050631 filed on 08/31/2022 and claims foreign priority to SG10202110185W filed on 09/15/2021. The certified copy of the foreign priority application filed on 03/11/2024 is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/11/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of the Claims
The preliminary claim amendments filed on 03/11/2024 is acknowledged. Claims 4-14, 16-17, and 19-22 are amended. Claims 3, 15, 18, 23-24, and 26-27 are cancelled.
Accordingly, claims 1-2, 4-14, 16-17, 19-22, and 25 are pending and being examined on the merits herein.
Specification
The disclosure is objected to because of the following informalities:
The chemical structures for formula (I), (II), and (III) on pages 10-11 have poor resolution, and the subscripts n and m have poor legibility.
Appropriate correction is required.
Claim Objections
Claim 9 is objected to because of the following informalities:
The chemical structures for formula (I), (II), and (III) have poor resolution, and the subscripts n and m have poor legibility.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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.
Claim 22 is 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 22 recites “The method according to claim 1”.
There is an antecedent basis issue for “The method according to claim 1” because claim 1 recites a composition and not a method.
For purposes of examination, claim 22 is being interpreted as the method according to claim 16.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 9 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 9 recites the conjugate has the structure as depicted by any one of formula (I), (II), or (III).
The formula (II) and (III) structures recite the first unmodified HA unit is n integers, and the modified HA unit is m integers, wherein m and n integers are independently in range of 1 to 30,000.
The structure of the formula (II) and (III) are drawn such that the first disaccharide unit has a n integer length followed by the second disaccharide unit that has a m integer length, which resembles that of a block copolymer structure (the first disaccharide unit (block) with a defined length followed by the second disaccharide unit (block) with a defined length).
However, the instant specification does not disclose or suggest that the flavonoid can be conjugated to the HA backbone in a block copolymer structure or in any defined structural pattern.
Therefore, claim 9 contains subject matter that was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor had possession of the claimed invention.
It is suggested to amend claim 9 to convey random conjugation of the flavonoid onto the HA backbone for formula (II) and (III), which would have sufficient written description support in the instant specification.
The prior art does not disclose synthesizing block copolymer structures of the HA-flavonoid conjugate as currently drawn in the formula (II) and (III) recited in claim 9.
However, for purposes of compact prosecution, the following rejections below are being applied on the basis that the structure in formula (II) and (III) convey random conjugation of the flavonoid on to the HA backbone as supported by the disclosed specification.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-2 and 4-11 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liang et al. (Acta Biomaterialia, 2016 in PTO-892).
Liang teaches targeted intracellular delivery of a cytotoxic GzmB (granzyme B) protein based on hyaluronic acid–green tea catechin nanogels for cancer therapy (Abstract).Liang illustrates the formation of their self-assembled nanogels comprising HA-EGCG (hyaluronic acid - epigallocatechin gallate conjugate), PEI (polyethylenimine), and GzmB (granzyme B) in Figure 1 (143) and shown below:
PNG
media_image1.png
403
944
media_image1.png
Greyscale
The chemical structure of the HA-EGCG conjugate meets the Formula II structure recited instant claim 9. Furthermore, the GzmB (active agent) meets the limitation of being physically bound to the HA-EGCG conjugate recited in instant claim 1 because the recited “physically bound” in instant claim 1 is being interpreted to include non-covalent interactions based on lines 26-31 page 8 of the instant specification, which discloses that physically interactions between the active agent and the flavonoid conjugate can include non-covalent interaction. Lastly, the PEI meets the limitation of the recited second water-soluble polymer partially encapsulating the nanocomplex recited in instant claim 1.
Liang discloses that the degree of substitution for the EGCG on the HA was 2.3 (number of EGCG dimer molecules per 100 repreating units of HA) or 2.3%. Liang discloses the HA used in the nanogel was 90 kDA (first paragraph section 2.1 Materials page 144). Therefore, the HA-EGCG conjugate would have a MW of 90.458 kDa based on ECGC having a MW of 0.458 kDA and meets the recited MW range in instant claim 10. Additionally, the 90 kDA HA with a EGCG degree of substitution of 2.3 (2.3%) disclosed in Lee would have a recited m and n integer values of around 10.35 and 439.65 based on each HA sugar unit having a MW of around 0.2 kDa.
Liang discloses that the HA–EGCG/lysozyme/PEI complex had a particle size of around 159.8 nm (Table 1 page 147).
Therefore, Liang anticipates instant claims 1-2 and 4-11.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-2, 4-8, and 10-13 are rejected under 35 U.S.C. 103 as being unpatentable over Kurisawa et al. (US20140271902A1 in PTO-892) in view of Liang et al. (Acta Biomaterialia, 2016 in PTO-892).
Kurisawa teaches particulate hyaluronic acid formulations for cellular delivery of bioactive agents (Abstract). Kurisawa teaches the particles comprise an agglomeration of a bioactive agent; and a plurality of conjugates of a hyaluronic acid and a flavonoid wherein the particles are on average from about 15 nm to about 300 nm in diameter and wherein the bioactive agent is releasably retained in the particles by the flavonoid (Abstract).
Kurisawa provides an illustration of their self-assembled particles in Figure 1 and shown below:
PNG
media_image2.png
204
497
media_image2.png
Greyscale
The HA is hyaluronic acid and the EGCG is epigallocatechin gallate (paragraph 0058). Kurisawa discloses that the formulation comprises further combining an endosomolytic agent with the bioactive agent and hyaluronic acid – flavonoid conjugate to form a suspension (claim 45). Kurisawa discloses that the endosomolytic agent can be polyethylenimine (paragraph 0018). Kurisawa teaches pharmaceutical compositions comprising their particle suspensions (paragraph 0144).
Kurisawa demonstrates the synthesis of their HA-ECGC conjugates in which a 90 kDA MW HA was used (paragraph 0152 and 0157) and the ECGC was conjugated to the HA via NHS/EDC linking chemistry (paragraph 0091). The exemplified HA-ECGC would have a MW of 90.458 based on ECGC having a MW of 0.458 kDA and meets the recited MW range in instant claim 10.
Kurisawa demonstrates the intracellular delivery of several proteins using their HA-ECGC composition (paragraphs 0179-187). Kurisawa demonstrates a particle composition comprising HA-ECGC, granzyme (protein), and polyethylenimine (PEI) (paragraph 0187).
Kurisawa teaches that the particle composition comprising HA-ECGC, Granzyme, and PEI was prepared by first mixing the PEI with Granzyme for 15 minutes before adding the HA-ECGC solution to the mixture and allowing complexation to take place for 45 minutes (paragraph 0177). Kurisawa also demonstrates the preparation of HA-ECGC Lysozyme particles by simply mixing the dissolved HA-EGCG and lysozyme solutions with gentle pipetting (paragraph 0163).
While Kurisawa demonstrates a self-assembled particle composition comprising a HA-CGGC conjugate, granzyme, and PEI, Kurisawa does not explicitly teach that the PEI at least partially encapsulates the HA-CGCG conjugate and granzyme particle.
The teachings of Liang are as described above, which illustrates polyethylenimine (PEI) partially encapsulates an HA-EGCG and granzyme complex as seen in Fig. 1 and further discloses the PEI having the same function as an endosomolytic agent for the same complex (second paragraph right column page 143).
Therefore, it would have been prima facie obvious before the effective filing date of the claimed invention that the PEI included in the particle composition comprising HA-ECGC and granzyme (protein) as disclosed in Kurisawa would also partially encapsulate the HA-ECGC and granzyme particle as seen in Liang to arrive at the claimed invention.
One of ordinary skill in the art would this reasonable expectation because both Kurisawa and Liang teach self-assembled particle compositions that comprise of the same HA-ECGC conjugate, granzyme, and PEI. Furthermore, both references disclose that the PEI has the same function as an endosomolytic agent for the complex.
In regards to instant claim 13, even though the combined teachings of Kurisawa and Liang described above do not exemplify the simultaneous or sequential steps of mixing an active agent to HA-ECGC and then adding a second polymer such as PEI to the active agent and HA-ECGC mixture, MPEP 2144.04 states that “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected result” and “Selection of any order of mixing ingredients is prima facie obvious”. Therefore, the ordinary skilled artisan would have been able to select any order of mixing the three components (active agent, HA-ECGC conjugate, and PEI) to arrive at the claimed invention, rendering the recited processing steps obvious.
Claim(s) 9 is rejected under 35 U.S.C. 103 as being unpatentable over Kurisawa et al. (US20140271902A1 in PTO-892) in view of Liang et al. (Acta Biomaterialia, 2016 in PTO-892), as applied to claim 1 above, and further in view of Lee et al. (Polymer Chemistry, 2015 in PTO-892).
The combined teachings of Kurisawa and Liang are as described above, and teach the composition of claim 1 as discussed in detail above.
Furthermore, Kurisawa teaches that the flavonoids used in the particle such as EGCG not only acts as a carrier to deliver the bioactive agent (paragraph 0064) but also has therapeutic effects such as induction of apoptosis, inhibition of tumor cell growth, and inhibition of angiogenesis or MMP gelatinases and may provide therapeutic synergism due to the combined delivery of bioactive agent and flavonoid to the cell (paragraphs 0068-0069).
Kurisawa discloses that the EGCG is conjugated to HA by first derivatizing the HA with diethoxyethyl amine (DA) and then linking EGCG to the derivatized location (paragraphs 0154-0157). Kurisawa provides chemical structures of either the HA-DA and HA-EGCG in Figure 2 and shown below:
PNG
media_image3.png
250
507
media_image3.png
Greyscale
The left unit is unmodified HA, the middle unit is the EGCG attached to HA via the DA derivatized location, and the right unit is the HA derivatized with DA before conjugation of the EGCG. The left and middle unit shown in Kurisawa is the same units as the Formula (II) structure in instant claim 9.
Even though Kurisawa teaches a HA-EGCG with the same units at the Formula (II) structure in instant claim 9, Kurisawa teaches that their HA-EGCG contains an additional unit (the right unit HA-DA) that is not recited in the structures of instant claim 9.
Lee discloses synthesis and bioactivity of a conjugate composed of green tea catechins and hyaluronic acid (Abstract).
Lee discloses that Epigallocatechin-3-gallate (EGCG) is a green tea polyphenol that has several biological activities, including anti-cancer activity and anti-inflammation, and Hyaluronic acid (HA) is a naturally-occurring poly saccharide that is widely used as a biomaterial for drug delivery and tissue engineering due to its visco elastic, biocompatible and biodegradable properties (Abstract). Lee teaches that by conjugating HA with EGCG, the resulting HA EGCG conjugate is expected to exhibit not only the inherent properties of HA but also the bioactivities of EGCG (Abstract).
Lee teaches that synthesis of the HA-EGCG involved first forming an ethylamine-bridged ECGC dimer using 2,2-diethoxyethylaine (DA) under acidic conditions and then first adding the HA to conjugate the ethylamine-bridged EGCG dimers to the HA (Abstract).
Lee provides a schematic of the synthesis in Scheme 2 (page 4466) and shown below:
PNG
media_image4.png
296
902
media_image4.png
Greyscale
The synthesized HA-EGCG conjugate in Lee meets the structure of the recited Formula (II) in instant claim 9.
Lee further discloses that the degree of substitution of EGCG on the HA was 0.8 for a 90 kDa HA (second paragraph right column page 4464).
It would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the HA-EGCG conjugate as disclosed by the combined teachings of Kurisawa and Liang described above with the HA-EGCG conjugate of Lee to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element for another to obtain predictable results and would have a reasonable expectation of success in doing so because both the combined teachings of Kurisawa and Liang described above and Lee teach the same HA-EGCG conjugate using the same DA derivatization to link the EGCG and both references also disclose their respective HA-EGCG conjugates as having the same therapeutic effects such as anti-cancer activity. Furthermore, the 80 kDA HA with a EGCG degree of substitution of 0.8 disclosed in Lee would have a recited m and n integer values of around 320 and 80 based on each HA sugar unit having a MW of around 0.2 kDa.
Claim(s) 1, 14, 16-17, 19-22, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Miyagawa et al. (Pharmaceutics, April 2020 in PTO-892) in view of Kurisawa et al. (US20140271902A1 in PTO-892) and Liang et al. (Acta Biomaterialia, 2016 in PTO-892).
Miyagawa teaches topical application of hyaluronic acid-RGD peptide-coated gelatin/epigallocatechin-3 gallate (EGCG) nanoparticles (NPs) to inhibit corneal neovascularization via inhibition of VEGF production (Abstract).
Miyagawa discloses that corneal neovascularization (NV) is the formation of new vessels from pre-existing vascular structures in the transparent cornea, resulting from a variety of ocular pathologic conditions which are detrimental to vision, and that these newly-formed vessels sprouting from the capillaries of the pericorneal plexus may block light, compromise visual acuity, cause inflammation and corneal scarring, and may eventually result in blindness (first paragraph section Introduction page 2). Miyagawa discloses that in order to combat this, vascular endothelial growth factor (VEGF) targeting antigen-binding fragment has been developed to treat NV and demonstrates great promise for the treatment of corneal NV (first paragraph section Introduction page 2).
Miyagawa teaches that EGCG has also been shown to effectively limit the upregulation of metalloproteinase (MMP)-9 and VEGF in a mouse model of corneal NV treated by subconjunctival injection of EGCG and therefore EGCG was chosen to treat corneal NV in their study (second paragraph section Introduction page 2). Miyagawa teaches that RGD peptide particularly recognize αvβ3 integrins, which is involved in ocular angiogenesis, on the tumoral endothelial cell membrane and newly-formed blood vessels during angiogenesis and therefore RGD-based targeting strategy could be used to enhance biomaterial-endothelial cell interaction to target pathological angiogenesis (second paragraph section Introduction page 2).
Miyagawa discloses that conventional methods of ocular drug delivery include topical administration, intravitreal injection, and intraocular implant with topical application representing a common, noninvasive approach for ocular drug delivery (third paragraph section Introduction page 2). However, Miyagawa discloses that eye drops have major drawbacks such as poor ocular drug bioavailability, nasolacrimal duct drainage, and poor penetration to the posterior segments of the eye (third paragraph section Introduction page 2).
Therefore, Miyagawa designed an eye drop formulation which contained gelatin-ECGG self-assembled NPs with hyaluronic acid (HA) that is conjugated to arginine-glycine-aspartic acid (RGD) peptide (Abstract). Miyagawa discloses that the application of NPs on ocular diseases allows targeted delivery, slow-release, and enhanced pharmacokinetics, thereby improving the bioavailability of drugs in the eyes (third paragraph section Introduction page 2).
Miyagawa illustrates the synthesis and treatment method of their GEH-RGD nanoparticles in Figure 1(A) and 1(B) (page 3) and shown below:
PNG
media_image5.png
805
648
media_image5.png
Greyscale
The GE (gelatin – EGCG) in the GEH-RGD NP illustrated above meets the limitation of a conjugate that comprises one or more flavonoid molecule and a first water-soluble polymer as recited in instant claim 1. Furthermore, the HA-RGD illustrated above meets the limitation of partially encapsulating a nanocomplex as recited in instant claim 1 because the HA-RGD is encapsulating the GE as illustrated above. Miyagawa teaches the particle size of the GEH-RGD NP was around 158 nm (last paragraph page 5).
Miyagawa further demonstrates in Figures 2-6 (pages 6-11) that GEH-RGD NP treatment significantly reduced endothelial cell tube formation and inhibited metalloproteinase (MMP)-2 and MMP-9 activity in HUVECs in vitro, topical application of GEH-RGD NPs (once daily for a week) significantly attenuated the formation of pathological vessels in the mouse cornea after chemical cauterization, and reduction in both vascular endothelial growth factor (VEGF) and MMP-9 protein in the GEH-RGD NP-treated cauterized corneas was observed (Abstract). Miyagawa concludes that these results confirm the molecular mechanism of the antiangiogenic effect of GEH-RGD NPs in suppressing pathological corneal NV (Abstract).
While Miyagawa teaches a method of treating NV by topically administering a GEH-RGD NP eye drop formulation once daily for a week, the GEH-RGD NP disclosed in Miyagawa does not teach including one or more active agents as recited in instant claim 1.
The combined teachings of Kurisawa and Liang are as described above, and teach the composition of claim 1as discussed in detail above.
Furthermore, Kurisawa teaches that the flavonoids used in the particle such as EGCG not only acts as a carrier to deliver the bioactive agent (paragraph 0064) but also has therapeutic effects such as induction of apoptosis, inhibition of tumor cell growth, and inhibition of angiogenesis or MMP gelatinases and may provide therapeutic synergism due to the combined delivery of bioactive agent and flavonoid to the cell (paragraphs 0068-0069). Kurisawa discloses that the bioactive agent can be a protein, peptide, antibody, enzyme, growth factor, cytokine, nucleic acids, and others as well as anti-inflammatory agents, chemotherapeutic agents, antihypertensive agents, and others (paragraph 0095).
It would have been prima facie obvious before the effective filing date of the claimed invention to have further included into the GEH-RGD NP disclosed in Miyagawa an antibody such as the VEGF targeting antigen-binding fragment disclosed in Miyagawa as the bioactive agent as suggested in the combined teachings of Kurisawa and Liang described above to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because the combined teachings of Kurisawa and Liang described above provide guidance of a similar HA-ECGC based nanoparticles that can include a bioactive agent for delivery into cells and further discloses that the ECGC has the same therapeutic effects of inhibiting angiogenesis as well as MMP gelatinases. Furthermore, Miyagawa provides guidance that VEGF targeting antigen-binding fragment have been developed to treat NV, and Kurisawa provides further guidance that the bioactive agent included in their HA-ECGC based nanoparticle can be antibodies.
Alternatively, it would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the GEH-RGD NPs in the eye drop formulation of Miyagawa with the HA-ECGC-PEI plus bioactive agent particles as disclosed by the combined teachings of Kurisawa and Liang described above and further selecting an antibody such as the VEGF targeting antigen-binding fragment disclosed in Miyagawa as the bioactive agent to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (GEH-RGD NPs) for another (HA-ECGC-PEI plus bioactive agent particles) to obtain predictable results and would have a reasonable expectation of success in doing so because both Miyagawa and the combined teachings of Kurisawa and Liang described above disclose similar HA-ECGC based nanoparticles and further disclose that the ECGC has the same therapeutic effects of inhibiting angiogenesis as well as MMP gelatinases.
One of ordinary skill in the art would have combined prior art elements according to known methods by selecting VEGF targeting antigen-binding fragment as the bioactive agent to yield predictable results and would have a reasonable expectation of success in doing so because Miyagawa provides guidance that VEGF targeting antigen-binding fragment have been developed to treat NV, and Kurisawa provides guidance that the bioactive agent included in their HA-ECGC based nanoparticle can be antibodies.
In regards to instant claim 14, it would have also been prima facie obvious before the effective filing date of the claimed invention to administer the HA-EGCG NP eye drop formulation as disclosed by the combined teachings of Miyagawa, Kurisawa, and Liang described above to inhibit endothelial cell proliferation activated by VEGF in vitro as suggested in Miyagawa to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Miyagawa provides guidance that their GEH-RGD NPs significantly attenuated the formation of pathological vessels and reduced VEGF in the cornea of a mouse model, and further demonstrates that their GEH-RGD NPs reduced endothelial cell tube formation and inhibited metalloproteinase (MMP)-2 and MMP-9 activity in HUVECs in vitro, which together suggests that the GEH-RGD NPs disclosed in Miyagawa would also inhibit endothelial cell proliferation when activated by a proangiogenic growth factor such as VEGF in vitro.
In regards to instant claim 19, it would have also been prima facie obvious before the effective filing date of the claimed invention to administer the HA-EGCG NP eye drop formulation as disclosed by the combined teachings of Miyagawa, Kurisawa, and Liang as described above intravitreally to the eye as disclosed in Miyagawa to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Miyagawa provides guidance that conventional methods of ocular drug delivery include topical administration, intravitreal injection, and intraocular implant.
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.
Claims 1-2, 4-8, and 10-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 9,226,899 in view of in view of Kurisawa et al. (US20140271902A1 in PTO-892) and Liang et al. (Acta Biomaterialia, 2016 in PTO-892).
The claims of US’899 recite a method of formulating a suspension of immiscible particles comprising combining in an aqueous solution: a. 0.01% w/v to about 1.0% w/v of a bioactive agent; and b. 0.05 μg/ml to about 5000 μg/ml of conjugates of a hyaluronic acid and a flavonoid; to form the suspension of particles the particles comprising an agglomeration of the bioactive agent and the conjugates of hyaluronic acid and a flavonoid, the particles having a hydrated interior and having an average diameter of from about 15 nm to about 300 nm, the bioactive agent being releasably retained in the particles by the flavonoid (claim 6). US’899 recites the method of claim 6 comprising combining an endosomolytic agent with the bioactive agent and the conjugates of a hyaluronic acid and a flavonoid to form the suspension and wherein the particles further comprise the endosomolytic agent (claim 7), and the method of claim 6 further comprising formulating the suspension into a therapeutic formulation (claim 8). US’899 recites the flavonoid is epigallocatchin gallate (claim 10), and the bioactive agent is anti-cancer agent, protein, intrabody, or Granzyme. US’899 recites the hyaluronic acid has a MW of 5000 to about 10000000 daltons (claim 18)
While US’899 recites a composition comprising particles that have a bioactive agent that is complexed with a HA-flavnoid conjugate and an endosomolytic agent, US’899 does not recite the particle complex being encapsulated by a second water-soluble polymer such as polyethylenimine (PEI).
The independent teachings of Kurisawa and Liang are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention that the endosomolytic agent recited in the claims of US’899 can be PEI as disclosed in Kurisawa and that the included PEI would partially encapsulate the modified particle composition based on the teachings of Liang to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because both the claims of US’899 and Kurisawa recite the same HA-flavonoid conjugate, bioactive agent, and endosomolytic agent particle complex, and Kurisawa provides further guidance that the endosomolytic agent can be PEI. Additionally, US’899 recites an overlapping MW range of the recited hyaluronic acid conjugate based on EGCG having a MW of 0.458 kDA, rendering the recited MW range of the conjugate in instant claim 10 obvious. See MPEP 2144.05 I.
Furthermore, one of ordinary skill in the art would a reasonable expectation that the included PEI would partially encapsulate the particle composition because both the combination of the claims of US’899 and Kurisawa described above and Liang teach self-assembled particle compositions that comprise of the same HA-ECGC conjugate, granzyme, and PEI. Furthermore, both references disclose that the PEI has the same function as an endosomolytic agent for the complex.
In regards to instant claim 13, MPEP 2144.04 states that “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected result” and “Selection of any order of mixing ingredients is prima facie obvious”. Furthermore, Kurisawa demonstrates mixing an active agent (lysozyme) with HA-ECGC for self-assembly of the particle as well as mixing the PEI (second polymer) with an active agent and subsequently mixing the HA-ECGC. Therefore, even though the combination of the claims of US’899,Kurisawa, and Liang do not exemplify the sequential steps of mixing an active agent to HA-ECGC and then adding a second polymer such as PEI to the active agent and HA-ECGC mixture, the ordinary skilled artisan would have been able to select any order of mixing the three components to arrive at the claimed invention, rendering the recited processing steps obvious.
Claims 1 and 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 9,226,899 in view of in view of Kurisawa et al. (US20140271902A1 in PTO-892), Liang et al. (Acta Biomaterialia, 2016 in PTO-892), and Lee et al. (Polymer Chemistry, 2015 in PTO-892).
The combination of the claims of US’899, Kurisawa, and Liang are as described above and recite the composition of instant claim 1 as discussed in detail above.
The combined references, however, do not recite the structures of instant claim 9.
The teachings of Lee are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the HA-EGCG conjugate as disclosed by the combination of the claims of US’899, Kurisawa, and Liang described above with the HA-EGCG conjugate of Lee to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element for another to obtain predictable results and would have a reasonable expectation of success in doing so because both the combination of the claims of US’899, Kurisawa, and Liang described above and Lee teach the same HA-EGCG conjugate and both references also disclose their respective HA-EGCG conjugates as having the same therapeutic effects such as anti-cancer activity. Furthermore, the 80 kDA HA with a EGCG degree of substitution of 0.8 disclosed in Lee would have a recited m and n integer values of around 320 and 80 based on each HA sugar unit having a MW of around 0.2 kDa.
Claims 1, 14, 16-17, 19-22, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 9,226,899 in view of in view of Kurisawa et al. (US20140271902A1 in PTO-892), Liang et al. (Acta Biomaterialia, 2016 in PTO-892), and Miyagawa et al. (Pharmaceutics, April 2020 in PTO-892).
The combination of the claims of US’899, Kurisawa, and Liang are as described above and recite the composition of instant claim 1 as discussed in detail above.
The combined references, however, do not recite a method of inhibiting endothelial cell proliferation when activated by a proangiogenic growth factor in vitro or a method of treating an eye disease such as corneal neovascularization by administering the composition topically to the eye.
The teachings of Miyagawa are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have selected an anitbody such as the VEGF targeting antigen-binding fragment disclosed in Miyagawa as the bioactive agent in the HA-ECGC-PEI plus bioactive agent particles as disclosed by the combination of the claims of US’899, Kurisawa, and Liang described above and further formulate and topically administer this particle complex as an eye drop formulation to treat corneal NV as disclosed in Miyagawa to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because both the combination of the claims of US’899, Kurisawa, and Liang described above and Miyagawa disclose similar HA-ECGC based nanoparticles and further disclose that the ECGC has the same therapeutic effects of inhibiting angiogenesis as well as MMP gelatinases. Furthermore, Miyagawa provides guidance that VEGF targeting antigen-binding fragment have been developed to treat NV, and Kurisawa provides guidance that the bioactive agent in their HA-ECGC based nanoparticle can be antibodies.
In regards to instant claim 14, it would have also been prima facie obvious before the effective filing date of the claimed invention to administer the HA-EGCG NP eye drop formulation as disclosed by the combination of the claims of US’899 and the teachings of Kurisawa, Liang, and Miyagawa described above to inhibit endothelial cell proliferation activated by VEGF in vitro as suggested in Miyagawa to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Miyagawa provides guidance that their GEH-RGD NPs significantly attenuated the formation of pathological vessels and reduced VEGF in the cornea of a mouse model, and further demonstrates that their GEH-RGD NPs reduced endothelial cell tube formation and inhibited metalloproteinase (MMP)-2 and MMP-9 activity in HUVECs in vitro, which together suggests that the GEH-RGD NPs disclosed in Miyagawa would also inhibit endothelial cell proliferation when activated by a proangiogenic growth factor such as VEGF in vitro.
In regards to instant claim 19, it would have also been prima facie obvious before the effective filing date of the claimed invention to administer the HA-EGCG NP eye drop formulation as disclosed by the combination of the claims of US’899 and the teachings of Kurisawa, Liang, and Miyagawa described above intravitreally to the eye as disclosed in Miyagawa to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Miyagawa provides guidance that conventional methods of ocular drug delivery include topical administration, intravitreal injection, and intraocular implant.
Claims 1-2, 4-8, and 10-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No 8,753,687 in view of in view of Kurisawa et al. (US20140271902A1 in PTO-892) and Liang et al. (Acta Biomaterialia, 2016 in PTO-892).
The claims of US’687 recite a suspension of immiscible particles in an aqueous solution, the particles comprising an agglomeration of: a bioactive agent; and a plurality of conjugates of a hyaluronic acid and a flavonoid; the particles having a hydrated interior and having an average diameter of from about 15 nm to about 300 nm, the bioactive agent being releasably retained in the particles by the flavonoid (claim 1), the suspension of claim 1 wherein the bioactive agent is releasably retained in the particles by a hydrophobic bond or an ionic bond between the flavonoid and the bioactive agent (claim 2), wherein the flavonoid is epigallocatechin gallate (claim 5), wherein the bioactive agent is an anti-cancer agent, a protein, an intrabody, or Granzyme B (claims 6-9), the HA has a molecular weight of from about 5000 to about 10000000 daltons (claim 10), and the particles further comprise an endosomolytic agent (claim 11).
While US’687 recites a composition comprising particles that have a bioactive agent that is complexed with a HA-flavnoid conjugate and an endosomolytic agent, US’687 does not recite the particle complex being encapsulated by a second water-soluble polymer such as polyethylenimine (PEI).
The independent teachings of Kurisawa and Liang are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention that the endosomolytic agent recited in the claims of US’687 can be PEI as disclosed in Kurisawa and that the included PEI would partially encapsulate the modified particle composition based on the teachings of Liang to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because both the claims of US’687 and Kurisawa recite the same HA-flavonoid conjugate, bioactive agent, and endosomolytic agent particle complex, and Kurisawa provides further guidance that the endosomolytic agent can be PEI. Additionally, US’687 recites an overlapping MW range of the recited hyaluronic acid conjugate based on EGCG having a MW of 0.458 kDA, rendering the MW range of the conjugate in instant claim 10 obvious. See MPEP 2144.05 I.
Furthermore, one of ordinary skill in the art would a reasonable expectation that the included PEI would partially encapsulate the particle composition because both the combination of the claims of US’687 and Kurisawa described above and Liang teach self-assembled particle compositions that comprise of the same HA-ECGC conjugate, granzyme, and PEI. Furthermore, both references disclose that the PEI has the same function as an endosomolytic agent for the complex.
In regards to instant claim 13, MPEP 2144.04 states that “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected result” and “Selection of any order of mixing ingredients is prima facie obvious”. Furthermore, Kurisawa demonstrates mixing an active agent (lysozyme) with HA-ECGC for self-assembly of the particle as well as mixing the PEI (second polymer) with an active agent and subsequently mixing the HA-ECGC. Therefore, even though the combination of the claims of US’687, Kurisawa, and Liang do not exemplify the sequential steps of mixing an active agent to HA-ECGC and then adding a second polymer such as PEI to the active agent and HA-ECGC mixture, the ordinary skilled artisan would have been able to select any order of mixing the three components to arrive at the claimed invention, rendering the recited processing steps obvious.
Claims 1 and 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No 8,753,687 in view of in view of Kurisawa et al. (US20140271902A1 in PTO-892), Liang et al. (Acta Biomaterialia, 2016 in PTO-892), and Lee et al. (Polymer Chemistry, 2015 in PTO-892).
The combination of the claims of US’687, Kurisawa, and Liang are as described above and recite the composition of instant claim 1 as discussed in detail above.
The combined references, however, do not recite the structures of instant claim 9.
The teachings of Lee are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the HA-EGCG conjugate as disclosed by the combination of the the claims of US’687, Kurisawa, and Liang described above with the HA-EGCG conjugate of Lee to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element for another to obtain predictable results and would have a reasonable expectation of success in doing so because both the combination of the claims of US’687, Kurisawa, and Liang described above and Lee teach the same HA-EGCG conjugate and both references also disclose their respective HA-EGCG conjugates as having the same therapeutic effects such as anti-cancer activity. Furthermore, the 80 kDA HA with a EGCG degree of substitution of 0.8 disclosed in Lee would have a recited m and n integer values of around 320 and 80 based on each HA sugar unit having a MW of around 0.2 kDa.
Claims 1, 14, 16-17, 19-22, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No 8,753,687 in view of in view of Kurisawa et al. (US20140271902A1 in PTO-892), Liang et al. (Acta Biomaterialia, 2016 in PTO-892), and Miyagawa et al. (Pharmaceutics, April 2020 in PTO-892).
The combination of the claims of US’687, Kurisawa, and Liang are as described above and recite the composition of instant claim 1 as discussed in detail above.
The combined references, however, do not recite a method of inhibiting endothelial cell proliferation when activated by a proangiogenic growth factor in vitro or a method of treating an eye disease such as corneal neovascularization by administering the composition topically to the eye.
The teachings of Miyagawa are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have selected an antibody such as the VEGF targeting antigen-binding fragment disclosed in Miyagawa as the bioactive agent in the HA-ECGC-PEI plus bioactive agent particles as disclosed by the combination of the claims of US’687, Kurisawa, and Liang described above and further formulate and topically administer this particle complex as an eye drop formulation to treat corneal NV as disclosed in Miyagawa to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because both the combination of the claims of US’687, Kurisawa, and Liang described above and Miyagawa disclose similar HA-ECGC based nanoparticles and further disclose that the ECGC has the same therapeutic effects of inhibiting angiogenesis as well as MMP gelatinases. Furthermore, Miyagawa provides guidance that VEGF targeting antigen-binding fragment have been developed to treat NV, and Kurisawa provides guidance that the bioactive agent in their HA-ECGC based nanoparticle can be antibodies.
In regards to instant claim 14, it would have also been prima facie obvious before the effective filing date of the claimed invention to administer the HA-EGCG NP eye drop formulation as disclosed by the combination of the claims of US’687 and the teachings of Kurisawa, Liang, and Miyagawa described above to inhibit endothelial cell proliferation activated by VEGF in vitro as suggested in Miyagawa to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Miyagawa provides guidance that their GEH-RGD NPs significantly attenuated the formation of pathological vessels and reduced VEGF in the cornea of a mouse model, and further demonstrates that their GEH-RGD NPs reduced endothelial cell tube formation and inhibited metalloproteinase (MMP)-2 and MMP-9 activity in HUVECs in vitro, which together suggests that the GEH-RGD NPs disclosed in Miyagawa would also inhibit endothelial cell proliferation when activated by a proangiogenic growth factor such as VEGF in vitro.
In regards to instant claim 19, it would have also been prima facie obvious before the effective filing date of the claimed invention to administer the HA-EGCG NP eye drop formulation as disclosed by the combination of the claims of US’687 and the teachings of Kurisawa, Liang, and Miyagawa described above intravitreally to the eye as disclosed in Miyagawa to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Miyagawa provides guidance that conventional methods of ocular drug delivery include topical administration, intravitreal injection, and intraocular implant.
Claims 1-2, 4-8, and 10-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No 10,052,307 in view of in view of Kurisawa et al. (US20140271902A1 in PTO-892) and Liang et al. (Acta Biomaterialia, 2016 in PTO-892).
The claims of US’307 recite a micellar nanocomplex comprising a micelle and an agent encapsulated within said micelle, said micelle comprising a polymer-flavonoid conjugate, wherein said polymer is bonded to the B ring of said flavonoid (claim 1), said polymer is bonded to said flavonoid via a linker such as a iminie group (claims 3-4), said polymer can be hyaluronic acid, polyethylenimine (PEI), and others (claims 10 and 12), said flavonoid is epigallocatechin gallate and others (claim 14), said agent is a therapeutic agent such as chemotherapeutic agent, peptide antibiotics, and others (claims 15-17), the micellar nanocomplex has a size of 30 to 300 nm (claim 18), and loading content of the agent in the micelle in 1 to 10 w/w% (claim 20). The claims of US’307 also recite a method for forming a micellar nanocomplex comprising a micelle and an agent encapsulated within said micelle, the method comprising the steps of: a. adding said agent in a suitable solvent to a polymer-flavonoid conjugate, wherein said polymer is bonded to the B ring of said flavonoid; and b. allowing the self-assembly of a micelle comprising said polymer-flavonoid conjugate and encapsulation of said agent within said micelle to thereby form said micellar nanocomplex (claim 21).
While US’307 recites a composition comprising nanocomplexes that have a bioactive agent that is complexed with a HA-flavonoid conjugate, US’307 does not recite the particle complex being encapsulated by a second water-soluble polymer such as polyethylenimine (PEI).
The independent teachings of Kurisawa and Liang are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention that to modify the composition of US’307 by selecting hyaluronic acid as the polymer in the molecular weights as disclosed in Kurisawa, selecting the epigallocatechin gallate as the flavonoid as disclosed in Kurisawa, and using granzyme as the agent as disclosed in Kurisawa, further include an endosomolytic agent such as PEI as disclosed in Kurisawa for the nanocomplex composition, and that the included PEI would partially encapsulate the modified particle composition based on the teachings of Liang to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because both the claims of US’307 and Kurisawa recite the same HA-flavonoid conjugate and bioactive agents particle complex, and Kurisawa provides further guidance of including endosomolytic agent that can be PEI to form a suspension. Additionally, Kurisawa recites an overlapping MW range of the recited hyaluronic acid conjugate based on EGCG having a MW of 0.458 kDA, rendering the recited MW range of the conjugate in instant claim 10 obvious. See MPEP 2144.05 I.
Furthermore, one of ordinary skill in the art would a reasonable expectation that the included PEI would partially encapsulate the particle composition because both the combination of the claims of US’307 and Kurisawa described above and Liang teach self-assembled particle compositions that comprise of the same HA-ECGC conjugate, granzyme, and PEI. Furthermore, both references disclose that the PEI has the same function as an endosomolytic agent for the complex.
In regards to instant claim 13, MPEP 2144.04 states that “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected result” and “Selection of any order of mixing ingredients is prima facie obvious”. Furthermore, Kurisawa demonstrates mixing an active agent (lysozyme) with HA-ECGC for self-assembly of the particle as well as mixing the PEI (second polymer) with an active agent and subsequently mixing the HA-ECGC. Therefore, even though the combination of the claims of US’307, Kurisawa, and Liang do not exemplify the sequential steps of mixing an active agent to HA-ECGC and then adding a second polymer such as PEI to the active agent and HA-ECGC mixture, the ordinary skilled artisan would have been able to select any order of mixing the three components to arrive at the claimed invention, rendering the recited processing steps obvious.
Claims 1 and 9 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U U.S. Patent No 10,052,307 in view of in view of Kurisawa et al. (US20140271902A1 in PTO-892), Liang et al. (Acta Biomaterialia, 2016 in PTO-892), and Lee et al. (Polymer Chemistry, 2015 in PTO-892).
The combination of the claims of US’307, Kurisawa, and Liang are as described above and recite the composition of instant claim 1 as discussed in detail above.
The combined references, however, do not recite the structures of instant claim 9.
The teachings of Lee are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have substituted the HA-EGCG conjugate as disclosed by the combination of the claims of US’307 and Kurisawa described above with the HA-EGCG conjugate of Lee to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element for another to obtain predictable results and would have a reasonable expectation of success in doing so because both the combination of the claims of US’307, Kurisawa, and Liang described above and Lee teach the same HA-EGCG conjugate using a similar linking derivatization to link the EGCG and both references also disclose their respective HA-EGCG conjugates as having the same therapeutic effects such as anti-cancer activity. Furthermore, the 80 kDA HA with a EGCG degree of substitution of 0.8 disclosed in Lee would have a recited m and n integer values of around 320 and 80 based on each HA sugar unit having a MW of around 0.2 kDa.
Claims 1, 14, 16-17, 19-22, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No 10,052,307 in view of in view of Kurisawa et al. (US20140271902A1 in PTO-892), Liang et al. (Acta Biomaterialia, 2016 in PTO-892), and Miyagawa et al. (Pharmaceutics, April 2020 in PTO-892).
The combination of the claims of US’307, Kurisawa, and Liang are as described above and recite the composition of instant claim 1 as discussed in detail above.
The combined references, however, do not recite a method of inhibiting endothelial cell proliferation when activated by a proangiogenic growth factor in vitro or a method of treating an eye disease such as corneal neovascularization by administering the composition topically to the eye.
The teachings of Miyagawa are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have selected an antibody such as the VEGF targeting antigen-binding fragment disclosed in Miyagawa as the bioactive agent in the HA-ECGC-PEI plus bioactive agent particles as disclosed by the combination of the claims of US’307, Kurisawa, and Liang described above and further formulate and topically administer this particle complex as an eye drop formulation to treat corneal NV as disclosed in Miyagawa to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because both the claims of US’307, Kurisawa, and Liang described above and Miyagawa disclose similar HA-ECGC based nanoparticles and further disclose that the ECGC has the same therapeutic effects of inhibiting angiogenesis as well as MMP gelatinases. Furthermore, Miyagawa provides guidance that VEGF targeting antigen-binding fragment have been developed to treat NV, and Kurisawa provides guidance that the bioactive agent in their HA-ECGC based nanoparticle can be antibodies.
In regards to instant claim 14, it would have also been prima facie obvious before the effective filing date of the claimed invention to administer the HA-EGCG NP eye drop formulation as disclosed by the combination of the claims of US’307 and the teachings of Kurisawa, Liang, and Miyagawa described above to inhibit endothelial cell proliferation activated by VEGF in vitro as suggested in Miyagawa to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Miyagawa provides guidance that their GEH-RGD NPs significantly attenuated the formation of pathological vessels and reduced VEGF in the cornea of a mouse model, and further demonstrates that their GEH-RGD NPs reduced endothelial cell tube formation and inhibited metalloproteinase (MMP)-2 and MMP-9 activity in HUVECs in vitro, which together suggests that the GEH-RGD NPs disclosed in Miyagawa would also inhibit endothelial cell proliferation when activated by a proangiogenic growth factor such as VEGF in vitro.
In regards to instant claim 19, it would have also been prima facie obvious before the effective filing date of the claimed invention to administer the HA-EGCG NP eye drop formulation as disclosed by the combination of the claims of US’307 and the teachings of Kurisawa, Liang, and Miyagawa described above intravitreally to the eye as disclosed in Miyagawa to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Miyagawa provides guidance that conventional methods of ocular drug delivery include topical administration, intravitreal injection, and intraocular implant.
Claims 1-2 and 4-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No 10,993,917 in view of in view of Kurisawa et al. (US20140271902A1 in PTO-892) and Liang et al. (Acta Biomaterialia, 2016 in PTO-892).
The claims of US’917 recite a method for forming a nanocomplex having a functionalized hyaluronic acid shell and a core comprising epigallocatechin gallate encapsulating a metal-containing compound selected from the group consisting of cisplatin, oxaliplatin, and carboplatin, the method comprising a step of mixing a solution of the metal-containing compound with a solution of a conjugate of the functionalized hyaluronic acid and the epigallocatechin gallate, thereby forming a reaction solution, wherein: said functionalized hyaluronic acid shell is a thiol-functionalized hyaluronic acid shell,
when the metal-containing compound is cisplatin, the cisplatin has a concentration of 0.4 mg/mL to 1.0 mg/mL in the reaction solution (claim 1), the conjugate of the functionalized HA and EGCG has the structure I (claim 4), which is the same structure as recited Formula (I) in instant claim 9, the hyaluronic acid having an average molecular weight of 20 kDa (claim 5),
While US’917 recites forming a nanocomplex comprising cisplatin that is complexed with a HA-EGCG conjugate at a concentration of 0.4 to 1.0 mg/mL, US’917 does not recite the particle complex being encapsulated by a second water-soluble polymer such as polyethylenimine (PEI).
The independent teachings of Kurisawa and Liang are as described above. Furthermore, Kurisawa teaches that the anti-cancer agent can also be cisplatin and others (paragraph 0099).
It would have been prima facie obvious before the effective filing date of the claimed invention that to substitute the recited metal-containing compounds of the claims of US’917 with granzyme as disclosed in Kurisawa, further include an endosomolytic agent such as PEI as disclosed in Kurisawa, and the included PEI would partially encapsulate the modified particle composition based on the teachings of Liang to arrive at the claimed invention.
One of ordinary skill in the art would have substituted one known element (metal-containing compounds) for another (granzyme) to obtain predictable results and would have a reasonable expectation of success in doing so because both the claims of US’917 and Kurisawa recite the same particle compositions comprising the same HA-ECGC conjugate and anticancer agents.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because both the claims of US’917 and Kurisawa recite the same HA-flavonoid conjugate and bioactive agent particle complex, and Kurisawa provides further guidance of including endosomolytic agent that can be PEI to form a suspension.
Furthermore, one of ordinary skill in the art would a reasonable expectation that the included PEI would partially encapsulate the particle composition because both the combination of the claims of US’917 and Kurisawa described above and Liang teach self-assembled particle compositions that comprise of the same HA-ECGC conjugate, granzyme, and PEI. Furthermore, both references disclose that the PEI has the same function as an endosomolytic agent for the complex.
In regards to instant claim 13, MPEP 2144.04 states that “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected result” and “Selection of any order of mixing ingredients is prima facie obvious”. Furthermore, Kurisawa demonstrates mixing an active agent (lysozyme) with HA-ECGC for self-assembly of the particle as well as mixing the PEI (second polymer) with an active agent and subsequently mixing the HA-ECGC. Therefore, even though the combination of the claims of US’917, Kurisawa, and Liang do not exemplify the sequential steps of mixing an active agent to HA-ECGC and then adding a second polymer such as PEI to the active agent and HA-ECGC mixture, the ordinary skilled artisan would have been able to select any order of mixing the three components to arrive at the claimed invention, rendering the recited processing steps obvious.
Claims 1, 14, 16-17, 19-22, and 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No 10,993,917 in view of in view of Kurisawa et al. (US20140271902A1 in PTO-892), Liang et al. (Acta Biomaterialia, 2016 in PTO-892), and Miyagawa et al. (Pharmaceutics, April 2020 in PTO-892).
The combination of the claims of US’917, Kurisawa, and Liang are as described above and recite the composition of instant claim 1 as discussed in detail above.
The combined references, however, do not recite a method of inhibiting endothelial cell proliferation when activated by a proangiogenic growth factor in vitro or a method of treating an eye disease such as corneal neovascularization by administering the composition topically to the eye.
The teachings of Miyagawa are as described above.
It would have been prima facie obvious before the effective filing date of the claimed invention to have selected an antibody such as the VEGF targeting antigen-binding fragment disclosed in Miyagawa as the bioactive agent in the HA-ECGC-PEI plus bioactive agent particles as disclosed by the combination of the claims of US’917, Kurisawa, and Liang described above and further formulate and topically administer this particle complex as an eye drop formulation to treat corneal NV as disclosed in Miyagawa to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because both the combination of the claims of US’917, Kurisawa, and Liang described above and Miyagawa disclose similar HA-ECGC based nanoparticles and further disclose that the ECGC has the same therapeutic effects of inhibiting angiogenesis as well as MMP gelatinases. Furthermore, Miyagawa provides guidance that VEGF targeting antigen-binding fragment have been developed to treat NV, and Kurisawa provides guidance that the bioactive agent in their HA-ECGC based nanoparticle can be antibodies.
In regards to instant claim 14, it would have also been prima facie obvious before the effective filing date of the claimed invention to administer the HA-EGCG NP eye drop formulation as disclosed by the combination of the claims of US’917 and the teachings of Kurisawa, Liang, and Miyagawa described above to inhibit endothelial cell proliferation activated by VEGF in vitro as suggested in Miyagawa to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Miyagawa provides guidance that their GEH-RGD NPs significantly attenuated the formation of pathological vessels and reduced VEGF in the cornea of a mouse model, and further demonstrates that their GEH-RGD NPs reduced endothelial cell tube formation and inhibited metalloproteinase (MMP)-2 and MMP-9 activity in HUVECs in vitro, which together suggests that the GEH-RGD NPs disclosed in Miyagawa would also inhibit endothelial cell proliferation when activated by a proangiogenic growth factor such as VEGF in vitro.
In regards to instant claim 19, it would have also been prima facie obvious before the effective filing date of the claimed invention to administer the HA-EGCG NP eye drop formulation as disclosed by the combination of the claims of US’917 and the teachings of Kurisawa, Liang, and Miyagawa described above intravitreally to the eye as disclosed in Miyagawa to arrive at the claimed invention.
One of ordinary skill in the art would have combined prior art elements according to known methods to yield predictable results and would have a reasonable expectation of success in doing so because Miyagawa provides guidance that conventional methods of ocular drug delivery include topical administration, intravitreal injection, and intraocular implant.
Conclusion
No claim is found allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID H CHO whose telephone number is (571)270-0691. The examiner can normally be reached M-F 8AM-5PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Goon can be reached at 571-270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
Prosecution Insights