FINAL 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 .
Status of the Claims
This action is in response to papers filed 09/16/2025 in which claims 3, 5, 10, 13, 17, and 21 were canceled; claims 22-24 were withdrawn; and claim 1 was amended. All the amendments have been thoroughly reviewed and entered.
Claims 1-2, 4, 6-9, 11-12, 14-16, and 18-20 are under examination.
Maintained-Modified Rejections
Modification Necessitated by Applicant’s Claim Amendments
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 3-8, 11, 14-15 and 18-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Artzi et al (US 2017/0333304) in view of Baran et al (Journal of Material Science: Materials in Medicine, 2004, 15: 759-765), Zhao et al (US 2004/0127699 A1), Wu et al (US 2015/0132384 A1), and Tang et al (PNAS, 28 October 2014, 111(43): 15344-15349).
Regarding claims 1, 6-7, 11, and 14, Artzi teaches a hydrogel composite comprising a hydrogel particles dispersed in a hydrogel host, wherein the hydrogel particles is formed from a polysaccharide functionalized with a functional group such as an aldehyde group and the host hydrogel is formed from a polymer functionalized with a functional group such as amine (Abstract; [0005]-[0113], [0147]-[0149]). Artzi teaches the hydrogel composite is formed by reacting by covalently crosslinking the polysaccharide functionalized with a functional group such as an aldehyde group with the polymer functionalized with a functional group such as amine to form imine bonds (Schiff base bond) between the aldehyde and amine groups ([0005]-[0097]). Artzi teaches the suitable polysaccharide for forming the hydrogel particles include starch, and the suitable polymer for forming the host hydrogel include chitosan ([0039]-[0047] and [0064]-[0096]). Artzi teaches the hydrogel particles have an average diameter of about 50 to about 1,500 nm, particularly, about 135 nm, about 150 nm, or about 180 nm ([0034]), which reads on the claimed “hydrogel particles having a diameter of between 50-250 nm” as recited in claim 1.
It would have been obvious to one of ordinary skill in the art to select starch as the polysaccharide for forming the polysaccharide hydrogel particles and select chitosan as the polymer for forming host hydrogel of Artzi and produce the claimed invention. One of ordinary skill in the art would have been motivated to so because per Baran, using biodegradable polymers including starch and chitosan are used to form hydrogels due to their biodegradability and non-cytotoxic, as well as, the combination of starch and chitosan form stable and biocompatible crosslinked products without the need to toxic crosslinking agents (pages 759-760 and 764). Baran further teaches that starch-chitosan hydrogel are great for use in drug delivery system (page 759). Thus, an ordinary artisan seeking to produce a stable hydrogel that is biocompatible, and with low toxicity, as well as, suitable as a drug delivery system would have looked to selecting starch form a list of known the polysaccharides for forming the polysaccharide hydrogel particles that is functionalized with an aldehyde group and selecting chitosan from a list of known polymers for forming host hydrogel of Artzi, and achieve Applicant’s claimed invention with reasonable expectation of success. It is noted that The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).
While Artzi does not expressly indicate that the starch-based nanoparticle is crosslinked to the polymer (chitosan) of the host hydrogel through covalent crosslinks, it would have been obvious to one of ordinary skill in the art to chemically crosslink the hydrogel starch-based nanoparticle to the polymer of the host hydrogel of Artzi in view of Baran by known methods in the art for covalent crosslinking to form a hydrogel composite in view of the guidance from Zhao.
Zhao teaches hydrogel formed from crosslinking a functionalized polysaccharide derivative to another polymer that can also be a functionalized polysaccharide derivative, wherein the crosslinking is by covalent crosslinking (Abstract; [0001], [0015]-[0062], [0077]-[0078]). Zhao teaches the covalent crosslinking can be by known covalent bonding via imino linkage or Schiff base bond ([0026]-[0034]).
It would have been obvious one of ordinary skill in the art to chemically crosslink the hydrogel starch-based nanoparticle to the polymer (chitosan) of the host hydrogel of Artzi in view of Baran by covalent crosslinking so as to form a desired hydrogel composite, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because Zhao provided the guidance to do so by teaching that forming hydrogel by crosslinking polysaccharide derivatives can be perform by not only physical crosslinking, but also by chemical crosslinking which forms a covalent bond between one polysaccharide derivative to a polymer of another polysaccharide derivative, and such chemical crosslinking can be performed by known methods of covalent bonding such as via imino linkage or Schiff base bond. Zhao indicated that covalent crosslinking of a polysaccharide derivative to another polymer provides a resultant hydrogel that is a desired biostability (Zhao: [0016], [0021] and [0077]-[0078]). One of ordinary skill in the art would have reasonable expectation of success in doing so because Artzi indicated that the polysaccharide hydrogel nanoparticles can be modified to include functional group that are capable of reacting with a functional group of at least one component of the host hydrogel (Artzi: [0064]-[0068]). Thus, an ordinary artisan seeking to form a biostable hydrogel composite would have looked to chemically react by crosslinking the hydrogel starch-based nanoparticle to the polymer (chitosan) of the host hydrogel of Artzi in view of Baran by known methods in the art for covalent crosslinking per guidance from Zhao, and achieve Applicant’s claimed invention with reasonable expectation of success.
However, Artzi, Baran, and Zhao do not teach the size of starch-based nanoparticle of claim 1.
Regarding the size of polysaccharide nanoparticle of claim 1, Wu teaches a hydrogel comprising starch-based nanoparticles, wherein the average size of the nanoparticles for effective crossing into the blood brain barrier or delivery to brain tumor is about 100 nm or less (Abstract; [0003]-[0072], [0106], [0154]-[0158] and [0256]).
It would have been obvious to one of ordinary skill in the art to optimize the polysaccharide nanoparticles in the hydrogel composite of Artzi to a size of less than 25 nm, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because Wu provided the guidance to do so by teaching the size of polysaccharide particles such as starch nanoparticles in a hydrogel can be optimize to about 100 nm or less so as the nanoparticles are effective in crossing into the blood brain barrier or in being delivered to a brain tumor. One of ordinary skill in the art would have reasonable expectation of success in optimizing the nanoparticles to a size less than 25 nm because it is well-established in the prior art in view of Tang, nanoparticles with smaller sizes, particularly less than 50 nm (i.e., 20 nm), are advantageous in nanomedicine cancer therapy, as the nanoparticles size of around or less than 50 nm exhibit enhanced performance in vivo, such as greater tissue penetration and enhanced tumor inhibition (Tang: Abstract; page 15344; page 15346). Thus, it is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985). Absent some demonstration of unexpected results from the claimed parameters, the optimization of the particle size of the polysaccharide nanoparticle in a hydrogel composition to increase tissue penetration would have been obvious before the effective filing date of applicant's invention. “Where 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 (I)-(II).
Regarding claim 4, Artzi teaches the size of the hydrogel particles composite can be optimize to controllably and/or selectively deliver the nanoparticles to a desired target site ([0025]-[0096]).
Regarding claim 8, as discussed above, Zhao provide the guidance for chemically crosslink the hydrogel polysaccharide nanoparticle to the polymer of the host hydrogel of Artzi by known methods of covalent crosslinking via imino linkage or Schiff base bond.
Regarding claim 15, Artzi teaches a hydrogel composite comprising a hydrogel nanoparticles dispersed in a hydrogel host, wherein the hydrogel nanoparticles is formed from a polysaccharide functionalized with a functional group such as an aldehyde group and the host hydrogel is formed from a polymer functionalized with a functional group such as amine (Abstract; [0005]-[0113]). Artzi teaches the hydrogel composite is formed by reacting by covalently crosslinking the polysaccharide functionalized with a functional group such as an aldehyde group with the polymer functionalized with a functional group such as amine to form imine bonds (Schiff base bond) between the aldehyde and amine groups ([0005]-[0097]). Artzi teaches the suitable polysaccharide for forming the hydrogel nanoparticle include starch, and the suitable polymer for forming the host hydrogel include chitosan ([0039]-[0047] and [0064]-[0096]). It would have been obvious to one of ordinary skill in the art to select starch as the polysaccharide for forming the polysaccharide nanoparticle and select chitosan as the polymer for forming host hydrogel of Artzi and produce the claimed invention. One of ordinary skill in the art would have been motivated to so because per Baran, using biodegradable polymers including starch and chitosan are used to form hydrogels due to their biodegradability and non-cytotoxic, as well as, the combination of starch and chitosan form stable and biocompatible crosslinked products without the need to toxic crosslinking agents (pages 759-760 and 764). Baran further teaches that starch-chitosan hydrogel are great for use in drug delivery system (page 759). Thus, an ordinary artisan seeking to produce a stable hydrogel that is biocompatible, and with low toxicity, as well as, suitable as a drug delivery system would have looked to selecting starch form a list of known the polysaccharides for forming the polysaccharide nanoparticle that is functionalized with an aldehyde group and selecting chitosan from a list of known polymers for forming host hydrogel of Artzi, and achieve Applicant’s claimed invention with reasonable expectation of success. It is noted that The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).
Regarding claim 18, Artzi teaches the polysaccharide nanoparticles is cationic and starch is suitably selected as the polysaccharide material ([0039]-[0040], [0085]-[0086]; claim 27).
Regarding claim 19, Artzi teaches crosslinking can be reversible over time and/or response to environmental stimuli such as pH ([0025]-[0096]). Zhao teaches the covalent crosslinking is a reversible covalent crosslinking (Zhao: [0026]-[0034]).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the in art the before the effective filing date of Applicant’s invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 2 is/are rejected under 35 U.S.C. 103 as being unpatentable over Artzi et al (US 2017/0333304) in view of Baran et al (Journal of Material Science: Materials in Medicine, 2004, 15: 759-765), Zhao et al (US 2004/0127699 A1), Wu et al (US 2015/0132384 A1), and Tang et al (PNAS, 28 October 2014, 111(43): 15344-15349), as applied to claim 1 above, and further in view of Yang (US 2018/0110801 A1).
The hydrogel composition of claim 1 is discussed above, said discussion being incorporated herein in its entirety.
However, Artzi, Baran, Zhao, Wu, and Tang do not teach the dimension of the hydrogel particles is greater than about 1 mm of claim 2.
Regarding claim 2, Yang teaches a hydrogel composition comprising polysaccharide-polyamine copolymer form by copolymerization of the following two parts: a selectively oxidized polysaccharide with 2,3-dialdehydo, and a polyamine with an amino functional group; the polyamine with an amino functional group and the selectively oxidized polysaccharide with 2,3-dialdehydo can form a net structure by means of covalent crosslinking, resulting in a hydrogel with an amino functional group or a granular polysaccharide-polyamine copolymer (Abstract; [0010]-[0037] and [0054]). Yang teaches the size of the hydrogel is in the range of from about 100 µm to about 10 mm ([0010]).
It would have been obvious to one of ordinary skill in the art to optimize the dimension of the hydrogel composite of Artzi to a size of greater than 1 mm, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because Yang provided the guidance to do so by teaching that the size of the hydrogel formed from an oxidized polysaccharide and amine functionalized polymer such as those of Yang when hydrated are normally in the range of from about 100 µm to about 10 mm, which overlaps the claimed dimension of greater than about 1 mm. Thus, it is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985). Absent some demonstration of unexpected results from the claimed parameters, the optimization of the dimension of the hydrogel composition would have been obvious before the effective filing date of applicant's invention. “Where 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 (I)-(II).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the in art the before the effective filing date of Applicant’s invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 9, 16, and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Artzi et al (US 2017/0333304) in view of Baran et al (Journal of Material Science: Materials in Medicine, 2004, 15: 759-765), Zhao et al (US 2004/0127699 A1), Wu et al (US 2015/0132384 A1), and Tang et al (PNAS, 28 October 2014, 111(43): 15344-15349), as applied to claim 1 above, and further in view of Shu (US 2012/0034271 A1).
The hydrogel composition of claim 1 is discussed above, said discussion being incorporated herein in its entirety.
Regarding claims 9, 16, and 20, Shu teaches disulfide-bond crosslinked hydrogel are formed from two thiol functionalized polysaccharides, and such thiol modification of the polysaccharides to form hydrogels are commonly known in the art (Abstract; [0012]-[0035]). Shu teaches the disulfide-bond crosslinked hydrogel are suitable for pharmaceutical application due to their good biocompatibility, as well as, disulfide-bond crosslinked hydrogel is non-toxic and simple to prepare as there is no need for a crosslinking agent ([0012]).
It would have been obvious to one of ordinary skill in the art to select starch as the polysaccharide for forming the polysaccharide nanoparticle that is functionalized with an aldehyde group and select chondroitin sulfate as the polymer for forming host hydrogel of Artzi and produce the claimed invention. One of ordinary skill in the art would have been motivated to so because Artzi indicated that starch is a suitable polysaccharide for forming polysaccharide nanoparticle and chondroitin sulfate is a suitable polysaccharide for forming the host hydrogel ([0039]-[0047] and [0064]-[0096]), and thus, the selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).
It would also have been obvious one of ordinary skill in the modify the polysaccharide nanoparticle of Artzi such that the polysaccharide is functionalized with a thiol group using known methods of thiolation in the art, as well as, use a thiolated chondroitin as the host hydrogel so as to form a resultant disulfide-bond crosslinked hydrogel, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because Shu teaches hydroxyl groups or amino groups of polysaccharides can be easily thiol modified by known methods thiolation in the art (Abstract; [0012]-[0035]). Furthermore, Shu teaches the use of two thiolated polysaccharides to form a disulfide-bond crosslinked hydrogel are simple prepare and such resultant disulfide-bond crosslinked hydrogel has good biocompatibility and is non-toxic, thereby are useful in pharmaceutical applications ([0012]-[0013]). Shu also teaches that disulfide-bond crosslinked hydrogels are advantageous in biomedicine field as they are useful for promoting wound healing and for tissue repair and generation ([0056]). Thus, an ordinary artisan seeking to produce a hydrogel that has good biocompatibility and is non-toxic, as well as, a hydrogel that is useful for promoting wound healing and for tissue repair and generation, would have looked to modifying the hydrogel composite of Artzi such that a disulfide-bond crosslinked hydrogels is produced by known methods of crosslinking two thiolated polysaccharides such as a thiolated starch nanoparticle and a thiolated chondroitin, and achieve Applicant’s claimed invention with reasonable expectation of success.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the in art the before the effective filing date of Applicant’s invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Artzi et al (US 2017/0333304) in view of Baran et al (Journal of Material Science: Materials in Medicine, 2004, 15: 759-765), Zhao et al (US 2004/0127699 A1), Wu et al (US 2015/0132384 A1), and Tang et al (PNAS, 28 October 2014, 111(43): 15344-15349), as applied to claims 1 and 11 above, and further in view of Rodgers et al (US 3,149,092)
The hydrogel composition of claims 1 and 11 are discussed above, said discussion being incorporated herein in its entirety.
However, Artzi, Baran, Zhao, Wu, and Tang do not teach bromobenzaldehyde moiety as the aldehyde moiety of claim 12.
Regarding claim 12, Rodgers teaches suitable aldehyde functional groups including bromobenzaldehyde in forming polymeric materials (columns 1-3).
It would have been obvious to one of ordinary skill in the art to use bromobenzaldehyde as the aldehyde functional group in the hydrogel composite of Artzi and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so with reasonable expectation of success because Rodgers indicated that that bromobenzaldehyde is a suitable aldehyde functional group for forming polymeric material and thus, the selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the in art the before the effective filing date of Applicant’s invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 09/16/2025 have been fully considered but they are not persuasive.
Applicant argues by alleging that page 15344 (second column, first paragraph) of Tang had disclosed that “20 nm NC has significant disadvantages, and that 50 nm is (or is close) to the optimal size of nanoparticles” and thus, “Tang does not state that nanoparticles having a size less than 50 nm are optimal, but rather about 50 nm is optimal.” Applicant goes on to allege that page 15345 (second column) of Tang “teaches away from smaller particle sizes (i.e. under 25 nm) being the most effective at being able to accumulate in tissues (for example, tumors).” Applicant goes to allege that pages 15347 (first paragraph) and page 15349 (left column, second paragraph) of Tang “teaches toward using a 50-nm particle size as a smaller particle size (20 nm) results in poor tumoral accumulation.” (Remarks, pages 7-8).
In response, the Examiner disagrees. As discussed in the pending 103 rejection, Tang was used for providing motivation for and reasonable expectation of success in optimizing the size of the polysaccharide nanoparticles (i.e., starch nanoparticles) in the hydrogel composite of Artzi to a size of less than 25 nm (see 103 rejection, page 7 of this office action). Note that the teachings from Tang was for the size of the polysaccharide nanoparticles (i.e., starch nanoparticles) and not the size of the hydrogel particles.
Contrary to Applicant’s allegation, Tang teaches that nanoparticles with smaller size, particularly less than 50 nm (i.e, 20 nm) exhibited enhanced performance in vivo such as greater tissue penetration (Tang: Abstract; page 15344 and page 15346, left column). Particularly, Tang teaches nanoparticle size of 20 nm had the greatest tissue penetration when compared to 50 nm or 200 nm (Tang: page 15346, left column). Thus, as discussed in the pending 103 rejection, it is maintained that Tang does provide a reasonable expectation of success in optimizing the polysaccharide nanoparticles to a size less than 25 nm so as to increase tissue penetration (see 103 rejection, page 7 of this office action), as Tang does in fact teach towards the use of nanoparticle size of less than 25 nm, particularly 20 nm to have the greatest tissue penetration (Tang: Abstract; page 15344 and page 15346, left column).
Applicant argues previously presented data from Dr. Hoare “showing the penetration and accumulation (based on fluorescence intensity)of nanoparticles in tumors.” Applicant again alleged that said data “shows that the particle size of 25 nm penetrate and accumulate in tumor significantly better than both the 45 nm and 61 nm particle sizes, in direct contrast to the nanoparticles disclosed in Tang, which found an optimal size of about 50 nm.” Applicant alleges that “[t]he data submitted by Dr. Hoare clearly demonstrates that smaller particle sizes lead to the highest penetration and accumulation, which is a result of the currently claimed hydrogel composition in which the hydrogel particles have a diameter of between 50-250 nm.” Applicant goes on to allege that “[t]he larger hydrogel particles allow for longer-term circulation to make the nanoparticles more likely to accumulate at the target site, and once at the target site, the smaller starch-NPs penetrate and accumulate more than larger particles.” Thus, Applicant alleges that “[a] person skilled in the art would not expect nanoparticles having a particle size of less than 25 nm to have the highest accumulation, as Tang clearly teaches away from using such size.” (Remarks, page 8, last paragraph to page 9).
In response, the Examiner disagrees. The previously presented Hoare Declaration containing comparative evidence provided therein filed on 04/22/2015 was previously considered, but remained insufficient to obviate the pending 103 rejections as set forth in this office action.
It is noted that the evidence provided in the Hoare Declaration is drawn to only showing the tissue penetration and accumulation of starch nanoparticles in tumor. There is nothing in the Hoare Declaration regarding the hydrogel particles, much less hydrogel particles having hydrogel a diameter of between 50-250 nm, as claimed.
The comparative evidence provided in the previously presented Hoare Declaration remained insufficient to obviate the pending 103 rejections as set forth in this office action because as discussed above, contrary to Applicant’s allegations, Tang teaches that nanoparticles with smaller size, particularly less than 50 nm (i.e, 20 nm) exhibited enhanced performance in vivo such as greater tissue penetration (Tang: Abstract; page 15344 and page 15346, left column). Particularly, Tang teaches nanoparticle size of 20 nm had the greatest tissue penetration when compared to 50 nm or 200 nm (Tang: page 15346, left column). Thus, the results shown in the Hoare Declaration showing “the particle size of 25 nm penetrate and accumulate in tumor significantly better than both the 45 nm and 61 nm particle sizes” is an expected results, as per Tang supra, nanoparticles with smaller size, particularly less than 25 nm (i.e, 20 nm) had the greatest tissue penetration. It is also noted that the data drawn in the Figure in the Hoare Declaration is not commensurate the with claimed “starch-based nanoparticles has a number average particle size of less than 25 nm” because the Figure does not pertain to any nanoparticle size of less than 25 nm, as the lowest number average particle size is to 25 nm, which outside the claimed “less than 25 nm”. Thus, the data provided in the Figure in the Hoare Declaration is not pertinent to the claimed invention.
It is also noted that Tang also indicated that nanoparticle size of 50 nm was found to retained in the tumors for longer dwell time or in other words, higher retention time in tumors (Tang: Abstract; page 15344 and page 15346, left column), which is consistent with the disclosure from Wu disclosing that nanoparticles having particle size s of 62 ±5 nm had greater tumor accumulation due to longer blood circulation (Wu: [0224] and [0237]-[0238]). Thus, Applicant’s additional allegation that “[t]he larger hydrogel particles [hydrogel particles having hydrogel a diameter of between 50-250 nm allow for longer-term circulation to make the nanoparticles more likely to accumulate at the target site,” is also an expected result per Wu and Tang supra.
As such, "[e]xpected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).
Applicant argues that the excerpts from paragraphs 155 and 256 of Wu “states that the particle size of the nanoparticles specifically disclosed in the application is between 70 nm and 310 nm (paragraph 77), and that the utility of the nanoparticles is particularly useful at a size under 100nm or less (paragraph 256).” Thus, Applicant alleges that “the Applicant respectfully submits that Wu does not disclose or suggest obtaining nanoparticles having a particle size under 25 nm, other than the general statement that they should be under 100 nm.” (Remarks, page 9, last paragraph to page 10).
In response, the Examiner disagrees. As discussed above, Tang teaches that nanoparticles with smaller size, particularly less than 50 nm (i.e, 20 nm) exhibited enhanced performance in vivo such as greater tissue penetration (Tang: Abstract; page 15344 and page 15346, left column). Particularly, Tang teaches nanoparticle size of 20 nm had the greatest tissue penetration when compared to 50 nm or 200 nm (Tang: page 15346, left column). Thus, as discussed in the pending 103 rejection, it is maintained that Tang does provide a reasonable expectation of success in optimizing the polysaccharide nanoparticles to a size less than 25 nm so as to increase tissue penetration (see 103 rejection, page 7 of this office action), as Tang does in fact teach towards the use of nanoparticle size of less than 25 nm, particularly 20 nm to have the greatest tissue penetration (Tang: Abstract; page 15344 and page 15346, left column).
Applicant argues by alleging that “Artzi does not disclose or suggest a hydrogel composition having hydrogel particles having a diameter between 50-250 nm that are comprised of nanoparticles having a number average particle size of less than 25 nm.” Applicant alleges that “the 50-1500 nm hydrogel particles in the disclosure of Artzi are the equivalent of the 25 nm or less NPs of the claimed invention, and the 50-1500 nm hydrogel particles are designed to deliver drug to a tumor site where it can be released, without the nanoparticles themselves needing to(or designed to) penetrate into the tumor.” Thus, Applicant alleges that “[i]n contrast, in the present invention, the hydrogel particles between 50-250 nm are the "large" particles that are used as a vehicle to more effectively transport the smaller and highly penetrative starch nanoparticles (of which they are comprised) to the target site, with the objective of enabling enhanced local penetration and accumulation of not just drug but also the nanoparticles themselves within that target tissue.” (Remarks, page 10, last paragraph to page 11).
In response, the Examiner disagrees. Artzi was used for teaching the claimed hydrogel particle diameter and not the claimed starch-based nanoparticle size. As discussed above, the starch-based nanoparticle size of “less than 25 nm” was rendered obvious by the teachings from Tang supra (see pages 16-19 of this office action).
With respect to the claimed hydrogel particle diameter of between 50-250 nm and contrary to Applicant’s allegation, Artzi teaches the hydrogel particles have an average diameter of about 50 to about 1,500 nm, particularly, about 135 nm, about 150 nm, or about 180 nm ([0034]), which reads on the claimed “hydrogel particles having a diameter of between 50-250 nm” as recited in claim 1. Thus, Artzi does in fact teach the claimed “hydrogel particles having a diameter of between 50-250 nm”.
Applicant argues by alleging that “none of the prior art references, alone or in combination, teach a hydrogel composition comprised of hydrogel particles with a particle size of between 50-250nm, and a nanoparticle size of less than 25 nm, which consequently leads to the unexpected advantages of higher penetration and accumulation in the target tissue.” Applicant alleges that “none of the prior art references teach or suggest the delivery of the nanoparticles in which larger (but still nanoscale) hydrogel particle degrades or decomposes to a smaller nanoparticle under physiological conditions.” (Remarks, page 11, 2nd paragraph).
In response, the Examiner disagrees. As discussed above, it is reiterated that he comparative evidence provided in the previously presented Hoare Declaration remained insufficient to obviate the pending 103 rejections as set forth in this office action because as discussed above, contrary to Applicant’s allegations, Tang teaches that nanoparticles with smaller size, particularly less than 50 nm (i.e, 20 nm) exhibited enhanced performance in vivo such as greater tissue penetration (Tang: Abstract; page 15344 and page 15346, left column). Particularly, Tang teaches nanoparticle size of 20 nm had the greatest tissue penetration when compared to 50 nm or 200 nm (Tang: page 15346, left column). Thus, the results shown in the Hoare Declaration showing “the particle size of 25 nm penetrate and accumulate in tumor significantly better than both the 45 nm and 61 nm particle sizes” is an expected result, as per Tang supra, nanoparticles with smaller size, particularly less than 25 nm (i.e, 20 nm) had the greatest tissue penetration. It is also noted that the data drawn in the Figure in the Hoare Declaration is not commensurate the with claimed “starch-based nanoparticles has a number average particle size of less than 25 nm” because the Figure does not pertain to any nanoparticle size of less than 25 nm, as the lowest number average particle size is to 25 nm, which outside the claimed “less than 25 nm”. Thus, the data provided in the Figure in the Hoare Declaration is not pertinent to the claimed invention.
It is also noted that Tang also indicated that nanoparticle size of 50 nm was found to retained in the tumors for longer dwell time or in other words, higher retention time in tumors (Tang: Abstract; page 15344 and page 15346, left column), which is consistent with the disclosure from Wu disclosing that nanoparticles having particle size s of 62 ±5 nm had greater tumor accumulation due to longer blood circulation (Wu: [0224] and [0237]-[0238]). Thus, Applicant’s additional allegation that “[t]he larger hydrogel particles [hydrogel particles having hydrogel a diameter of between 50-250 nm] allow for longer-term circulation to make the nanoparticles more likely to accumulate at the target site,” is also an expected result per Wu and Tang supra.
As such, Applicant’s alleged “the unexpected advantages of higher penetration and accumulation in the target tissue” of nanoparticle size of less than 25 nm, is not an unexpected result, but rather an expected result in view of Tang supra. It is reiterated that "[e]xpected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).
As a result, for at least the reasons discussed above and the preponderance of evidence, claims 1-2, 4, 6-9, 11-12, 14-16, and 18-20 remain rejected as being obvious and unpatentable over the combined teachings of the cited prior arts in the pending 103 rejections as set forth in this office action.
New Rejection
Necessitated by Applicant’s Claim Amendments
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 2 is not further limiting from claim 1 because claim 1 recites the hydrogel particles have a diameter of between 50-250 nm and thus, the limitation of “each dimension of the hydrogel particles is greater than 1 mm” has broaden from the scope of claim 1 with respect to “hydrogel particles having a diameter of between 50-250 nm.”
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/DOAN T PHAN/ Primary Examiner, Art Unit 1613